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(Chest. 2004;125:158S-162S.)
© 2004 American College of Chest Physicians

Screening for Lung Cancer: Current Status and Future Directions*

Thomas A. Neff Lecture

James R. Jett, MD, FCCP and David E. Midthun, MD, FCCP

* From the Mayo Clinic, Rochester, MN.

Correspondence to: James R. Jett, MD, FCCP, Mayo Clinic, 200 First St SW, Rochester, MN 55905; e-mail: jett.james{at}mayo.edu


   Abstract
TOP
 Abstract
Introduction
 Is the Chest Radiograph...
 Spiral CT Scan and...
 Mayo Clinic Spiral CT...
 Future Strategies
 References
 
Lung cancer is the number one cancer killer in North America. Currently, screening for lung cancer is not recommended. Therefore, patients will not receive a diagnosis until they present with symptomatic disease, which is usually advanced stage disease. Previous trials of screening with chest roentgenograms and sputum cytology have failed to show a decrease in lung cancer mortality. Some reports of screening with low-dose spiral CT scans have detected lung cancers at a smaller size (average size, 1.5 cm) than those usually detected by chest radiographs (mean size, 3.0 cm). Spiral CT scanning has been shown to detect between 58% and 85% of non-small cell lung cancers (NSCLCs) while they are in stage IA, and this compares favorably to the current medical practice, in which only 15% are detected as localized disease (Surveillance, Epidemiology, and End Results study data). This article summarizes the spiral CT screening data, and reviews some of the data related to screening with sputum cytology, sputum methylation, and autofluorescence bronchoscopy. Last, there is a brief discussion of some promising future strategies, with emphasis and data from studies presented at this Aspen Lung Conference.


   Introduction
TOP
 Abstract
 Introduction
Is the Chest Radiograph...
 Spiral CT Scan and...
 Mayo Clinic Spiral CT...
 Future Strategies
 References
 
In 2003, there will be approximately 172,000 cases of lung cancer in the United States. The overall 5-year survival rate is 15%.1 Lung cancer alone accounts for more cancer deaths than the next four most common cancer causes of death combined (Table 1 ). Currently, 47% of all lung cancers occur in women, and more women die of lung cancer than breast cancer in America (68,800 vs 39,800, respectively). What is striking from Table 1 is the disparity in the 5-year survival rate for lung cancer compared to those for the other most common cancers causing death. Of these common cancer killers, lung cancer and pancreatic cancer are the only ones for which screening is not recommended. We also know that symptomatic lung cancer is usually at an advanced cancer (ie, stage IIIA/B or stage IV) and is associated with a 5-year survival rate of <= 10%. According to recent data from the Surveillance, Epidemiology, and End Result (SEER) program of the National Cancer Institute (NCI), only 15% of lung cancers are localized at the time of diagnosis.1 Currently, the American Cancer Society does not recommend screening for lung cancer, even in high-risk individuals.2 Why is screening for lung cancer not recommended? Past screening trials using chest radiographs and sputum cytology that were conducted at the Mayo Clinic, Johns Hopkins University, and Memorial Sloan Kettering Cancer Center were unable to demonstrate a decrease in lung cancer mortality in the screened population. These NCI-sponsored studies34 were conducted in the 1970s and are now > 20 years old.


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  		Table 1.. Cancer Statistics 2003

 
It is generally agreed that lung cancers of stage IA/B and stage IIA/B are surgically resectable, provided that the patient has adequate pulmonary reserve and is otherwise medically fit for the operation. Resection offers the best chance for a cure of early-stage NSCLC.5 The 5-year survival rates for pathologic stage IA disease (T1N0M0) and stage IB disease (T2N0M0) are 67% and 57%, respectively, based on the revised international staging system for lung cancer.4 The survival rates with clinical stage IA and stage IB disease are lower, at 61% and 38%, respectively. SEER data demonstrate that the 5-year survival rate is 49% in patients in whom localized disease was diagnosed and treated.1 The primary problem is that too few patients have their lung cancer detected while it is asymptomatic and in an early stage.


   Is the Chest Radiograph a Good Screening Tool?
TOP
 Abstract
 Introduction
 Is the Chest Radiograph...
Spiral CT Scan and...
 Mayo Clinic Spiral CT...
 Future Strategies
 References
 
The reported frequency of missed diagnoses has varied significantly in the literature. In one report from the Mayo Lung Project,6 90% of peripheral carcinomas (45 of 50) were visible in retrospect despite the fact that three physicians (radiologists and pulmonologists) had prospectively reviewed all chest radiographs. Twenty-seven carcinomas had been visible for <= 1 year, but 4 carcinomas had been visible for > 2 years (a patient in the screening trial had chest radiographs performed every 4 months). Seventy-five percent of the perihilar carcinomas were visible in retrospect (ie, 12 of 16 carcinomas). Similarly, two thirds of the lung cancers were visible in retrospect in the Memorial Sloan Kettering Cancer Center screening trial conducted simultaneously with the Mayo Clinic Trial.7 Austin and colleagues,8 from New York City, reported on 27 lung cancers that had been missed on previous chest radiographs. The mean diameter of the missed lesion was 1.6 cm. Five cancers (19%) were < 1 cm, 13 cancers (50%) were 1.0 to 1.9 cm, and 5 cancers (19%) were 2.0 to 2.9 cm at the time that they were missed. The interval to eventual diagnosis was 10 months, with a range of 0.2 to 47 months. Quekel and colleagues9 reviewed all cases of proven lung cancer from 1992 to 1995 in a large teaching hospital in the Netherlands. The lesion was missed in 49 of 259 patients (19%) with NSCLC presenting as a nodular lesion. The median diameter of the missed lesion was 1.6 cm (range, 0.6 to 3.8 cm). The median delay in diagnosing the missed lesion was 472 days (range, 7 to 3,233). The miss rate for lesions <= 10 mm was 71%, for lesions between 10 and 20 mm the miss rate was 29%, and for lesions 21 to 30 mm the miss rate was 24%. A major reason for the limitation in detecting lung lesions is that 25% of the lung parenchyma on the standard posteroanterior chest radiograph is hidden by normal structures such as the heart, mediastinum, and diaphragm.10 In summary, these studies make it very clear that a chest radiograph is not a sensitive tool for detecting early lung cancer, especially those < 2 cm in size.


   Spiral CT Scan and Lung Cancer Detection
TOP
 Abstract
 Introduction
 Is the Chest Radiograph...
 Spiral CT Scan and...
Mayo Clinic Spiral CT...
 Future Strategies
 References
 
Screening reports1112 using low-dose spiral CT scans have uniformly shown that CT scanning detects many lung cancers that are not visible by chest roentgenogram. Henschke et al12 detected 27 lung cancers by spiral CT scans, but only 7 of these were visible on chest radiographs obtained at the same time. Sone and colleagues13 from Japan detected 44 lung cancers by screening CT scan, and only 11 were visible by chest radiograph. The chest radiograph failed to detect 79% of the lung cancers that were <= 2 cm.13 Thus, CT scanning is far better at detecting smaller and presymptomatic lung cancers.

Numerous reports,111213141516 from three different continents, have shown that spiral CT scan screening is capable of detecting a large percentage of lung cancers while they are in stage I. The Early Lung Cancer Action Project trial12 from New York reported that 22 of 27 lung cancers detected by spiral CT scan screening were in stage IA. Sobue and colleagues14 from Japan observed that 71% of prevalence cancers and 82% of incidence cancers were at stage IA at the time of diagnosis. A trial from Germany15 reported prevalence data only and noted that 58% of the lung cancers detected were at stage I. These screening trials and the Mayo Clinic trial (summarized below) have shown a substantially higher rate of detection of localized lung cancer compared to the SEER data (the current practice in the United States), which documented that only 15% of all lung cancers are localized at the time of diagnosis. Thus, spiral CT scan screening is the most promising tool currently available that offers a substantial chance of detecting lung cancer at a smaller size, of improving survival time, and decreasing lung cancer mortality.


   Mayo Clinic Spiral CT Scan Screening Trial
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 Abstract
 Introduction
 Is the Chest Radiograph...
 Spiral CT Scan and...
 Mayo Clinic Spiral CT...
Future Strategies
 References
 
In 1999, Mayo Clinic investigators initiated a low-dose spiral CT scan screening trial.16 The eligibility criteria included age >= 50 years, either gender, current or former smoker (ie, having quit for <= 10 years) of >= 20 pack-years, and a life expectancy of 5 years. Patients could have no history of prior malignancy within 5 years and could not be receiving supplemental oxygen therapy. Spiral CT scanning was performed with a scanner that used four detectors (Light-Speed multi-detector scanner; General Electric; Fairfield, CT), using 5-mm collimation with 3.75-mm reconstruction intervals in the high-speed mode, and radiation settings of 120-kVp at 40 mA. Most patients also provided an induced sputum sample for cytology, and a blood sample for research purposes.

From January through December 1999, we enrolled 1,520 participants. The mean age was 59 years (age range, 50 to 85 years). Sixty-one percent of participants were current smokers, and 39% were former smokers. The median number of pack-years of smoking was 51 (range, 20 to 230 pack-years). The rate of yearly follow-up CT scans has been excellent (>= 95%).

The results through 2001 (ie, baseline CT scan plus two yearly follow-up CT scans) have been reported and are summarized here.16 There have been 40 primary lung cancers diagnosed (prevalence cancers, 27; incidence cancers, 11; and interval cancers [which developed between screening tests], 2). Thirty-six of the 40 lung cancers were detected by screening spiral CT scans, 2 were detected by sputum cytology alone, and 2 were interval cancers. The mean size of the detected cancers was 15 mm. The cell types and stages of the cancers are shown in Tables 2 and 3 , respectively. Of note is the fact that 25 of 36 NSCLCs were stage IA/IB disease. Most of the cancers in this report were prevalence cancers (ie, present on the baseline screen). For screening to be effective, one would expect a high proportion of incidence-detected cancers to be at early stage. In 2002 and 2003, we detected a substantial number of additional cancers, most of which were incidence cancers. These will be reported on at a later time.


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  		Table 2.. Cell Type of NSCLC

 

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  		Table 3.. Stage of Lung Cancer

 
On the baseline spiral CT scan, 782 of 1,520 participants (51%) had at least one uncalcified nodule that required periodic follow-up with CT scans. After three scans (ie, baseline plus two incidence scans), 1,049 of the 1,520 participants (69%) have had at least one nodule identified (total, 2,832 uncalcified nodules). The nodules were distributed in size as follows: <= 3 mm, 61%; 4 to 7 mm, 34%; 8 to 20 mm, 5% [136 nodules]; and > 20 mm, 0.4% [11 nodules]). An article17 is in preparation on the 3-year follow-up of all of the baseline nodules. If a baseline nodule was <= 9 mm, then the chance of malignancy was 0.69%.17

Potentially curative pulmonary resections were performed in 31 of 40 participants with lung cancer. There were no pneumonectomies, 26 lobectomies, 1 segmentectomy, and 4 wedge resections. Eight patients underwent the removal of benign lesions, seven with wedge resections and one with lobectomy. Overall, 19 of 1,520 participants have died since enrollment into the study. Five of these deaths were due to lung cancer, including two due to small cell cancer.

To date, we can conclude that screening spiral CT scans can detect early-stage lung cancers at a smaller size (mean size, 15 mm) and an earlier stage than those observed in standard clinical practice. No conclusions can be made about the impact of cancers detected during screening on lung cancer mortality. Also clear is the fact that spiral CT scan screening detects a high percentage of noncalcified nodules that require follow-up. In our series, only 1 to 2% of all detected noncalcified nodules subsequently were proven to be cancers.

These data, and others, have paved the way for the National Lung Cancer Screening Trial (NLST).18 This trial is financially supported by the NCI and will enroll 50,000 participants. They will be randomized to screening with low-dose spiral CT scan or digital chest radiograph. Volunteers must be 55 to 74 years of age and a current or former smoker of 30 pack-years. Former smokers cannot have quit > 15 years earlier. Participants will receive a baseline CT scan plus two annual incidence CT scans, and then telephone/mail follow-up at 6 to 12 months. The study has a 90% power to detect a 20% difference in lung cancer mortality. Studies ancillary to the NLST will evaluate cost-effectiveness and quality-of-life issues. A subset of participants in the NLST is providing blood, sputum, and urine samples for banking and subsequent testing with promising biomarkers.


   Future Strategies
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 Abstract
 Introduction
 Is the Chest Radiograph...
 Spiral CT Scan and...
 Mayo Clinic Spiral CT...
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References
 
Spirometry, Sputum Cytology, and Sputum Markers
Table 4 outlines the current screening strategies used by investigators and some potential screening methods and tools. Some authors have advocated the development of prediction models of risk to help determine individual risk similar to the Gail model of risk assessment for breast cancer. This risk assessment might help to make decisions as to whom should be screened. Bach and colleagues19 developed a model for predicting lung cancer risk based on data derived from the Beta-Carotene and Retinol Efficacy Trial chemoprevention trial. Their model was based on age, duration of smoking, average number of cigarettes smoked per day, and duration of abstinence. Their model predicted a large variation of risk in a cohort of participants randomly selected from the previously mentioned Mayo Clinic spiral CT scan screening trial.


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  		Table 4.. Current and Future Strategies for Lung Cancer Screening

 
Other pundits have opined that spirometry should be part of the screening process. Previous reports have noted an increase in lung cancer risk of fourfold to sixfold in individuals with obstructive airway disease, independent of their smoking history. Bechtel et al (see page 163S) presented data at the Aspen Lung Conference from a community-screening project in Grand Junction, CO. Spirometry was the first screening test used in individuals aged >= 50 years with at least 30 pack-years of smoking. If spirometry showed airway obstruction (ie, FEV1, <70% predicted; FEV1/FVC ratio, < 70%), then they enrolled participants in a screening trial that employed sputum cytology, a chest CT scan, and a chest radiograph. Of 88 patients screened, five lung cancers were detected. Of note is the fact that spirometry cost only $40 and was a fairly inexpensive initial screen. Additionally, sputum cytology was positive in two of the five patients with cancer and was the only positive test result in one patient. The authors acknowledged that not all patients with lung cancer have obstructive airway disease, but this screening algorithm would help to detect cancers in the highest risk group. In the Mayo Clinic spiral CT scan screening trial,16 spirometry was obtained at baseline. Approximately one half of all participants had some degree of airway obstruction. Of the first 40 patients with lung cancer, 28 had some degree of airway obstruction.16

Investigators at the University of Colorado have utilized sputum cytology and chest radiographs in individuals with documented COPD and a 30 pack-year smoking history.20 Pathologists graded the cytology findings as mild, moderate, or severe dysplasia or carcinoma in situ. In individuals with moderate dysplasia, the risk of subsequent lung cancer was 3.9% (13 of 336 individuals), and in those with severe dysplasia it was 33% (6 of 18 individuals). Hirsch et al21 reported preliminary results of a nested case control study that evaluated the sputum methylation of seven tumor suppression gene promoters. The odds ratio of developing lung cancer was 3.8 if any of genes showed methylation. The risk of lung cancer was significantly higher when aberrant DNA methylation was combined with moderate or worse sputum dysplasia.21

The hypermethylation of promotor genes has been shown to occur frequently in patients with resected lung cancers. Belinsky and colleagues22 have reported a case control study of lung cancer patients and current or former smokers without lung cancer. Aberrant promotor methylation (four genes tested) was present in at least one bronchial biopsy specimen in 40% of case patients and control subjects. Methylation of the p16 gene was detected in sputum from 23 of 66 control subjects. Seventeen of 18 cancers showed absolute concordance between methylation status in the lung cancer specimen and bronchial epithelial cells. Thus, sputum methylation of a panel of key genes may be a marker of high risk for lung cancer. Other investigators are evaluating fluorescence in situ hybridization (FISH) of sputum for early genetic lesions. However, no data on FISH were presented at the Aspen Lung Conference.

Autofluorescence Bronchoscopy
A previous report of a multicentered trial23 has shown that the relative sensitivity of autofluorescence bronchoscopy (AFB), vs standard white light bronchoscopy (WLB), is 6.3-fold for detecting intraepithelial lesions and 2.7-fold for detecting invasive cancer. At the Aspen Lung Conference, Beamis reported (see page 148S) very similar results with a D-light AFB system. This multicenter trial evaluated 300 patients with the end point of detecting class III lesions (ie, abnormal/premalignant lesions). AFB plus WLB vs WLB had a relative sensitivity of 6.22. Kennedy et al (see page 109S) performed AFB and WLB in 83 individuals with moderate dysplasia revealed by sputum cytology. Six of those persons (7.2%) had lung cancer (carcinoma in situ, two individuals; and invasive carcinoma, four individuals), and seven had severe dysplasia and are at very high risk for subsequent cancers. Loewen and colleagues (see page 163S) from Roswell Park Cancer Institute combined low-dose spiral CT scans and AFB screening in a high-risk group and have detected eight lung cancers in 99 participants. The two screening tools have been complimentary.

Different investigators have employed various screening tools or combinations in efforts to detect early and asymptomatic lung cancer. A concern and limitation of spiral CT scan screening is that it will not be very good at detecting small central airway lesions. Accordingly, the logic of employing sputum cytology, other sputum markers (ie, methylation and FISH), or AFB is logical. Obviously, the less invasive the screening tool, the more practical and less expensive it is likely to be. Another concern about screening with spiral CT scanning is that, even if we are able to detect cancers 1 cm in diameter (ie, before they are symptomatic), they still are relatively biologically advanced with 109 cells and at 30 doubling times into their existence.

Proteomics
Perhaps one of the most exciting, and preliminary, areas of screening is proteomics. Early reports have demonstrated the use of proteomic patterns in the serum to identify ovarian and prostate cancer. A fascinating article by Petricoin et al24 used serum samples from 50 ovarian cancer patients and 50 control subjects to generate a proteomic spectra from mass spectroscopy. An algorithm identified a cluster pattern in the cancer patients that completely segregated them from the noncancer patients. The discriminatory pattern then was tested on an independent set of 50 ovarian cancers and 66 control subjects. The discriminatory pattern identified 50 ovarian cancers in the independent set with 100% sensitivity and 95% specificity. Eighteen stage I cancers were identified. It is presently uncertain as to how early these protein abnormalities may appear in the serum.

The only report on proteomics for lung cancer at the Aspen Lung Conference was presented by Hirschowitz (see page 105S) from the University of Kentucky. He presented a feasibility study for detecting antibodies in the serum to NSCLC antigens. Preliminary testing shows that a panel of five antibodies is better able to discriminate lung cancer from normal tissue. They have developed a fluorescent protein microarray to measure antibodies against multiple antigens simultaneously. The preliminary testing of unknown samples (ie, cases and control subjects) is underway.

In summary, lung cancer is the number one cancer killer in the Western world. Most patients present with advanced-stage disease that is incurable. Screening offers the hope that cancer will be diagnosed in many of these individuals at an earlier stage, with a greater chance of a cure. To date, no study with any screening tool or test has been shown to decrease lung cancer mortality. The current dictum is that there is no role for screening for lung cancer, even in high-risk individuals. However, as physicians and scientists, we should keep in mind the compelling words of Albert Einstein, "The important thing is not to stop questioning."


   Footnotes
 
Abbreviations: AFB = autofluorescence bronchoscopy; FISH = fluorescence in situ hybridization; NCI = National Cancer Institute; NLST = National Lung Cancer Screening Trial; NSCLC = non-small cell lung cancer; SEER = Surveillance, Epidemiology, and End Result; WLB = white light bronchoscopy

This research was supported by National Cancer Institute grant CA79935–01 and by the Mayo Foundation.


   References
TOP
 Abstract
 Introduction
 Is the Chest Radiograph...
 Spiral CT Scan and...
 Mayo Clinic Spiral CT...
 Future Strategies
 References
 

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