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Screening for Lung Cancer With Low-Dose Helical Computed Tomography: Anti-Lung Cancer Association Project

From the Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Diagnostic Radiology and Endoscopy Divisions, National Cancer Center Hospital, and Social Health Insurance Medical Center, Tokyo; Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba; Department of Radiology, Gifu University School of Medicine, Gifu; and Shikoku Cancer Center, Ehime, Japan.

Address reprint requests to Tomotaka Sobue, MD, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji Chuo-ku, Tokyo 104-0045, Japan; email: tsobue{at}ncc.go.jp

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Because efficacy of lung cancer screening using chest x-ray is controversial and insufficient, other screening modalities need to be developed. To provide data on screening performance of low-dose helical computed tomography (CT) scanning and its efficacy in terms of survival, a one-arm longitudinal screening project was conducted.

PATIENTS AND METHODS: A total of 1,611 asymptomatic patients aged 40 to 79 years, 86% with smoking history, were screened by low-dose helical CT scan, chest x-ray, and 3-day pooled sputum cytology with a 6-month interval.

RESULTS: At initial screening, the proportions of positive tests were 11.5%, 3.4%, and 0.8% with low-dose helical CT scan, chest x-ray, and sputum cytology, respectively. In 1,611 participants, 14 (0.87%) cases of lung cancer were detected, with 71% being stage IA disease and a mean tumor diameter of 19.8 mm. At repeated screening, the proportions of positive tests were 9.1%, 2.6%, and 0.7% with low-dose helical CT, chest x-ray, and sputum cytology, respectively. In 7,891 examinations, 22 (0.28%) cases of lung cancer were detected, with 82% being stage IA disease and a mean tumor diameter of 14.6 mm. The 5-year survival rate for screen-detected lung cancer was 76.2% and 64.9% for initial and repeated screening, respectively.

CONCLUSION: Screening with low-dose helical CT has potential to improve screening efficacy in terms of reducing lung cancer mortality. An evaluation of efficacy using appropriate methods is urgently required.

	INTRODUCTION

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LUNG CANCER IS THE most common cause of cancer death not only in Japan but in most developed countries. In 1998, 36,880 males and 13,991 females died of lung cancer in Japan, which ranked first among males and third among females in the number of cancer deaths.¹ Lung cancer screening using chest x-ray and sputum cytology was introduced by the Japanese government in 1987 as one lung cancer control strategy, and 7,030,639 people were screened under this program in 1998.² This approach has not been recommended for the asymptomatic general population in other countries.³ Although the efficacy of lung cancer screening using chest x-ray remains controversial,^4-6 it seems to be insufficient. This is underscored by the low survival rate among patients with screen-detected lung cancer compared with patients with cancer at other sites⁷; therefore, more effective screening modalities need to be developed. Low-dose helical computed tomography (CT) scanning is one candidate for this because of its great ability to detect small peripheral nodules.^8,9

There have been several projects in which low-dose helical CT scanning was used as a screening modality. Kaneko et al¹⁰ reported the results from the Anti-Lung Cancer Association (ALCA) project from September 1993 to April 1995, in which 3,457 low-dose helical CT examinations were conducted for 1,369 participants, and 15 (0.4%) cases of lung cancer were detected. Of these, 14 (93%) were stage I disease, and the mean tumor diameter was 16 mm. Sone et al^11,12 reported that in 1996 to 1998, population-based annual lung cancer screening using low-dose helical CT scanning was provided for 5,483 people (13,786 examinations), and 60 cases of lung cancer (0.4%) were detected. Among them, 55 (92%) were stage I, and the mean tumor diameter was 13.4 mm. Henschke et al¹³ reported the baseline findings from the Early Lung Cancer Action Project (ELCAP), in which 1,000 high-risk male patients were screened by low-dose helical CT scan and 27 (2.7%) cases of lung cancer were detected. Of these, 23 (85%) were stage I disease. These studies have consistently indicated that CT screening can detect lung cancer in an earlier stage than conventional chest x-ray, which may bring greater efficacy in terms of a reduction in mortality from lung cancer. In the present study, we provide an update on the findings from the ALCA project, including the survival data for patients with screen-detected lung cancer.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Study Population
The ALCA is a for-profit organization established in 1975 to thoroughly screen dues-paying participants for lung cancer. Participants are continuously recruited from the general population who smoke cigarettes and are 40 years of age or older, although some exceptions have been allowed in practice. The participants underwent chest x-ray and sputum cytology twice a year until August 1993. From 1975 to 1993, 26,338 examinations were conducted for 2,529 participants, and 43 cases of lung cancer were detected, as reported elsewhere.¹⁰

In September 1993, low-dose helical CT scanning was introduced in addition to the above two modalities. By December 1998, 742 participants who had been members of this project since before the introduction of CT screening and 940 new participants who entered into the project after the introduction of CT screening had undergone screening using low-dose helical CT scanning at least once. In total, 9,847 screening examinations for 1,682 participants were conducted from September 1993 to December 1998.

In this analysis, we excluded 233 examinations for 70 participants who were aged 39 years or younger or 80 years or older at the initial CT screening and one examination for one member whose smoking status was unknown at the initial CT screening. Also, data for 29 participants who reached 80 years of age during the study period were not used afterward (111 examinations). These exclusion criteria left 9,502 examinations for 1,611 participants in the analysis. Of these, 3,355 examinations for 1,320 participants conducted from September 1993 to April 1995 and 14 cases of lung cancer detected by helical CT scanning (10 at initial screening and four at repeated screening) overlapped with the previous study.¹⁰

Screening Procedures
Screening was conducted at one clinic (ALCA) located in central Tokyo. At initial screening, a simple questionnaire regarding smoking history and symptoms was completed, and helical CT scan, chest x-ray (posterior-anterior position), and sputum cytology pooled for 3 days were conducted after obtaining informed consent from each participant. A TCT-900S Superhelix (Toshiba Medical, Tokyo Japan) was used for helical CT scanning, with parameters as follows: 120 kVp, 50 mA, 10-mm collimation, one rotation of the x-ray tube per second, and a table speed of 20 mm/sec (pitch, 2:1). A thoracic area spanning 30 cm was scanned from a level 2 cm superior to the apex to the level of the diaphragm with a 15-second breath hold. Image construction was performed with 180-degree linear interpolation at intervals of 1 cm.

All CT images were checked by two of seven readers (radiologists or thoracic physicians; M.K., M.K., R.K., H.O., H.N., E.M., and K.E), one using hard-copy film and the other using a cathode ray tube (CRT) monitor. Display conditions were a window width of 2,000 HU and a window level of -700 HU. When using hard-copy film, CT images taken at previous examination were also referred to, if available. The two readers classified the images independently into five categories according to the classification tentatively developed by this study group at the beginning of the project and later authorized by the Japan Lung Cancer Society, as follows: (A) inadequate image; (B) normal; (C) scar lesion caused by a previous inflammatory episode; (D) benign tumor or an active inflammatory disease; and (E) suspected lung cancer.¹⁴ Chest x-ray films were read by two readers using the classification of the Japan Lung Cancer Society,¹⁴ and the second reader, who was aware of the first reader’s judgment, made a summary judgment. From 1993 to August 1996, cases classified as D or E either by helical CT scan or chest x-ray were considered for additional diagnostic workup, and a third reader determined the necessity of thin-section CT (TSCT) scanning when the findings showed a solitary nodule without calcification, a nodule greater than 4.9 mm in diameter, or an area of localized opacification increasing in size with sequential comparison. In September 1996, the checking procedure was changed with the introduction of a computer-aided diagnosis (CAD) system.¹⁵ The first reader checked the helical CT on a CRT monitor using the CAD system. Then the second reader made the summary judgment using hard-copy display, referring to the findings by the first radiologist on CRT and hard-copy film of previous CT images in cases with repeated screening. Checks by the third reader were no longer conducted. Participants with positive helical CT scan tests were defined as those who were asked to undergo TSCT, and participants with positive chest x-ray tests were defined as those who were classified as D or E regardless of the judgment based on helical CT scan.

TSCT was conducted at the same clinic (ALCA) with the following parameters: 120 kVp, 250 mA, 2-mm collimation, one rotation of the x-ray tube per second, table speed of 2 mm/sec (pitch, 1:1), and thin-section algorithm. If lung cancer was suspected, the participant was referred to the National Cancer Center Hospital or National Cancer Center Hospital East for diagnostic procedures, such as CT fluoroscopy-guided transbronchial biopsy, CT fluoroscopy-guided percutaneous needle biopsy (CTPNB), or video-assisted thoracoscopic surgery (VATS).

Sputum specimens were processed by the Sacomanno method and checked by trained cytoscreeners. Abnormal findings were confirmed by a certified cytopathologist and classified as follows: (A) inadequate sample; (B) normal or squamous metaplasia with mild atypia; (C) squamous metaplasia with moderate atypia; (D) squamous metaplasia with severe atypia; or (E) lung cancer according to the classifications of the Japan Lung Cancer Society.¹⁴ Test positives for sputum cytology were defined as patients who were classified as having D or E. For these patients, sputum cytology was repeated at an ALCA clinic. If lung cancer was still suspected, participants were referred to the National Cancer Center Hospital or National Cancer Center Hospital East for bronchoscopy. Participants were invited twice a year by mail after the initial screening to repeat the same screening procedures.

Statistical Analysis
Statistical P values for the difference in proportions and means were evaluated by ² test and t test, respectively, with a two-sided level. The cumulative survival rate for lung cancer cases was calculated with the Kaplan-Meier method, with survival time defined as starting from the date of diagnosis, when microscopic evidence for malignancy was initially obtained, until the date of death or February 1, 2000, whichever came first.

	RESULTS

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Screening Tests at Initial CT Screening
Participants were mainly middle-aged males with a smoking history and had initial CT screening in 1993 or 1994 (Table 1). Of 1,611 participants, 186 (11.5%), 55 (3.4%), and 13 (0.8%) tested positive on helical CT scan, chest x-ray, and sputum cytology, respectively, approximately three times higher for helical CT than for chest x-ray. The proportion of test positives for chest x-ray and sputum cytology varied according to age and smoking status, whereas the proportion for helical CT scan varied by age and year at screening, although none of the differences were statistically significant (P > .05). Variation for test positives in helical CT scan with the year of screening (P = .001) indicates that the checking criteria were not constant throughout the study period.

Diagnostic Workups at Repeated Screening
At repeated screenings, 770 (9.8%) participants from 7,891 examinations were asked to undergo additional diagnostic workups on the basis of various combinations of test results (Table 3). Among 721 participants who had positive helical CT findings and were asked to have TSCT, 719 participants underwent TSCT at the ALCA clinic and two participants refused. For 49 participants who had positive findings for sputum cytology alone, sputum cytology was repeated at the ALCA clinic. On the basis of TSCT and repeated sputum cytology, 72 participants were referred to the National Cancer Center Hospital or National Cancer Center Hospital East because of suspected lung cancer lesions. Of these, 21 participants were diagnosed with benign lesions by repeated TSCT, two participants rejected additional diagnostic workup, and 49 participants had biopsies. For those who had positive findings on helical CT scan and no abnormality on sputum cytology at screening, the final diagnosis was based mainly on VATS and CT fluoroscopy-guided transbronchial biopsy. For 15 cases, VATS or open thoracotomy was performed solely on the basis of findings from TSCT, 11 cases were proven to be lung cancer, and four cases were proven to be other lesions (two atypical adenomatous hyperplasias, one focal fibrosis, and one metastasis from colon cancer). Twenty-two (45%) of the 49 participants who had biopsies had lung cancer. Predictive value for test positives was 2.6%, 1.5%, and 7.7% for helical CT scan, chest x-ray, and sputum cytology, respectively.

In total, 22 (0.28%) cases of lung cancer were detected out of 7,891 examinations (Table 2). The detection rate of lung cancer became slightly lower with additional screening rounds, but no substantial difference in sex, age, or smoking status was observed.

Characteristics of Screen-Detected Lung Cancer
Table 4 lists the distribution of characteristics for screen-detected lung cancers by screening round and method of detection. Of the 14 lung cancer cases detected at initial screening, eight (57%) were detected by helical CT scan alone, two (10%) by both helical CT and chest x-ray, one (7%) by sputum cytology alone, and three (21%) by all three methods. At repeated screenings, 16 (73%) cases were detected by helical CT scan alone, two (10%) by helical CT scan and chest x-ray, three (14%) by sputum cytology alone, and one (5%) by all three methods. The proportion of cases detected by helical CT scan alone tended to be higher and the proportion detected by all three methods tended to be lower in repeated screenings than in initial screenings, but the difference was not statistically significant (P > .05).

Survival for Screen-Detected Lung Cancer
Of 36 lung cancer cases detected in the screening, eight patients died before February 1, 2000. Of these eight patients, three with stage III or IV disease died of lung cancer, two with stage IA disease died of pulmonary infection 6 months and 9 months after surgery without recurrence, two with stage IA disease died of hepatic failure attributable to liver cirrhosis and an unknown cause (the patient was 82 years of age at the time of death) without recurrence, and one with stage IIIa disease died suddenly, probably because of a cardiac event, without recurrence. The mean follow-up duration for censored cases was 3.7 years. The overall 5-year survival rate was 71% (95% confidence interval [CI], 52.4% to 89.6%). If three deaths attributable to other causes are treated as censored, the 5-year survival rate becomes 85.5% (95% CI, 73.7% to 97.2%). When cases were additionally divided by screening round, the overall 5-year survival rate seemed to be higher for those detected at initial screening (76.2%; 95% CI, 52.2% to 100%) than repeated screening (64.9%; 95% CI, 33.5% to 96.3%), although the difference was not statistically significant (P > .05) (Fig 1).

View larger version (13K): [in this window] [in a new window]   Fig 1. Cumulative survival curves for patients with lung cancer detected at initial screening (thin line; n = 14)and repeated screening (thick line, n = 22).

View larger version (26K): [in this window] [in a new window]   Fig 2. Cumulative survival curves for patients with screen-detected lung cancers by stage (A), tumor diameter (B), histologic type (C), and mode of detection (D).

	DISCUSSION

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When screenings were repeated, detection rate (0.3%) was one third that of initial screening (0.9%), and the proportion of stage I disease was 81.8% and mean tumor diameter was 14.6 mm, which seemed better than in initial screening, although the difference was not statistically significant. In Sone’s study, no difference was observed for detection rate between initial (0.4%) and repeated screening (0.4%), and the proportion of stage I was lower in repeated screening (86%) than initial screening (100%), which is not consistent with the present study, but mean tumor diameter appeared smaller in repeated screening (12.0 to 12.1 mm) compared with initial screening (15.1 mm), which is consistent with the present study.¹²

The 5-year survival rate for 36 patients with screen-detected lung cancer was 71%, clearly higher than that of patients detected by conventional chest x-ray, which is reported to be around 30% to 40%.⁷ When divided into initial and repeated screening, the 5-year survival rate was 76.2% and 64.9%, respectively, slightly lower among those detected at repeated screening, although the difference was not statistically significant. Theoretically, lung cancer detected at initial CT screening inevitably included some cases that were already advanced, but slow-growing tumors with a long preclinical detectable phase tend to be oversampled. On the other hand, cases detected at repeated screening will include less advanced cases, but the proportion of rapidly growing cancers will be higher than at initial screening. Survival will be affected by the balance of these factors, and the slightly better survival for patients detected at initial screening may indicate that growth speed is more influential. However, we should remember that because approximately half of the participants in this study had already been screened twice a year by chest x-ray and sputum cytology before initial CT screening, cases of advanced cancer were already less prevalent at the initial screening.

The proportion of test positives with helical CT scan was three to four times higher than the proportion with chest x-ray for both initial and repeated screenings. Although the proportion of test positives with helical CT scan is expected to be much lower at repeated screening than initial screening, this was not the case in this study. When the proportion of test positives at initial screening was divided by calendar year, it became higher in the later period. This indicates that the criteria for test positives with helical CT scan had changed during the study period. In 1993, when CT screening was introduced, there was limited knowledge as to what characteristics of CT images were related to malignancy for small nodules of less than 2 cm. Thereafter, through review of previous CT images for accumulated series of screen-detected cases, more subtle abnormalities that seemed to be related to malignancy came to be checked in the later screenings. The reasons for detection failures were retrospectively evaluated and reported in detail elsewhere.¹⁶ In this case series, in a review of screening CT images from before the detection for 19 cases of lung cancer that were detected at repeated screening from abnormalities on helical CT scan, nodules were identified for 15 cases (82%) in the previous screening CT images; these were from the initial screening in eight cases and the second or later screening in seven cases. Therefore, comparisons of test positive and detection rates between the initial and repeated screenings should be interpreted with caution in the present study. Preferably, these should be reevaluated in another series using fixed criteria for test positives. The proportion of test positives with helical CT screening varied to the great extent in other studies, 23% in ELCAP,¹³ 3.5% to 5.1% in the study by Sone,¹² and 9.1% to 11.5% in the present study, which clearly indicates that standardized criteria for test positives are urgently needed.

Of 186 participants who had positive findings on helical CT scan at initial screening, 21 participants (11.3%) underwent biopsies in this study. In the ELCAP study, 31 (13.3%) of 233 patients who had positive findings on helical CT scan had biopsies, which is almost the same level as in this study. Of 13 cases of lung cancer that were detected at initial CT screening based on positive findings on helical CT scan in this study, four (31%) cases were diagnosed by VATS. In the ELCAP study,¹³ nine (33%) of 27 cases of lung cancer were diagnosed by VATS, whereas in Sone’s study,¹¹ 10 (53%) of 19 lung cancers were diagnosed by VATS or open thoracotomy. Of the cases detected at repeated CT screenings in the present study, 11 (58%) of 19 lung cancer cases for which there were positive findings on helical CT scan were diagnosed by VATS or open thoracotomy. The choice of diagnostic procedure for small peripheral nodules varies by institution, and future research is needed to standardize the procedures.

Regarding the choice of treatment in this study, 10 (83%) of 12 patients with lung cancer detected at initial screening and treated surgically underwent lobectomy, whereas for those detected at repeated screening, eight (47%) of 17 patients treated surgically underwent lobectomy and the remaining nine (53%) underwent limited resection. These nine patients had peripherally located tumors that were less than 2 cm (seven adenocarcinomas and two squamous cell carcinomas), and six of seven adenocarcinomas were classified to be Noguchi’s type A or B, which are considered in situ peripheral adenocarcinoma.¹⁷ On the other hand, in the ELCAP study, 24 (96%) of 25 patients with lung cancer treated surgically underwent lobectomy. This reflects the different treatment options between the United States and Japan; ie, Japanese surgeons may intentionally choose limited resection for T1N0M0 small-cell lung cancer,¹⁸ whereas in the United States, lobectomy is the treatment of choice even for small-cell lung cancer.¹⁹ This is another point that should be standardized through additional research.

This study showed that the survival rate of patients with lung cancer detected by CT screening was high, which strongly indicates that CT screening has great potential for mortality reduction. However, because the preclinical detectable phase for lung cancers detected by helical CT scan must be longer than that for cancers detected by chest x-ray, the survival analysis will be influenced to a greater extent by lead-time bias and length-biased sampling. This indicates that the magnitude of mortality reduction estimated simply from survival comparison is inevitably overestimated, and studies that directly measure lung cancer mortality are essential. We are planning to measure lung cancer mortality rates among all screening participants, taking into account deaths from lung cancer that could not be detected by screening as well as deaths from lung cancer detected by screening.

On the other hand, there are several potential harmful events attributable to helical CT screening. First, a higher proportion of test positives with helical CT scan (9.1% to 11.5%) than with chest x-ray (2.6% to 3.4%) was observed in this study, which leads to a higher proportion of false positives and results in unnecessary diagnostic workups. Moreover, 35 of 71 patients who had biopsies in this study had negative results. Of these, 17 patients had biopsies because of an abnormality on helical CT scan alone. Although there were no severe adverse events attributable to biopsy in this series, the procedure itself tends to be aggressive and cause discomfort and anxiety. Because this is a preliminary project, however, the frequency of negative biopsy tended to be high, and less aggressive workups should be developed in the future studies. Second, among patients who were diagnosed as having stage I lung cancer, two patients died of postsurgical infection 6 and 9 months after diagnosis. Because death attributable to postsurgical infection among patients with lung cancer is reported to be less than .5% in routine practice in the National Cancer Center Hospital, this experience may be accidental because of the small number of cases in this series and not applicable to other situations. Finally, the high detection rate and high proportion of adenocarcinoma imply overdiagnosis. Although we cannot identify these overdiagnosed cases at the individual level, it is possible that a certain proportion of screen-detected cases were overdiagnosed and received unnecessary treatment. These benefits and harmful events should be evaluated in a quantitative manner in larger trials before deciding whether lung cancer screening using helical CT scan can be recommended for the general population.

The accumulated evidence indicates that the major cause of lung cancer is cigarette smoking. Considering the fact that the prevalence of present smokers is still high (57.5% in 1996) among males and is now increasing in younger females,²⁰ it is evident that controlling smoking should be the first priority in any lung cancer control strategy. Additional measures should be taken, however, because the risk of lung cancer remains at a high level even after cessation of smoking for a long time,²¹ the attributable risk percent due to cigarette smoking is low in Japan mainly because of the high proportion of adenocarcinoma,²² and the proportion of adenocarcinoma is now increasing in Japan similar to other countries.²⁰ Low-dose helical CT screening has potential to improve screening efficacy in terms of reducing lung cancer mortality. It is urgent that its efficacy in terms of reducing mortality or incidence of advanced lung cancer should be evaluated with appropriate research methods.

	ACKNOWLEDGMENTS

 
Supported by a Grant-in-Aid from the Ministry of Health and Welfare of Japan for Comprehensive 10-Year Strategy for Cancer Control.

We thank the physicians and technical staff of the ALCA; Jun Misawa; the late Dr Akira Suzuki; Drs Tsuguo Naruke, Keiichi Suemasu, Mamoru Tadera, Seiichi Suzuki, Sakae Okumura, Akiko Narimatsu, Naganobu Hayashi, and Motofumi Masaki; Noriko Kodera, and Miho Iizuka.

	REFERENCES

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Submitted May 17, 2001; accepted October 24, 2001.

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