Seminars in Oncology
Volume 32, Issue 3 , Pages 253-258, June 2005

Screening for Non-Small Cell Lung Cancer

  • Rendell W. Ashton

      Affiliations

    • Corresponding Author InformationAddress reprint requests to Rendell W. Ashton, MD, Pulmonary Medicine and Medical Oncology, Mayo College of Medicine, 200 1st St SW, Rochester, MN 55905
    • ,
  • James R. Jett

Department of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN

Article Outline

Lung cancer is the leading cause of cancer mortality and is usually discovered at an advanced stage, when treatment is generally not effective. Many researchers have investigated the value of screening for lung cancer, which would theoretically allow earlier detection and more effective treatment. Unfortunately, no trials of screening strategies for lung cancer have shown a mortality benefit, and as a result, no major medical organization currently recommends screening. Research continues to seek proof of the benefit of screening as new techniques are developed, including low-dose spiral computed tomography (CT), autofluorescence bronchoscopy, and advanced techniques of sputum analysis. Although there are promising data on the sensitivity of these newer screening methods, especially low-dose CT, for detecting early lung cancer, none of the published trials are controlled, and they have not yet proven a decrease in mortality. There are ongoing randomized, controlled trials aiming to demonstrate a mortality benefit. Patients who are interested in being screened for lung cancer should be encouraged to participate in well-designed clinical trials whenever possible.

 

The advent of effective screening measures has sharply decreased the morbidity and mortality of many diseases through detecting the diseases at an earlier, often preclinical stage, thus providing an opportunity to apply treatment when there is a greater chance for cure. Considering the success of screening in lowering the mortality of other malignant diseases, notably cervical cancer and breast cancer, and the large numbers of lung cancer cases and deaths each year, many investigators have hoped to develop screening strategies for lung cancer that might reduce the mortality from this dreaded disease. This review will discuss principles of screening, the modalities currently available for lung cancer screening, the published evidence on lung cancer screening to date, the evolving evidence from ongoing trials, and recommendations based on the evidence.

Lung cancer would seem an ideal disease for which screening could have great impact. Current statistics show 170,000 new cases of lung cancer per year, with 160,000 deaths. Seventy-five percent of new cases present with unresectable disease, and 50% are stage IV disease. The best chance for cure is discovering the disease early when resection is possible. There are several noninvasive and minimally invasive techniques to detect lung cancer at an early stage. However, the evidence for mortality benefit from lung cancer screening has been disappointing to date, and currently no major medical organizations recommend screening for lung cancer as part of their clinical practice guidelines.1, 2, 3, 4, 5, 6, 7, 8, 9 Table 1 lists some of the organizations whose guidelines recommend against screening.

Table 1. Medical Organizations With Guidelines Recommending Against Screening for Lung Cancer
US Preventive Services Task Force
Canadian Task Force on the Periodic Health Examination
American Cancer Society
American College of Physicians
American Academy of Family Physicians
American College of Radiology
American Thoracic Society
American College of Chest Physicians

In spite of the lack of evidence and the current recommendations against it, there is optimism for the future of lung cancer screening. Trials hoping to prove efficacy are ongoing. Screening technology is progressing rapidly. As our methods of diagnosis allow us to detect cancer at an earlier stage with less cost and risk to the patient, it appears feasible that screening will eventually be shown to lower lung cancer mortality. Current trials may provide definitive evidence that screening reduces lung cancer mortality.

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Principles of Screening 

Screening strategies ideally share certain characteristics, including those outlined in Table 2: sensitivity, specificity, safety, acceptability, and cost-effectiveness. A screening strategy may consist of history taking, physical examination, laboratory studies, imaging studies or other diagnostic procedures, or a combination of these. The strategy is calculated to differentiate asymptomatic patients who have the disease in question (or may have it, requiring further diagnostic testing) from those who do not. Implicit in the decision to screen an individual is the intent to pursue definitive diagnosis and treatment in patients who have a positive screening result.

Table 2. Characteristics of Screening Tests
High sensitivityRequired to detect preclinical disease in an early stage
Sufficient specificityNeeded to limit the number of false positive results, which will need further testing or treatment
SafetyMinimally invasive with low risk of complications
AcceptabilityPatients must be willing to undergo screening test in setting of no clinically apparent disease
Cost-effectivenessCost of screening at-risk population less than cost of treating advanced, unscreened disease later

Certain confounding problems are inherent to screening, especially when outcome measures other than mortality are used to gauge the success of the screening program. These common screening biases are outlined in Table 3, and make proving the utility of a screening program more difficult, as scientists and third-party payers often will accept only a change in cancer mortality as proof of the effectiveness of the screening strategy.

Table 3. Problems That May Lead to Biased Results in Trials Evaluating Screening
DefinitionHow Results May Be Biased
Lead-time biasScreening results in diagnosis earlier in the natural history of diseaseLength of survival from diagnosis appears longer, even with unchanged natural history
Length-time biasTendency of screening to identify more indolent diseases, with longer natural historyIn prevalence study, higher proportion of indolent disease may be represented
OverdiagnosisDiagnosis of disease which would never become clinically apparent or lead to the death of the patientOverestimate of prevalence of clinical disease; may lead to unnecessary treatment

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Screening Tools for Lung Cancer 

Screening tools for non-small cell lung cancer include some tests that have been clinically available for many years, and have been studied in clinical trials, as well as other tests that are more recent additions and have not been extensively evaluated. Following are the strengths and limitations of the major screening modalities.

Sputum cytology is noninvasive and very specific (>99%) in most studies. The drawback is low sensitivity, with different studies showing sensitivity to detect occult malignancy between 5% and 60%.10, 11 Sensitivity is 50% to 70% for central airway tumors and drops to 20% to 50% for peripheral lesions.10 Combination with newer techniques, such as high-resolution image cytometry12 and assays to detect molecular markers of malignancy,13 may eventually increase the sensitivity, but these modalities are currently unproven.

Chest roentgenograms often detect one or more pulmonary nodules, which may represent preclinical lung cancer. The advantages of the chest x-ray as a screening tool include availability and ease of performing the test, low cost, and low risk to the patient. The disadvantages are low sensitivity and specificity. Using thin-section computed tomography (CT) as the reference standard, the sensitivity of chest radiographs to detect a localized, peripheral bronchioloalveolar cell carcinoma was 59%. The sensitivity to detect other tumor types was 79%, with rates even lower if the lesion was associated with ground glass opacity or measured less than 15 mm.14 Retrospective analyses from the large screening studies discussed below showed that 60% to 90% of the lung cancers eventually diagnosed were visible on screening radiographs taken months to years prior to detection, but were missed by the radiologists and pulmonologists prospectively reviewing the radiographs.15, 16, 17 One large review of diagnosed lung cancers showed that visible lesions were missed on chest x-ray approximately 50% of the time.18 The two-dimensional projection of a chest x-ray causes 25% of the lung parenchyma to be obscured by other anatomic structures, lowering the sensitivity for detecting nodules that could be lung cancer.19

Computed tomography is much more sensitive for detecting small nodules in the lungs that are likely to represent earlier stages of lung cancer. CT screening trials have shown that chest radiographs miss 60% to 80% of the lung cancers detected by CT20, 21, 22, 23, 24, 25 (Fig 1). Disadvantages are cost and higher amounts of radiation for the patient. There is also a greater risk of overdiagnosis, not only of nonmalignant lung nodules, but other incidental findings as well, which may be found in the course of screening with CT.26 Nevertheless, CT is currently the most promising modality for future screening trials.

  • View full-size image.
  • Figure 1. 

    CT examinations 1 year apart, showing a lung nodule, which was subsequently identified as non-small cell lung cancer. The lesion was not visible on chest radiograph.

Autofluorescence bronchoscopy is a technique using laser-induced fluorescence to detect very early lesions in the central airways. The sensitivity for detecting neoplastic lesions, including moderate dysplasia and carcinoma-in-situ, is 69%, compared to 21% with white light bronchoscopy.27 This tool is still in development, but represents a more sensitive way to detect and localize very early lung neoplasms. As a result of its use, a new morphologic entity, angiogenic squamous dysplasia, has been recognized28 and is thought to be a precursor of malignancy. Currently, the clinical utility of autofluorescence bronchoscopy is limited to high-risk individuals who have sputum cytology positive for dysplasia or malignancy, or who have a history of previously diagnosed lung cancer.29, 30 The technique is limited to evaluation of the central airways, which are accessible to inspection with a flexible bronchoscope.

Combinations of modalities using different techniques to increase the overall sensitivity are also under evaluation, for example, spiral CT and autofluorescence bronchoscopy.

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Historical Perspective of Lung Cancer Screening Trials 

Many clinical researchers have examined the question of screening for non-small cell lung cancer, but overall their results have shown little evidence to recommend widespread screening. There have been four large prospective, randomized, controlled trials, which comprise the strongest published evidence to date on lung cancer screening. These trials are detailed in Table 4.

Table 4. Comparison of Randomized Controlled Trials of Lung Cancer Screening
Trial AllocationInterventionNPrevalence CasesIncidence CasesMortality5-Year Survival
MSK31
ExpAnnual CXR + sputum cytology every 4 mo5,072301142.7⁎35%
ControlAnnual CXR4,968231212.7⁎35%
JHU32
ExpAnnual CXR + sputum cytology every 4 mo5,265391943.4⁎20%
ControlAnnual CXR5,122402023.8⁎20%
MLP33
ExpCXR + sputum cytology every 4 mo4,618(91 in all)2063.2⁎33%
ControlRecommended annual CXR and sputum cytology4,593 1603.0⁎15%
Czech35
ExpCXR + sputum cytology every 6 months × 3 yr3,172(19 in all)1082815%
ControlCXR + sputum cytology at end of 3 yr3,174 821818%

Abbreviations: MSK, Memorial Sloan-Kettering; JHU, Johns Hopkins University; MLP, Mayo Lung Project; Czech, Czechoslovakia study; Exp, experimental arm; CXR, chest x-ray.

⁎ PER 1,000 person-years.

Two of the studies, the Memorial Sloan Kettering trial31 and the Johns Hopkins University trial,32 were designed to compare outcomes in high-risk patients given a “dual-screen” strategy consisting of annual chest x-ray and sputum cytology every 4 months versus patients screened with annual chest x-ray alone. Screening was conducted for 5 years, and follow-up data were obtained for 5 to 8 additional years.

In the Memorial Sloan-Kettering trial, 144 cancers were detected in each group. Five-year survival in both groups was 35%. Forty percent of all lung cancers detected were stage one, with 5-year survival of 76%. Mortality was 2.7 per 1,000 person-years in both groups. Both groups had markedly better survival than the generally reported 5-year survival for lung cancer at that time, which was 10%, but no difference in lung cancer mortality.

The Johns Hopkins University trial identified 242 prevalence and incidence cancers in the group with chest x-ray only and 233 cancers in the dual-screen group. Eight-year survival for both groups was 20%, and lung cancer mortality was 3.8 per 1,000 person-years in the chest x-ray group and 3.4 per 1,000 person-years in the dual-screen group. This difference was not statistically significant, and approximated the mortality rate of unscreened lung cancer patients at that time. These results again demonstrated that adding sputum cytology to annual screening chest radiograph does not improve survival or mortality.

The Mayo Lung Project33 assessed the value of screening chest radiographs compared to standard care. After an initial chest x-ray and sputum cytology, high-risk patients were randomized to evaluation with chest x-ray and sputum cytology every 4 months or to “usual care,” which consisted of recommending a yearly radiograph and sputum cytology. The period of screening was 6 years.

The initial chest x-ray and sputum cytology identified 91 prevalence cancers, 45% of which were stage I or II. Five-year survival for all prevalence cancers was 40%, and for those with stage I or II cancers, 5-year survival was 70%.

The incidence screening portion of the study was troubled by low compliance in the intervention arm, which led to a likely statistical underestimate of the screening effect. Results from this portion showed a difference in the resectability of detected cancers, with 46% of cancers resectable in the screened group compared to 32% in the control group. Five-year survival was better in the screened group, but lung cancer mortality was not significantly different. The improved survival in the screened group has been hypothesized to be due to overdiagnosis, since there were more cancers in this group than in the control group (206 v 160). Analysis of the data after 20 years of follow-up confirmed no difference in mortality between the study groups.34

The Czechoslovakian study35 compared high-risk subjects screened with chest x-ray and sputum cytology every 6 months to subjects tested with chest x-ray and sputum cytology at the end of the screening period of 3 years. Results showed no difference in survival or mortality. The allocation process resulted in unequally matched groups in the experimental and control arms. There were statistically significant differences in all-cause, cancer-, and smoking-related mortality rates in the intervention group, which brings into question the validity of the trial.

The first trial to compare screening to no screening is the Prostate, Lung, Ovarian and Colorectal Cancer Study (PLCO), which began in 1992. This trial is also the first to include women as well as men. Participants at high-risk for lung cancer are randomized to receive an annual chest radiograph for 4 years or usual care. Results are expected in 2010.

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Trials Evaluating CT Screening Strategies 

The emphasis in screening for lung cancer is currently on low-dose spiral chest CT. The reasons for this include the improved technology, which allows faster scanning time (12 seconds to scan the thorax during a single breath), detection of very small nodules (2–3 mm) with thin slices to determine if calcification is present, decreased radiation exposure using low-dose techniques, and decreased cost compared to standard CT. There have been numerous nonrandomized trials evaluating low-dose spiral CT as a screening tool and some larger prospective trials are ongoing.

A study that generated widespread enthusiasm for CT lung cancer screening was published in 1999.20 One analysis of this trial compared lung nodules detected by chest x-ray and CT, and then analyzed how many were malignant, the stages of the cancers found, and resectability rates. The conclusions of the study were that low-dose CT was four times as sensitive as chest x-ray for detecting lung cancer, and six times as sensitive for detecting stage I lung cancer. Despite the lack of mortality data from this nonrandomized, uncontrolled trial, some have used these results as the basis for advocating a change in policy to recommend widespread screening with CT.

Studies from Japan,21, 23, 36, 37, 38 Germany,24 and the Mayo Clinic in the United States25 have been reported, and all show that CT is significantly more sensitive for detecting lung cancers than chest radiographs and detects these tumors at a smaller size on average (1.5 cm v 3.0 cm).23, 25 Accompanying this is an increase in detection of benign nodules with CT screening. The results of these single-arm, nonrandomized trials have fueled the debate over the advisability of recommending lung cancer screening with CT (Table 5).

Table 5. Results of Nonrandomized, Single-Arm Trials of CT Lung Cancer Screening
First AuthorParticipantsParticipants With Nodules on CT (%)Prevalence CancersStage I (%)Incidence CancersStage I (%)
Sobue231,611907(56)1310(77)1915(79)
Diederich24817350(43)127(64)——
Swensen251,5201049(69)2618(69)106(60)
Sone375,483588(11)2323(100)3732(86)
Nawa387,956541(7)3628(78)——
Henschke201,000233(23)2723(85)——

In 2002, Sobue et al reported their CT screening study in Japan, in which 1,611 participants, both men and women of various risk levels for lung cancer, were screened every 6 months with low-dose CT, chest x-ray, and sputum cytology. CT screening identified abnormalities in 11.5% of scans, while chest x-ray identified abnormalities in 3.4% and sputum cytology in 0.8%. Thirteen prevalence cancers were identified by CT in the initial screening, and 77% of these were stage I. The 5-year survival for prevalence cancers identified was 76%. Subsequent CT screening identified 19 incidence cancers, 79% of which were stage I. Five-year survival for all incidence cancers discovered through screening was 65%.23

Diederich et al from Germany reported their prevalence CT screening data. They studied 817 asymptomatic participants at high risk for lung cancer, who underwent a single CT screening procedure. Noncalcified nodules greater than 10 mm were considered potentially malignant and were resected or followed with serial CT examinations to prove no growth. Smaller noncalcified nodules were followed with serial CT scans to ensure no growth. A total of 15 nodules were resected, 12 of which were cancer. Seven (64%) were stage I.24

Swensen et al have published results of the Mayo Clinic experience with CT screening for lung cancer. A total of 1,520 high-risk patients were screened annually for 3 years with CT and sputum cytology. Sixty-nine percent of patients in the trial had noncalcified nodules identified by CT. Twenty-six prevalence cancers were identified by baseline screening CT, and 69% were stage I. The second and third annual CT screens detected 10 incidence cancers, and 60% were stage I. There were two interval cancers diagnosed between screening episodes, representing failure of screening to detect disease before it was detected clinically.25

Although these trials do not provide a definitive answer, there are some clear conclusions to be gleaned from the studies of CT lung cancer screening. First, CT is far more sensitive at detecting lung cancer than chest roentgenogram, especially smaller lesions that may be hidden by normal mediastinal structures, the spine or diaphragm, or peripheral lesions that are of low density. Second, CT screening identifies a large number of nonmalignant nodules and other abnormalities, some of which will result in biopsy or resection of a benign lesion. All noncalcified nodules that are not resected require periodic imaging follow-up until they have demonstrated stability for at least 2 years.

The limitation of all of the CT screening trials reported to date is that there were no control groups. All of these trials were large phase II, proof-of-principle trials. It remains uncertain whether spiral CT screening will reduce lung cancer mortality. In an effort to determine if spiral CT screening can reduce mortality, a large randomized, controlled trial has been launched in the United States.39 In this trial, 50,000 high-risk participants were randomized to screening with chest radiograph or spiral CT. Participants were screened at baseline and then yearly for 2 additional years, with yearly telephone follow-up thereafter. The trial is powered to detect a 20% decrease in mortality. Accrual was completed in February 2004. It is anticipated that some results of this trial will be published by 2008.

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Evolving Recommendations Based on Current Evidence 

Currently, no major medical organizations recommend screening for lung cancer. However, as the technology for screening advances, including better laboratory and radiologic methods of detecting early lung cancer, investigators will continue to pursue evidence that screening can impact lung cancer mortality. The stakes are high. Given the current rates of lung cancer, even a 20% reduction in lung cancer mortality would save more than 30,000 lives per year in the United States alone.

Until the results of the ongoing research trials evaluating mortality in subjects screened with CT and other newer screening methods are known, these modalities should be considered unproven.9 Patients who are interested in lung cancer screening should be encouraged to participate in well-designed clinical trials to help obtain the evidence needed to assess screening strategies. As patients are counseled regarding screening, they need to understand the absence of proof that it improves mortality from lung cancer. They also need to understand that screening may lead to unnecessary further testing, even surgery, as more benign lesions are identified. Intuitively, screening makes sense in lung cancer, but until we can prove that the mortality benefit is real, ongoing research is the most rational approach to this issue.

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PII: S0093-7754(05)00082-5

doi:10.1053/j.seminoncol.2005.02.012

Seminars in Oncology
Volume 32, Issue 3 , Pages 253-258, June 2005

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