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© 2002 American Society for Clinical Oncology
Screening for Lung Cancer: No Longer a Taboo SubjectMayo Clinic, Rochester, MN THE FACT THAT lung cancer is the number one cancer problem in the United States is documented by the American Cancer Society 2002 Statistics.1 Table 1 lists the number of new cases and deaths from the four major cancer causes of death.
The 5-year survival for colorectal, breast, and prostate cancer has improved substantially from the mid-1970s to the mid-1990s. The same cannot be said for lung cancer. Why? We screen, to a variable extent, for the three cancers that have shown the most improvement in survival, but we do not screen for lung cancer. Are these correlations true, but unrelated? The current position of the American Cancer Society is to not recommend screening for early lung cancer detection, even in individuals at high risk for lung cancer.2 This position has been heavily influenced by the results of the three large National Cancer Institute–sponsored screening trials performed in the 1970s and early 1980s at Johns Hopkins, Memorial Sloan-Kettering Cancer Center, and the Mayo Clinic. These trials did not show a reduction in lung cancer mortality in the screened group.3-5 In this issue, Strauss6 reports a detailed and scholarly reanalysis of the Mayo Lung Project trial. While I have been familiar with the Mayo data for 20 years, Strauss makes a new observation and emphasizes some points that many of us may have overlooked. The new observation is that when the analysis is restricted to lung cancer cases only, the experimental (screened) group had a better survival from randomization than the control group. He contends that survival analysis from time of randomization, rather than from the time of diagnosis, removes lead time bias issue. This analysis also emphasizes the importance of detecting resectable cancers. In a multivariate Cox regression analysis, resection was the only important predictor of survival. Screen detection was important because it detected more resectable cases. Surgeons have told us for years that a chance to cut is a chance to cure. Could they have been right after all? Recently, Marcus et al7 performed a 20-year follow-up of the Mayo Lung Project data.7 They observed, once again, that the screen-detected group had a better overall survival than the control group, but there was no difference in the lung cancer mortality between the two groups. They explain this discrepancy between survival and mortality as over diagnosis of lung cancer in the screened group, which is defined as a cancer that never would have led to the patient’s death. To physicians who diagnose and treat lung cancer, this concept is difficult to accept. Rarely have I observed a patient survive 5 years without treatment. Most lung cancer patients develop progressive disease and die, as documented by the 155,000 lung cancer deaths per year in the United States. Their problem was under diagnosis or a diagnosis too late in the disease course to alter the outcome. On the other hand, prostate cancer in the elderly is a good example of the over diagnosis concept. Strauss’ opinion is that because effective treatment was the only significant multivariate predictor for lung cancer mortality the data are inconsistent with over diagnosis. As a clinician, the concept of over diagnosis of lung cancer is also one that I grapple with and have not totally accepted. Since the completion of the National Cancer Institute screening trials, technology and understanding of the biology of lung cancer have advanced tremendously. Studies have been shown that the chest radiograph is not very sensitive at detecting small lung cancers.8,9 Data suggests that more than 50% of lung cancers less than 2 cm are missed by chest roentgenograms.8-10 Investigators are evaluating low-dose spiral computed tomography (CT) for detection of lung cancer. In a large Japanese trial, the mean size of lung cancer detected by chest radiograph was 3.0 cm versus a mean size of 1.5 cm for a lung cancer detected by spiral CT scan.11 Nonrandomized trials by investigators from Japan, Cornell, and the Mayo Clinic have all documented a stage shift toward earlier diagnosis with low-dose spiral CT scan screening.10-13 These data suggest that 70% to 80% of non–small-cell lung cancers are stage I or II at the time of diagnosis with spiral CT screening as compared with approximately 20% stage I or II in standard clinical practice, in which we now wait for patients to present with symptomatic disease. A drawback to spiral CT screening is the high rate of incidental nodule detection (50% in the Mayo Clinic trial on the baseline scan) and the subsequent costs or morbidity associated with observation or biopsy of these nodules.13 With the data that is currently available, the stage is set for a randomized control trial to answer the questions of benefit and cost of screening for lung cancer with spiral CT. Although spiral CT scan screening offers the possibility of detecting cancers earlier, in most reports the average diameter has been 1.5 to 1.7 cm. At this size, the tumor already contains over 109 cells and has gone through more than 30 doublings.14 What is the possibility of detecting it even earlier? Currently, there is a great deal of research aimed at early detection. One area of focus is on sputum detection of early genetic or epigenetic changes that may herald malignancy. Studies have shown loss of heterozygosity (LOH) in the bronchial epithelium of smokers, similar to those observed in resected lung cancers.15-17 LOH changes are multiple and do precede cancer, but so far, we are not certain which LOH changes predict malignancy. Detection of methylation of genes in the sputum is another promising area for screening and early detection.18,19 Methylation of the promoter region of a gene blocks gene expression. Other investigators are evaluating biomarkers in the serum such as microsatellite alterations of DNA or promoter hypermethylation of tumor suppressor genes.20,21 Exciting new work is underway to search for autologous antibodies that recognize human lung cancer antigens.22,23 Presently, none of these sputum or blood markers are ready for standard practice, but the field is very dynamic. In 5 or 10 years, we may be able to perform a sputum or blood test that indicates the presence of a very early cancer or a premalignant lesion. In contrast to the late 1980s and early 90s, the subject of screening for lung cancer is a live issue. Strauss has consistently challenged the interpretation of the Mayo Lung Project screening trial. In this issue, he makes several key observations. His analysis of the data strongly supports the position that resection is the most important predictor of survival. He has helped resurrect the issue of screening for lung cancer based on a conference that he and Professor Lorenzo Dominioni organized in December 1998, in Varese, Italy. Based on these efforts and the encouraging data from the spiral CT scan screening trials, we are now poised to conduct a randomized control trial for lung cancer screening. This year, a randomized controlled trial with 50,000 volunteers will begin in the United States, comparing screening with chest roentgenogram versus low-dose spiral CT scan. This large multi-institutional trial is sponsored by the National Cancer Institute and will have the ability to detect a 20% difference in lung cancer mortality. In my 20 years of conducting and participating in lung cancer clinical trials, this is the most exciting one of all. REFERENCES
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Quekel GBA, Kessels AGH, Goei R, et al: Miss rate of lung cancer: On the chest radiograph in clinical practice. Chest 115: 720-724, 1999 10. Sone S, Li F, Yang ZG, et al: Results of three-year mass screening program for lung: Cancer using mobile low-dose spiral computed tomography scanner Br J Cancer 84: 25-32, 2001[CrossRef][Medline] 11. Ohmatsu H, Kakinuma R, Kaneko M, et al: Successful lung cancer screening with low-dose helical CT in addition to chest x-ray and sputum cytology: The comparison of two screening periods with or without helical CT. Radiology 217: 242, 2000 (suppl, abstr 182) 12. Hensche CI, McCauley DI, Yankelvitz DF, et al: Early lung cancer action project: Overall design and findings from baseline screening. Lancet 354: 99-105, 1999[CrossRef][Medline]
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Palmisano WA, Divine KK, Saccomanno G, et al: Predicting first-line lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 60: 5954-5958, 2000
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Sozzi G, Musso K, Ratcliffe C, et al: Detection of microsatellite alterations in plasma DNA of non-small cell lung cancer patients: A prospect for early diagnosis. Clin Cancer Res 5: 2689-2692, 1999
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Gure AO, Altorki NK, Stockert E, et al: Human lung cancer antigens recognized by autologous antibodies: Definition of a novel cDNA derived from the tumor suppressor gene locus on chromosome 3p21.3. Cancer Res 58: 1034-1041, 1998 23. Sioud M, Hansen MH: Profiling the immune response in patients with breast cancer by phage-displayed cDNA libraries. Eur J Immunol 31: 716-725, 2001[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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