Fluorescence Bronchoscopy and Photodynamic Therapy for Early Detection and Treatment of Lung Cancer
By Tracey Weigel, MD
In 1998, more than 160,000 individuals died of lung cancer in the United States alone, exceeding the total mortality from breast, prostate, pancreatic and all lymphomas and leukemias. Currently, only 14% of patients with invasive lung cancer are cured using conventional treatment modalities.1 Early (stages IA, IB) lung cancer is a curable disease with a five-year survival of 57%-67%.2 Unfortunately, by the time a carcinoma of the lung is diagnosed it has progressed locally beyond resectability (stage IIIB) or metastasized (stage IV) in 80% of the cases. The most significant way to prevent this high mortality from lung cancer appears to be identification of the disease at an earlier stage, prior to its becoming a systemic disease.
The histological response of the respiratory mucosa to exogenous environmental stresses is a predictable progression from normal mucosa through metaplasia, dysplasia, and carcinoma in situ (CIS), eventually resulting in invasive carcinoma.3 However, only 29% of CIS and 69% of micro-invasive tumors can be identified with conventional bronchoscopy.4
As long ago as the 1930s and 1940s, the diagnostic potential of tissue fluorescence was exploited using a Wood’s light to differentiate malignant from normal mucosa.5 Florescence bronchoscopy is now available at approximately 20 medical centers throughout the United States and can be used to detect early non-small cell lung cancers (NSCLCs) and even intraepithelial neoplasias (IENs) with a high degree of sensitivity. The autofluorescent tracheobronchial imaging system currently approved by the Food and Drug Administration (FDA) is the Xillix Lung Imaging Fluorescence Endoscopy (LIFE-lung) system. The LIFE system uses a helium-cadmium laser to deliver monochromatic (442 nm) blue light to the bronchial surface via a standard, Olympus BF20, bronchoscope. Tracheobronchial mucosal and submucosal fluorescence in the red (> 630 nm) and green (520 nm) spectra are simultaneously captured using filters and transmitted via the fiberoptic bundles of the bronchoscope to an image intensified camera.6 In vivo spectroscopy, with an optical multichannel analyzer, then allows the bronchoscopist to identify dysplasia, CIS, and microinvasive carcinomas in the absence of exogenous photo-sensitizers.7 In a normal bronchus, the predominant source of fluorescence is the submucosa, and the mucosa appears a bright green.8 Areas of dysplasia, CIS, and invasive carcinoma exhibit a progressive decrease in autofluorescence that is more prominent in the green spectra, resulting in these lesions appearing reddish-brown. These differences in autofluorescence may result from morphologic changes (i.e., from thickening of the overlying, abnormal epithelium or the increase in the bronchial capillary density of IENs and invasive carcinomas). Alternatively, a loss of natural fluorophors as bronchial mucosa undergoes malignant transformation may be responsible for the observed differences in their patterns of autofluorescence.
Fluorescence bronchoscopy is routinely conducted as an outpatient procedure using intravenous conscious sedation along with aerosolized 1% lidocaine and cetacaine spray to achieve topical anesthesia of the oro- and hypopharynx. The fluorescence exam is usually performed after conventional white-light bronchoscopy (WLB) simply by changing to the helium-cadmium light source and connecting the LIFE camera to the BF20 bronchoscope.9
Results of Fluorescence (LIFE) Bronchoscopy Screening and Surveillance
A multi-institutional, clinical trial conducted by Lam et al documented that the LIFE-lung system, when used as an adjunct to conventional WLB, improved the physician’s ability to identify moderate/severe dysplasia or worse.10 The relative sensitivity of LIFE vs. WLB for invasive carcinoma was 146% in this trial. Fluorescence bronchoscopy’s superiority in detecting early, intraepithelial lesions was clearly demonstrated; 57 intraepithelial neoplasias diagnosed on the LIFE examination versus only nine lesions by WLB alone. The relative sensitivity for LIFE vs. WLB for intraepithelial neoplasias in this trial was 630%.10
A recent collective review of 1406 patients reported an incidence of second-primary lung cancers of 11.4% in patients with a history of lung cancer.1 A prospective study at the University of Pittsburgh using LIFE as a surveillance tool in these high-risk, post-resection lung cancer patients (believed to be disease free) identified occult lesions in 12% of patients.11 The addition of the LIFE exam to conventional WLB increased the overall sensitivity of post-operative screening from 33% to 66%; the relative sensitivity of LIFE vs. WLB was 200%. With respect to early lesions (i.e., IENs), 67% were correctly identified with LIFE bronchoscopy vs. 0% with WLB.12
Curative Photodynamic Therapy (PDT) for Early, Non-Small Cell Lung Carcinomas
In January 1998, the FDA approved PDT as a curative treatment modality for microinvasive NSCLCs in patients that were poor candidates for surgery and/or radiation therapy. Photodynamic therapy is a promising new modality for curative treatment of early lung cancers. Investigators at the Mayo Clinic documented a greater than 90% complete response rate using PDT to treat microinvasive NSCLCs. In the Mayo series, 43% of the patients were spared surgery at 68 months follow-up.13 More recently, an 88% complete response rate to PDT at was achieved in a similar cohort of patients at the University of Pittsburgh, with a mean follow-up of 19 months.14
Early detection and careful mapping of pre-invasive lung lesions in high-risk patients with the fluorescence bronchoscopy may translate into improved survival. Fluorescence bronchoscopic surveillance can identify lesions at an early stage, when they are potentially curable with minimally invasive, therapeutic interventions such as photodynamic therapy. In addition, longitudinal monitoring of IENs with fluorescence bronchoscopy may help to better define their natural history.
The current paradigm of lung carcinogenesis depicts a multistage process with potential genetic markers at each stage.15 Fluorescence bronchoscopy may afford investigators the opportunity to identify early mucosal abnormalities harboring molecular genetic lesions prior to apparent histologic abnormalities.16 Biopsy specimens from these pre-malignant lesions may help unravel the cascade of molecular events that occur in tracheobronchial mucosa carcinogenesis. Identification of early molecular markers may facilitate the development of efficient, molecular sputum screening techniques for NSCLC as an adjunct to, and/or replacement of traditional, costly, labor-intense cytologic screening.
1. Lam S, Becker H. Chest Surg Clin North Am 1996;6:363-380.
2. Mountain CF. Chest 1997;111:1710-1717
3. Auerbach O, Stout AP, Hammond EC, et al. N Engl J Med 1961;265:253-267.
4. Woolner LB, Fontana RS, Cortese DA, et al. Mayo Clin Proc 1984;59:453-466.
5. Erly L. Cancer Res 1943;1:227-231.
6. George PJM. Thorax 1999;54:181.
7. Palcic B, Lam S, Hung J, et al. Chest 1991;99:742-743.
8. Lam S, Palcic B. Fluorescence detection. In: Roth JA, et al (eds.). Lung Cancer. Boston: Blackwell Scientific Publications; 1991:325-338.
9. Wiegel TL, et al. Fluorescence bronchoscopic surveillance in post-resection non-small cell lung cancer patients. Ann Surg Oncol, accepted for publication.
10. Lam S, Kennedy T, Unger M, et al. Chest 1998;113:696-702.
11. Weigel T, et al. Fluorescence bronchoscopic screening for second primaries in post-resection non-small cell lung cancer patients. Accepted for oral presentation, Chest Nov. 2,1999, Abstract #850179.
12. Weigel T, et al. Fluorescence bronchoscopie surveillance in patients with a history of non-small cell lung carcinoma. Diagn Therapeaut Endoscopy October 1999, (in press).
13. Cortese DA, Pairolero PC, Bergstralh EJ, et al. J Thorac Cardiovasc Surg 1983;86:373-380.
14. Weigel T, et al. Photodynamic therapy for early, non-small cell lung cancer. Accepted for oral presentation, International Biomedical Optics Symposium, San Jose, CA, January 21-28, 2000.
15. Tockman MS, Gupta PK, Pressman NJ, et al. Can Res 1992;52(9 Suppl):2711s-2718s.
16. Lam S, Macd Aulay CE. Endoscopic localization of preneoplastic lung lesions. In: Martinet Y, Hirsch FR, Martinet N, et al (eds). Clinical and Biologic Basis of Lung Cancer Prevention. Basel: Birkhauser Verlag; 1998:231-237.