 Lung cancer detection Mark Lega, M.D. Background: Lung cancer is the leading cause of cancer deaths in North America. Approximately one in eight smokers will develop this disease during his lifetime. In 1999, there were approximately 170,000 new cases of lung cancer in the United States, with an overall five-year survival of only 14 percent.1 More people die from lung cancer than from colon, prostate and breast cancer combined. Lung cancer now exceeds breast cancer as the leading cause of cancer deaths among women. This epidemic was delayed several decades in women relative to men because smoking was a rare habit for women before World War II. The main reason for the continued low survival rate for lung cancer patients is that tumors are found at a late invasive stage, when most options for treatment are mainly palliative. Unlike the other leading cancers that have screening tools available (such as the mammogram, Pap smear, PSA level and hemocult), there is no proven screening test for lung cancer. In the 1970s, the National Cancer Institute supported three mass screening programs with more than 30,000 patients enrolled.2,3,4 All were men older than 45 who smoked at least one pack of cigarettes daily. The trials at Johns Hopkins and Memorial Sloan Kettering examined annual chest X-rays with and without sputum cytologic analysis every four months and found no improved cancer survival rates with the use of these basic surveillance measures. The third study, conducted by the Mayo Clinic, compared annual chest X-ray to "standard care" and was able to resect 46 percent of early cancers compared with 32 percent in the control group. Surprisingly, the mortality of 3.2 per 1,000 person years was not statistically different from the control "standard care" group. However, in reviewing all of the above patient study groups, the five-year survival rates were 35 percent, which is well above the historical average of 13 percent.5 The conclusion remains that screening chest X-rays and sputum cytology will not show a benefit unless the strategy is refined to target those patients at highest risk and to use new disease detection techniques. With the escalating incidence of lung cancer, recognition of risk factors and advanced technology may aid in early detection (Table 1). Most studies show that about 85 percent of lung cancers develop in smokers or former smokers. The risk increases with the number of cigarettes smoked per day, tar content of the cigarette and duration of smoking.6
Pre-existing chronic obstructive pulmonary disease may be the best indicator for the potential development of lung cancer. Skillrud found that a forced expiratory volume in one second (FEV1) of 70 percent or less increased the risk of lung cancer fourfold, compared to matched smokers of the same age, sex and occupation.7 Tockman found a sixfold greater risk if the FEV1 was less than 60 percent of predicted.8 Other clinical risk factors for the development of lung cancer include occupational or environmental exposures to asbestos, silica, heavy metals and radon. A history of prior cancer of the lung or head and neck is also associated with a higher risk of lung cancer. Patients with underlying pulmonary fibrosis9 and individuals whose diets are insufficient in vegetables and fruits may also be at greater risk for the development of cancer in general and lung cancer specifically.10 Given the above risk factors, physicians interested in the early detection of lung cancer can potentially identify individuals at increased risk for whom surveillance programs can be directed. Certainly, a very appropriate group of patients to target such management for would be those with significant chronic obstructive pulmonary disease and a strong smoking history. Several methodologies are being explored to further identify patients among these high-risk groups with early, potentially curable lung cancer. New technology: Research conducted during the past 20 years has revealed a tremendous amount about the biology of lung cancer. This has led to the development of a number of promising new tools that could lead to effective screening for lung cancer, some of which are briefly outlined here. Molecular biology: Advances in molecular biology have resulted in the development of sputum techniques that are more sensitive than cytology in detecting lung cancer. A particular focus on carcinogenesis (steps in cancer development from mild irritation to frank cancer) changes the paradigm from detection of gross malignancy to detection of genetic and protein markers of neoplastic progression that precede clinical cancer. Investigations led by Tockman with monoclonal antibody staining of sputum for specific oncogenes may allow lung cancer to be detected many months to years earlier than a clinical diagnosis.11 Mutations in the K-ras family of oncogenes and/or the p53 onco-protein have been identified in archived sputum specimens from patients who were originally in the Johns Hopkins cancer surveillance trial of the late 1970s. Abnormalities in these oncogenes predicted the development of adenocarcinoma in 30 percent of patients. It is believed that the sensitivity and specificity of these investigations can be increased dramatically if bronchoalveolar lavage (BAL) specimens are studied rather than induced sputum specimens only.12 Thus, in the near future, sputum and BAL markers might enable physicians to identify individuals at very high risk to develop lung cancer. Radiography: As discussed earlier, plain chest roentgenography is an insensitive screening method for lung cancer. Among lung cancers detected, only 16 percent were of an early stage.5 The latest generation of spiral chest CT scanners has the ability to scan the entire thorax in about 15 seconds with a radiation dose that is approximately equivalent to that of mammography. Recent trials in Japan, Germany and the United States demonstrate the ability to detect lung cancer at an early stage.3,14 Kaneko screened 1,400 high-risk patients and identified 15 peripheral lung carcinomas, of which 14 were early stage 1 lesions. Only four of these lesions were visible by plain chest X-ray. As spiral CT becomes readily available, and the cost reduced, this may prove to be the most applicable screening study for appropriately selected patients with increased risk for lung cancer (Figure 1). Clinical trials for this are under way.
Serum markers: Serum markers specific to lung cancer detection have not been successful to date. Clinical studies of serum CEA, CA-125 and tissue polypeptide antigen (TPA) reveal low sensitivities from clinical lung cancer (15 to 45 percent). The specificity of these studies is similarly poor.15 Fluorescent bronchoscopy/Lifescope (Lung Imaging Fluorescence Endoscopy): The role of surveillance bronchoscopy in the early detection of lung cancer is being determined. Traditional "white-light" bronchoscopy has a diagnostic yield of more than 90 percent for visible gross malignant lesions in the bronchus.16 However, the changes of significant microscopic cellular dysplasia or carcinoma in situ are much more subtle findings that can be easily missed with standard bronchoscopic visibility. The use of "fluorescent" bronchoscopic techniques can reveal such early invasive cancers not seen on standard white light bronchoscopy. This technique relies upon the detection of the natural auto-fluorescence of the bronchial airways when a blue-green laser wavelength of light is used to view through the bronchoscope. A helium-cadmium laser with a 442-nm wavelength provides the blue-green light source. The physical mechanisms allowing for detection of bronchial abnormalities relate to the natural blue-green autofluorescence of the cartilage layer of the bronchial mucosa when excited by the light source. If there is an increase in the thickness of the epithelial (lining cell layer) of the bronchus secondary to dysplasia or carcinoma in situ, less fluorescent light is emitted from the tissue, producing a reddish-brown color. In contrast to laser illumination of the airway, the bronchial surface illuminated by white light results in significant light reflection, back-scattering and absorption. Thus, tissue autofluorescence is not visible to the unaided eye because the fluorescent intensity is very low and it is overwhelmed by reflected and back-scattered light.17
The Lifescope imaging system is an advanced way of performing bronchoscopy in which a commonly used fiberoptic bronchoscope facilitates the detection of early-stage lung cancer (Figure 2). This laser computerized system allows a bronchoscopist to perform a bronchoscopy using an ultra-sensitive multicamera system fitted to the eyepiece of a regular fiberoptic bronchoscope. Because normal and abnormal tissue respond to the laser light differently, the areas appearing red-brown instead of the normal blue-green coloration are appropriate sites for guided biopsies, which would not be identified with standard white light bronchoscopy. Using this laser autofluorescence technique, Lam achieved a 90 percent improvement in sensitivity for the identification of moderate or severe bronchial dysplasia, and 128 percent improvement in sensitivity for the identification of carcinoma in situ of the lung.18 Further studies may show that Lifescope fluorescent bronchoscopy may have a role in monitoring patients with a history of being treated for lung cancer with surgical resection, radio-therapy or chemo-therapy. It may also be considered in clinical trials for the surveillance of patients with abnormal sputum cytology. Patients with a known abnormal sputum cytology but a clear chest X-ray and normal CT scan are ideal patients to undergo Lifescope fluorescent bronchoscopy. This can help identify the earliest possible bronchial mucosal abnormalities that would not necessarily be visualized under standard white light bronchoscopy. Local therapies that may avoid the need for surgical resection or extensive chemo/ radiotherapy may be able to be applied. Studies at Allegheny General Hospital: At Alle- gheny General Hospital, we are involved in a number of investigations using a combined multimodality approach to the diagnosis and treatment of lung cancer. Currently, patients who undergo lung resection for carcinoma have the option of entering a study in which sputum samples are studied on an annual basis after surgical resection. The aim of this study is to identify obvious microscopic abnormalities and possible early genetic markers on the cells within the sputum of these patients, which could lead to an early detection of possible recurrent cancer. Such abnormalities may then prompt the performance of Lifescope fluorescent bronchoscopy if there are any sputum abnormalities identified. Potential lesions identified can be removed with fiberoptic Nd:YAG laser or photodynamic laser therapeutic techniques. There are approximately 20 Lifescopes being used in a clinical setting in North America. We are pleased to be part of evaluating this new and potentially important diagnostic tool, which only adds approximately 10 minutes to a standard white light bronchoscopic examination without any side effects. Summary: Lung cancer is the leading cause of cancer deaths among North American men and women. Efforts at identifying the most appropriate means of early detection among individuals at risk for this malignancy are gaining momentum. Answers to this screening problem will emerge as we develop better insights into the biology of lung cancer and as we learn how to apply newer diagnostic tools available to us today. Our research efforts at the Allegheny Center for Lung and Thoracic Disease will, we hope, assist in determining the proper course for the early detection of carcinoma of the lung. However, we should also remember that the effort at early detection of lung cancer should not diminish our efforts to emphasize the need for smoking cessation as well in reducing the epidemic of lung cancer in our country. References 1. Landis SH, Murray T, Bolden S, et al. Cancer statistics, 1999. CA: A Cancer Journal for Clinicians. 1999; 49:8-31. 2. Frost JK, Ball WC, Levin ML, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. Am Rev Respir Dis. 1984; 130:549-554. 3. Flehinger BJ, Melamed MR, Zaman MB, et al. Early lung cancer detection: results of initial (prevalence) radiologic and cytologic screening in the Memorial Sloan-Kettering study. Am Rev Respir Dis. 1984;130:555-560. 4. Fontana RS, Sanderson DR, Taylor WF, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic study. Am Rev Respir Dis. 1984;130:561-565. 5. Flehinger BJ, Melamed MR. Current status of screening for lung cancer. Chest Surg Clin N Am. 1994;4:1-15. 6. Wynder EL, Mabuchi K, Beattie EJ. The epidemiology of lung cancer: recent trends. JAMA. 1970;213:2221-2228. 7. Skillrud DM, Offord KP, Miller RD. Higher risk of lung cancer in chronic obstructive pulmonary disease: a prospective, matched, controlled study. Ann Intern Med. 1986; 105:503-507. 8. Anthonisen NR, Connett JE, Kiley JP, et al. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1: the Lung Health Study. JAMA. 1994;272:1497-1505. 9. Griffen JP. Interstitial pulmonary fibrosis and lung cancer. Chest. 1995;108: 1193-4. 10. Kvale G, Bjelke E, Gatt JJ. Dietary habits and lung cancer risk. Int J Cancer 1983; 31:397-405. 11. Tockman MS, Gupta PK, Myers JD, et al. Sensitive and specific monoclonal antibody recognition of human lung cancer antigen on preserved sputum cells: a new approach to early lung cancer detection. J Clin Oncol. 1988; 11:1685-1693. 12. Mills NE, Fishman CL, Scholes J, et al. Detection of K-ras oncogene mutations in bronchoalveolar lavage fluid for lung cancer diagnosis. J Natl Cancer Inst. 1995; 87:1056-1060. 13. Frost JK, Ball WC, Levin ML, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. Am Rev Respir Dis. 1984; 130:549-554. 14. Flehinger BJ, Melamed MR, Zaman MB, et al. Early lung cancer detection: results of initial (prevalence) radiologic and cytologic screening in the Memorial Sloan-Kettering study. Am Rev Respir Dis. 1984;130:555-560. 15. Strauss GM, Skarin AT. Use of tumor markers in lung cancer. Hematol Oncol Clin North Am. 1994; 8:507-82. 16. Shure D, Astarita RW. Bronchogenic carcinoma presenting as an endobronchial mass: optimal number of biopsy specimens for diagnosis. Chest. 1983; 83:865-867. 17. Lam S, Kennedy T, Unger M, Miller Y, Glemont D, Rusch V, Gipe B, Howard D, LeRiche J, Coldman A, Gazdar A. Localization of Bronchial Intraepithelial Neoplastic Lesions by Fluorescence Bronchoscopy. Chest. 1998;113(3):696-702. 18. Lam S, MacAulay C, LeRichie JC, et al. Early localization of bronchogenic carcinoma. Diagn Ther Endoscopy. 1994; 1:75-78.
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