Chest X-ray Screening Improves Outcome in Lung Cancer: A Reappraisal of Randomized Trials on Lung Cancer Screening

doi:10.1378/chest.107.6_Supplement.270S

Chest

Volume 107, Issue 6, Supplement, June 1995, Pages 270S-279S

https://doi.org/10.1378/chest.107.6_Supplement.270S Get rights and content

It is believed that population-based screening for cancer should be advocated only when screening reduces disease-specific mortality. Four randomized controlled studies on lung cancer screening have been conducted in male cigarette smokers, and none has demonstrated reduced mortality. Accordingly, no organization that formulates screening policy advocates any specific early detection strategies for lung cancer. Yet, despite this public policy against screening, there is considerable evidence that chest x-ray screening is associated with earlier detection and improved survival. Two randomized trials, the Memorial Sloan-Kettering and Johns Hopkins Lung Projects, were specifically designed to evaluate the effectiveness of sputum cytologic study. Both evaluated the efficacy of the addition of sputum cytologic studies to annual chest radiographs, and both demonstrated that cytologic study did not favorably influence outcome. All individuals in experimental and control groups in both studies had annual chest radiographs. Because survival rates observed in both studies were about three times higher than predicted, based either on the National Cancer Institute's Surveillance Epidemiology and End Results database or based on the American Cancer Society's annual Cancer Statistics, raises the possibility that the periodic chest radiographs performed in all patients in both studies contributed to an improved outcome. In the Mayo Lung Project and in the Czechoslovak study on lung cancer screening, the experimental groups underwent a program of relatively intensive and regular rescreening with chest radiographs and sputum cytologic study, while the control groups underwent either less-frequent rescreening or no rescreening. In both studies, the screened groups achieved meaningful improvements in stage distribution, resectability, and survival. However, increases in cumulative incidence of lung cancer in the experimental group in both studies (which in the Mayo Lung Project reached statistical significance) prevented significant improvements in survival from translating into corresponding reductions in mortality. The possibility that screening may be associated with lung cancer “overdiagnosis” has been widely postulated to account for higher survival and incidence rates and equivalent mortality rates. However, analysis of autopsy information and of disease outcome in individuals with screen-detected early stage lung cancer who do not undergo surgical resection strongly supports the conclusion that screening does not lead to overdiagnosis of lung cancer. Similarly, lead-time and length bias do not adequately account for the differences in cumulative incidence observed in the Mayo and Czech studies. Because chest radiographs lead to meaningful improvements in stage distribution, resectability, and survival in lung cancer, and because neither overdiagnosis bias nor lead-time bias accounts for these improvements in outcome, a reconsideration of the role of chest radiographs in the early detection of lung cancer would be appropriate. A consensus conference would be a suitable forum to reexamine fully the existing data on lung cancer screening and to formulate specific guidelines for early detection strategies in individuals at high risk for lung cancer.

Section snippets

Randomized Trials on Lung Cancer Screening: Review of the Literature

Four randomized controlled studies, which have collectively included 37,724 participants, have been conducted to evaluate lung cancer screening. Because these trials were all initiated in the 1970s, before the epidemic of lung cancer in women became so apparent, eligibility to participate in each of these trials was limited to male cigarette smokers. Although lung cancer subsequently surpassed breast cancer as the most common cause of cancer death in women,⁵ to our knowledge, no existing

Potential Explanations for Differences in Cumulative Incidence

The four screening biases represent potential explanations for these incidence discrepancies. Selection bias influences participation in screening trials, but randomization eliminates selection bias as a factor in whether individuals enter an experimental or control group.

Lead-time bias predicts an initial excess of cases, reflecting earlier detection through screening.³ This is due to increased detection of relatively indolent cancers, which, because of length bias, are most likely to be

Imbalance of Coexisting Risk Factors for Lung Cancer

We believe that existing data support the conclusion that neither the four conventional screening biases nor radiation exposure from screening chest radiographs nor chance can credibly explain the observed differences in cumulative incidence of lung cancer in the Mayo Lung Project and the Czechoslovak study. We believe it is necessary to look for an alternative explanation for the observed differences in case detection. We also understand that since none of the studies were designed to

Mayo Lung Project Reexamined

In the Mayo study,¹⁰ the cumulative incidence of lung cancer in the experimental group was 4.46% vs 3.48% in the control group. The difference in absolute incidence was 0.98%. This led to a 29% relative excess in case numbers in the experimental population, indicating that the size of the group at risk for lung cancer mortality was 29% larger, a statistically significant difference (p=0.019).

If incidence rates between experimental and control groups in randomized trials differ, not because of a

Changing Epidemiology of Lung Cancer

In 1980, the American Cancer Society modified its previous recommendation in favor of annual screening chest radiographs in cigarette smokers to a recommendation supporting no screening whatsoever.³⁷ Table 7 lists the changes that have occurred in lung cancer epidemiology from 1980 through 1994, based on the American Cancer Society's annual cancer statistics.38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 During this period, annual incidence increased 47%. The percentage of women who

Discussion

Existing evidence from all four of the randomized controlled studies on lung cancer screening supports the conclusion that periodic chest radiographs lead to increased detection of early-stage disease, increased rates of resectability, and improvements in lung cancer-specific survival. A mortality reduction, however, was not demonstrated in any of these four studies.

In the Memorial Sloan-Kettering and Johns Hopkins Lung Project, the failure to demonstrate a mortality difference was likely due

Conclusions

We believe, based on the analysis presented herein, that existing data from randomized trials are most consistent with the conclusion that periodic chest x-ray screening is beneficial, as reflected by improvements in stage distribution, resectability, and survival. A case can be made to consider the adoption of periodic chest x-ray screening as standard care for individuals at high risk of lung cancer. Data from the Memorial and Hopkins studies support annual screening as the appropriate

Acknowledgment

Data analysis assisted by CDMAS data management and analysis system at the Brigham and Women's Hospital.

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This finding in the lung cancer trials was accompanied by a significant increase in cancer incidence in the screen groups, but no reduction in late-stage incidence. Both together suggest that overdiagnosis was the main contributor to the absence of reduction in mortality.28 This result differs from UKCTOCS, in which no significant increase in cancer incidence was observed in either of the screen groups.
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Between April 17, 2001, and Sept 29, 2005, of 1 243 282 women invited, 202 638 were recruited and randomly assigned, and 202 562 were included in the analysis: 50 625 (25·0%) in the MMS group, 50 623 (25·0%) in the USS group, and 101 314 (50·0%) in the no screening group. At a median follow-up of 16·3 years (IQR 15·1–17·3), 2055 women were diagnosed with tubal or ovarian cancer: 522 (1·0%) of 50 625 in the MMS group, 517 (1·0%) of 50 623 in the USS group, and 1016 (1·0%) of 101 314 in the no screening group. Compared with no screening, there was a 47·2% (95% CI 19·7 to 81·1) increase in stage I and 24·5% (−41·8 to –2·0) decrease in stage IV disease incidence in the MMS group. Overall the incidence of stage I or II disease was 39·2% (95% CI 16·1 to 66·9) higher in the MMS group than in the no screening group, whereas the incidence of stage III or IV disease was 10·2% (−21·3 to 2·4) lower. 1206 women died of the disease: 296 (0·6%) of 50 625 in the MMS group, 291 (0·6%) of 50 623 in the USS group, and 619 (0·6%) of 101 314 in the no screening group. No significant reduction in ovarian and tubal cancer deaths was observed in the MMS (p=0·58) or USS (p=0·36) groups compared with the no screening group.
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Chest

Chest X-ray Screening Improves Outcome in Lung Cancer: A Reappraisal of Randomized Trials on Lung Cancer Screening

Section snippets

Randomized Trials on Lung Cancer Screening: Review of the Literature

Potential Explanations for Differences in Cumulative Incidence

Imbalance of Coexisting Risk Factors for Lung Cancer

Mayo Lung Project Reexamined

Changing Epidemiology of Lung Cancer

Discussion

Conclusions

Acknowledgment

Med Clin North Am

Chest

Chest

Chest

Chest

Clin Chest Med

J Nutr

Screening for lung cancer

Ann Intern Med

Screening in chronic disease

Cancer screening: degrees of proof and practical application

Cancer

The National Cancer Institute cooperative early lung cancer detection program

Am Rev Respir Dis

Survival and mortality from lung cancer in a screened population: the Johns Hopkins study

Chest

Cancer patient survival rates: SEER program results for 10 years of followup

CA Cancer J Clin

Lung cancer screening: the Mayo Program

J Occup Med

Screening for lung cancer, a critique of the Mayo Lung Project

Cancer

Lung cancer detection: results of a randomized prospective study in Czechoslovakia

Cancer

Lack of benefit from semi-annual screening for cancer of the lung: follow-up report of a randomized controlled trial on population of high-risk males in Czechoslovakia

Int J Cancer

An analysis of the mortality effect in a breast cancer screening study

Int J Epidemiol

Analysis of breast cancer mortality and stage distribution by age for the Health Insurance Plan clinical trial

J Natl Cancer Inst

Screening for lung cancer: recent experience in the United States

Prostate cancer screening: what we know and what we need to know

Ann Intern Med

Latent carcinoma of prostate at autopsy in seven areas

Int J Cancer

Latent malignancies

Results of conservative management of clinically localized prostate cancer

N Engl J Med

Handbook of radiation doses in nuclear medicine and diagnostic x-ray

On the question of cancer induction by small x-ray doses

AJR

Smoking and lung cancer: an overview

Cancer Res

Asbestos exposure, cigarette smoking, and death rates

Ann NY Acad Sci