Chest X-Ray and Sputum Cytology
Spiral Computed Tomography (CT)

Chest X-Ray and Sputum Cytology

The most common screening tests for lung cancer are the chest x-ray and sputum cytology. Early studies evaluating these modalities include the following:

1. Philadelphia Pulmonary Neoplasm Research Project,[1] a nonrandomized, uncontrolled study begun in 1951;
2. Veterans Administration study,[2] a nonrandomized, uncontrolled study performed from 1958 to 1961;
3. South London Lung Cancer Study,[3] a nonrandomized, uncontrolled study done from 1955 to 1963;
4. North London Cancer Study,[4,5] a randomized study done in the early 1960s with industrial firms randomized between screening and no screening; and
5. Kaiser Foundation Health Plan multiphasic screening trial,[6,7] a controlled trial begun in 1964 with annual chest x-ray, spirometry, and medical questionnaire as part of the multiphasic screening.

None of these studies reported a statistically significant benefit of screening on lung cancer mortality. As an example, the South London study reported an increase in survival from the time of diagnosis of screen-detected lung cancer cases compared with other cases found in the same geographical region. There was, however, no adjustment for self-selection bias, lead-time bias, overdiagnosis bias, or length bias. Additionally, these studies were small, with a short follow-up period of typically less than 10 years, so that a small-to-moderate size or long-term effect was not demonstrable.

Other lung cancer screening investigations include a randomized trial in Czechoslovakia,[8] a nonrandomized but controlled trial in the former German Democratic Republic (GDR),[9] and case-control studies in the former GDR [10] and Japan.[11,12] The participants in the randomized arms of the Czechoslovakian study were screened with x-ray and cytology at two different frequencies, semiannual versus every 3 years. There was no unscreened control group. No difference in lung cancer mortality was observed; the relative risk (RR, screen group/control group) was 1.36 (95% confidence interval [CI], 0.94–1.98). The GDR nonrandomized study used semiannual chest fluoroscopy over a 6-year period in the intervention arm, while control patients were scheduled to undergo the same exam at 1-year to 2-year intervals. Allocation was based on district of residence. No reduction was observed in lung cancer mortality; the RR was 1.34 (95% CI, 0.94–1.98). Chest x-rays originally used for control of tuberculosis were evaluated in the German case-control study. The odds ratio (OR) showed no association between lung cancer death and having received a screening chest x-ray in both a general population-based control group (OR = 0.9; 95% CI, 0.5–1.5) and a hospital-based control group (OR = 1.1; 95% CI, 0.7–1.8).[10] X-ray histories among deceased lung cancer cases and matched controls were considered in a Japanese case-control study. In contrast to the German study, there was a suggestion of some screening benefit; the OR of dying from lung cancer for those screened within 12 months versus those not screened was 0.72 (95% CI, 0.50–1.03).[11] A meta-analysis of four other case-control studies conducted in Japan suggested mortality reductions of approximately 40%,[13] but potential for bias in these studies has been noted.[11]

Three other randomized trials have been conducted. The Mayo Lung Project (MLP) was initiated in 1971, and involved males aged 45 years or older who were heavy smokers.[14-16] Patients free of lung cancer on initial screening were randomized either to be offered screening with sputum cytology and chest x-ray every 4 months or to a group merely advised once at baseline to seek screening annually. At Johns Hopkins University [17-20] and Memorial Sloan-Kettering Cancer Center,[21,22] individuals were randomized to intervention and control groups, which were both offered annual chest x-ray. In addition, the intervention group was offered sputum cytology every 4 months. None of the three trials reported a reduction in lung cancer mortality in the more intensively screened study group compared with the control group. Extension of follow-up to a median of 20.5 years in the MLP did not alter this conclusion.[23] The sustained excess of incident cases of lung cancer in the screened versus unscreened arms of the MLP during long-term follow-up, in the absence of evidence of a reduction in mortality, suggests that chest x-rays resulted in overdiagnosis of lung cancer.[24]

The Mayo trial is the most pertinent study for assessing annual x-ray screening because the use of screening x-rays differed in the two arms. There are several reservations about the Mayo study. The study was designed to detect a 50% reduction in lung cancer mortality and had insufficient power to demonstrate a lesser but medically important reduction of 10% to 15%. Also, about 50% of men in the control group received an annual chest x-ray,[16] so that contamination may have been sufficient to obscure an effect. Therapeutic advances may render early detection more effective today. Additionally, the spectrum of lung cancer type has shifted over the last 2 decades. Whereas the most common type used to be squamous cell cancer (usually centrally located), the most common type is now adenocarcinoma (usually peripherally located). The latter may be more amenable to early detection by chest x-ray. In contrast, sputum cytology is more sensitive in the detection of squamous cell cancer than in detecting adenocarcinoma.[25,26]

There is no good evidence that screening for lung cancer using chest x-ray or sputum cytology can reduce lung cancer mortality. Sputum cytology has not been shown to be effective when used as an adjunct to annual chest x-ray. Screening with chest x-ray plus sputum cytology appears to detect lung cancer at an earlier stage, but this would be expected in a screening test whether or not it was effective at reducing mortality. Similarly, case survival was improved relative to cases diagnosed through usual care, but this may simply reflect lead-time bias or overdiagnosis bias.[27] No reduction in lung cancer mortality has been observed.

Uncertainty in interpretation of results from completed studies has led to conflicting positions in the medical community and confusion in populations at risk regarding the value of chest x-ray screening. Only a properly designed randomized trial can demonstrate whether an important benefit exists. To this end, the National Cancer Institute (NCI) is conducting the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. This is a long-term randomized controlled trial in which 37,000 men are screened for prostate, lung, and colorectal cancers and 37,000 women are screened for lung, colorectal, and ovarian cancers. The lung component uses annual posteroanterior view chest x-ray as the screening modality. Equal numbers of men and women are followed with routine medical care as controls.[28] In the baseline screen, 9% of participants had a positive screen, with significant increases in prevalence of positive screens with older age and more extensive smoking histories.[29] A total of 126 participants were subsequently diagnosed with lung cancer, and approximately one-half of these were stage I.[29]

There are intensive efforts to improve lung cancer screening with newer technologies, including low-dose helical computed tomography (LDCT) and molecular techniques.[30,31] LDCT is more sensitive than chest radiography. In the Early Lung Cancer Action Project (ELCAP) screening study,[31] LDCT detected almost six times as many stage I lung cancers as chest radiography and most of these tumors were no larger than 1 cm in diameter. The effectiveness of screening with LDCT has not yet been evaluated in a controlled clinical trial.

Eight ongoing observational studies of LDCT in various parts of the world have been reported and summarized.[32] These are relatively small studies, ranging from about 600 to 8,000 participants, which were begun between 1992 and 2000. Most include a substantial percentage of females, and the studies in Japan include nonsmokers. Findings include a nodule or positivity rate of 5% to 51%, 0.4% to 3% lung cancers, 50% to 95% adenocarcinomas, 50% to 91% stage I or IA cancers, and estimates of sensitivity ranging from 40% to 95%.

Two harms must be considered against any potential benefit of screening with LDCT: false-positive test results and overdiagnosis. The false-positive test result, which is the more common and familiar harm, may lead to anxiety and invasive diagnostic procedures, such as percutaneous needle biopsy or thoracotomy. In the ELCAP study,[31] which used a CT slice thickness of 10 mm, noncalcified nodules were detected in 21% of patients without lung cancer at the prevalence screen. Thirty-one of 233 (13%) individuals with noncalcified nodules underwent biopsies, of which close to 90% (27/31) resulted in a diagnosis of malignancy, and the prevalence of cancers detected was 2.7%.

In a study that defined the population at high risk of lung cancer by occupations associated with asbestos exposure, 58% accepted an invitation to participate in an LDCT screening program. The ELCAP screening protocol was applied in 1,119 asbestos-exposed people whose average age was 57 years. Twenty-five biopsies resulted in the detection of one stage IA and four late stage lung cancers. The authors concluded the screening program was not able to replicate the ELCAP results and was not cost effective for lung cancer screening in this population.[33]

A study in Ireland,[34] which aimed to reproduce the ELCAP study in high-risk but younger individuals, revealed a similar proportion of noncalcified nodules were detected using 10 mm CT slice thickness. In the Irish study (N = 449), however, the prevalence of cancers detected was substantially smaller (0.46%). Furthermore, several individuals underwent invasive procedures for ultimately benign conditions (three of four patients with nodules >10 mm who underwent biopsy had benign cytology; one had a thoracotomy that confirmed benign disease; three patients with mediastinal masses underwent biopsy and two had benign cysts). In two other studies, which used 5 mm CT slices, noncalcified nodules were detected in a much higher proportion of patients.[35,36]

In the Mayo Clinic study,[35] noncalcified nodules were detected in 51% of 1,520 patients at the prevalence screen and cumulatively in 74% after five subsequent annual screens.[37] Ninety-five percent of these nodules were less than 8 mm in diameter, for which the recommended follow-up was noncontrast CT in 3 to 6 months. However, eight patients had surgery for benign lesions, five of which appeared to grow on follow-up CT. In addition, screening with LDCT can detect abnormalities other than noncalcified nodules, including enlarged lymph nodes, abdominal aortic aneurysms, and renal and adrenal masses. During the first three rounds of screening in the Mayo clinic study, 696 such abnormalities were found in the 1,520 patients.

In a 2008 systematic review of chest CT lung cancer screening studies, the mean proportion of patients with any incidental abnormality was 65.2% (95% CI, 63.5%–66.9%). The mean proportion of patients with clinically significant incidental findings—defined as any abnormality considered to require additional diagnostic workup—was 14.2% (95% CI, 13.2%–15.2%).[38] It is not clear whether the detection of these abnormalities produces a net benefit or a net harm.[35]

A less familiar harm is overdiagnosis,[27] the diagnosis of a condition that would not have become clinically significant had it not been detected by screening. In the case of screening with LDCT, overdiagnosis could lead to unnecessary diagnosis of lung cancer requiring some combination of surgery (e.g., lobectomy, chemotherapy, and radiation therapy). Although overdiagnosis is almost impossible to document in a living individual, autopsy studies suggest that many individuals die with lung cancer rather than from it. In one study, about one-sixth of all lung cancers found at autopsy had not been clinically recognized before death.[39] Even this may be an underestimate because autopsy probably fails to detect many small lung cancers that are detectable by CT.[40] Studies in Japan provide additional evidence that screening with LDCT could lead to a substantial amount of overdiagnosis.[41] In a study in which smokers and nonsmokers were annually screened for lung cancer between 1996 to 1998 using LDCT, the overall rate of screen-detected lung cancers was very similar in the two groups: 0.46% for smokers (mainly men) and 0.41% for nonsmokers (mainly women).[42] The nonsmoking group may have included individuals who were at an elevated risk for lung cancers for other reasons, but no information is provided on this point. A second study involving both smokers and nonsmokers reported a similar finding of a 1.1% lung cancer detection rate in both groups.[43] Confirmative studies are needed to establish the level of overdiagnosis that might be associated with CT screening for lung cancer. In that same population, the volume-doubling times of 61 lung cancers were estimated using an exponential model and successive CT images. Lesions were classified into three types: type G (ground glass opacity), type GS (focal glass opacity with a solid central component), and type S (solid nodule). The mean-doubling times were 813 days, 457 days, and 149 days for types G, GS, and S, respectively. In this study, annual CT screening identified a large number of slowly growing adenocarcinomas that were not visible on chest x-ray.[44] Before spiral CT is accepted into medical practice, it is critical to determine whether this modality does more good than harm in a randomized controlled trial with lung cancer mortality as the endpoint.[45,46]

To assess the feasibility of conducting a randomized controlled trial in asymptomatic individuals at high risk of lung cancer because of a history of smoking, the NCI conducted the Lung Screening Study (LSS). Six PLCO contract screening centers recruited 3,318 heavy or long-term smokers (inclusion required a 30 pack-year smoking history) who were not participants in the PLCO trial and randomly assigned them to receive LDCT (1,660) or chest x-ray (1,658) between September 5, 2000 and November 15, 2000. Ninety-six percent of patients in the LDCT arm and 93% of patients in the chest x-ray arm were screened. Findings that were suspicious for lung cancer were reported in 20.5% (325/1,586) of screened patients in the LDCT and 9.8% of screened patients (152/1,550) in the chest x-ray arm. After a positive screen, lung cancer was diagnosed in 1.9% (30) of screened patients in the LDCT arm and 0.45% (7) in the chest x-ray arm. In this prevalence screen, 16 of 30 patients in the LDCT arm and six of seven patients in the chest x-ray arm, were stage I. The two study arms were essentially identical on age, sex, and history of smoking. Men represented 60% of participants and about 60% of participants were current smokers. Positive rates were higher among current smokers and older patients. Almost all patients with positive screening results received at least one follow-up diagnostic procedure (98% in the LDCT arm and 96% in the chest x-ray arm). In a survey of all study patients, which had greater than a 98% response rate, 2.6% of chest x-ray patients reported having a CT exam outside the trial between annual screens and 13% of LDCT patients had outside chest x-rays.[47] The findings at the 1-year screen and the final results of the LSS have been reported. Compliance with screening declined from 96% at baseline to 86% at 1 year in the LDCT arm and from 93% at baseline to 80% at 1 year in the chest x-ray arm. Positivity rates for the 1-year screen were 25.8% for LDCT and 8.7% for chest x-ray. Cancer yield at 1 year for LDCT was 0.57% and 0.68% at 1 year for chest x-ray. Forty cancers in the LDCT arm (48% were stage I) and 20 in the chest x-ray arm (40% were stage I) were diagnosed over the study period. A total of 16 stage III to stage IV cancers were observed in the LDCT arm versus nine in the chest x-ray arm.[48] This information proved the feasibility of the National Lung Screening Trial (NLST).[47,48]

The NCI is conducting the NLST, a randomized controlled trial designed to determine whether annual screening with LDCT can reduce lung cancer mortality among persons at elevated risk for that disease (NCI-NLST). More than 50,000 persons aged 55 to 74 years with a history of heavy or long-term smoking have been enrolled in NLST, and the trial is now closed to further recruitment. Participants in NLST have been randomly assigned to receive either three annual LDCTs or three annual chest x-rays. Data collection and analysis in NLST are scheduled to continue for 8 years (NLST).

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