© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 18, 1385-1391,
September 19, 2001
© 2001 Oxford University Press
Fluorescence Versus White-Light Bronchoscopy for Detection of Preneoplastic Lesions: a Randomized Study
Affiliations of authors: F. R. Hirsch, W. A. Franklin (Department of Pathology), S. A. Prindiville, P. A. Bunn, Jr. (Department of Medical Oncology), J. R. Murphy (Department of Preventive Medicine), University of Colorado Health Sciences Center and Cancer Center, Denver; Y. E. Miller, E. C. Dempsey, Division of Pulmonary Sciences and Critical Care, Denver Veterans Affairs Medical Center; T. C. Kennedy, Lung Cancer Institute of Colorado/HealthOne Alliance, Denver.
Correspondence to: Timothy C. Kennedy, M.D., Lung Cancer Institute of Colorado, 1721 E. 19th Ave., #366, Denver, CO 80218 (e-mail: TchesK{at}AOL.com).
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ABSTRACT |
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 TopNotes Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Background: There are no currently approved methods for the screening and early detection of lung cancer. We compared the ability of conventional white-light bronchoscopy (WLB) and laser-induced fluorescence endoscopy (LIFE) to detect preneoplastic lung lesions in a randomized trial in which both the order of the procedures and the bronchoscopists were randomly assigned. Methods: The study included high-risk subjects enrolled because of a cigarette smoking history of at least 30 pack-years, an air-flow obstruction, and either an abnormal sputum cytology (n = 48) or a previous or suspected lung cancer (n = 7). LIFE and WLB were performed on all patients. Biopsy specimens were assessed for histologic abnormalities, including the presence of angiogenic squamous dysplasia. All statistical tests were two-sided. Results: A total of 391 biopsy specimens were taken from the 55 patients. Thirty-two patients (58%; 95% confidence interval [CI] = 44% to 71%) had at least one biopsy with moderate or severe dysplasia, and 19 (59%; 95% CI = 41% to 76%) of these patients could be diagnosed based solely on the results of LIFE. LIFE was statistically significantly more sensitive than WLB for detecting moderate dysplasia or worse (68.8% versus 21.9%, respectively) (difference = 46.9%; 95% CI = 25% to 68%; P<.001). The relative sensitivities (WLB = 1.0) were 3.1 (95% CI = 1.6 to 6.3) for LIFE and 3.7 (95% CI = 1.9 to 7.3) for LIFE and WLB combined. LIFE was less specific than WLB (69.6% versus 78.3%, respectively; P = .45), but the difference was not statistically significant. The relative specificities (WLB = 1.0) were 0.9 for LIFE (95% CI = 0.6 to 1.3) and 0.6 (95% CI = 0.4 to 1.0) for LIFE and WLB combined. The results were similar regardless of the order of the procedures or the order of the bronchoscopists. Also, LIFE was better at identifying angiogenic squamous dysplasia lesions than WLB (detection ratio [DR], which indicates the relative likelihood of getting a positive result in a sample with dysplasia compared with one without, for LIFE = 1.39 [95% CI = 1.17 to 1.65] versus DR for WLB = 0.67 [95% CI = 0.38 to 1.21]). Conclusion: LIFE was more sensitive than WLB in detecting preneoplastic bronchial changes in high-risk subjects. The prognostic implication of this finding is not yet clear.
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INTRODUCTION |
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TopNotesAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Lung cancer is the most common cause of cancer-related death in North America, accounting for more deaths than prostate, breast, and colorectal cancers combined (1). Approximately 170 000 new patients will be diagnosed with lung cancer in 2001, and less than 15% of them will survive 5 years after diagnosis (1). The prognosis for patients with lung cancer is associated strongly with the stage of the disease at the time of diagnosis. The 5-year survival rates for patients with stage IA disease are about 70%; however, for those with disease at stages II–IV, the rates range from 40% to less than 5% (2). More than two thirds of all lung cancer patients have mediastinal lymph node involvement or distant disease at the time of diagnosis (3). The poor prognosis for patients with lung cancer reflects both the lack of effective early-detection methods, which would provide the opportunity for curative excision, and the inability to cure metastatic disease. Thus, current research efforts are aimed at the early identification of preneoplastic lesions and intervention in lung cancer.
Historically, the only diagnostic tests available for the early detection of lung cancer were sputum cytology and chest radiography. The efficacy of these tests as screening tools has been evaluated extensively during the last few decades (4–6). Although the methodology and interpretation of the data from these studies (4–6) have been debated extensively (7,8), the lack of a reduction in lung cancer mortality led the National Cancer Institute to conclude that mass screening programs for lung cancer involving periodic sputum cytology and chest radiography were not justified.
These results prompted a search for better diagnostic approaches that would take advantage of recent developments in molecular biology, gene technology, and radiology (9). In addition, several studies (10–13) have suggested that local treatment (i.e., photodynamic therapy, high-dose-rate brachytherapy, electrocautery, and surgery) of carcinoma in situ (CIS) and stage I non-small-cell lung cancer in patients with radiographically occult lung cancer results in a very favorable outcome. Thus, investigations have focused on improving the ability to detect and localize dysplastic premalignant lesions and CIS lesions by bronchoscopy. Because these lesions are small, with a surface diameter of only a few millimeters, and they often lack characteristics that would make them visible on white-light bronchoscopy (WLB), they are frequently not observed with WLB. Indeed, Woolner et al. (14) reported that, even for centrally located squamous cell carcinoma in situ, the lesions were visible to experienced bronchoscopists in only 29% of patients. Furthermore, the need to detect premalignant lesions and CIS lesions is critical because approximately 10% of patients with moderate cellular atypia in sputum samples and 40%–80% of patients with severe cellular atypia may develop invasive cancer (15–17).
To improve bronchoscopy detection, laser-induced fluorescence endoscopy (LIFE) was developed to detect high-grade (moderate to severe) dysplasia and CIS by tissue autofluorescence, instead of porphyrin, which causes phototoxicity (18). Several studies (19–22) have compared whether LIFE, when used as an adjunct to WLB, improves the bronchoscopist's ability to locate dysplasia or CIS over that of WLB alone. In a validation study (19) that examined 700 biopsy specimens from 173 high-risk subjects from seven U.S. and Canadian institutions, the relative sensitivity of WLB and LIFE combined was 6.3 times that of WLB alone for detecting dysplasia and CIS and 2.7 times that of WLB alone for detecting moderate or severe (i.e., high grade) dysplasia, CIS, and invasive carcinoma. In two other studies (21,22), the combination of LIFE and WLB also improved the detection rate of preneoplastic lesions and CIS lesions. By contrast, another study (20) found no difference in the diagnostic efficacy of WLB and LIFE in a population of smokers.
The differences in various results might reflect differences in the study populations (23). In addition, the order in which the different bronchoscopy examinations were done and the fact that the same bronchoscopist performed both procedures are two potential methodologic biases.
In this article, we evaluated these potential influences in a single-institution study, in which high-risk patients were randomly assigned, both in terms of the order in which the WLB and LIFE procedures were performed and which bronchoscopist performed each procedure. Also, because individuals with low-grade (metaplasia and mild dysplasia) premalignant lesions, individuals with high-grade (moderate or severe dysplasia) premalignant lesions, or individuals with both low-grade and high-grade premalignant lesions were included in the study, we evaluated the performance of the LIFE procedure for detecting both types of lesions.
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PATIENTS AND METHODS |
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TopNotesAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients
All of the patients were recruited through the University of Colorado Cancer Center network for high-risk individuals (current or former cigarette smokers with a smoking history of >30 pack-years [i.e., more than one cigarette pack a day for 30 years or two packs a day for 15 years] and air-flow obstruction [forced expiratory volume in 1 second/forced expiratory volume 
0.75 and forced expiratory volume in 1 second <70% predicted]). The protocol was approved by the Colorado Multi-Institutional Review Board and by the HealthOne Alliance Institutional Review Board, Denver. All of the patients who entered the trial gave written informed consent. Individuals were eligible for the study (a) if they had sputum cytology results of moderate or severe cellular atypia and, within the previous 6 months, a chest radiograph with no lesions suspicious for malignancy and (b) if they had known or suspected lung cancer on the basis of x-ray or computed tomography (CT) scan. Individuals were not eligible if they ever had received photosensitizing drugs (e.g., hematoporphyrin derivatives), chemopreventive agents (e.g., retinoids) within 3 months of the enrollment date, or radiation therapy and/or cytotoxic chemotherapeutic agents within 6 months of the enrollment date. Individuals were also excluded from the study if they were pregnant or had acute bronchitis, uncontrolled hypertension, bleeding disorders, known or suspected pneumonia, unstable angina, or a known reaction to topical lidocaine. Ultimately, we enrolled 57 patients in total—50 with abnormal sputum cytology but no evidence of lung cancer and seven with known or suspected lung cancer. Two patients were excluded for protocol violations, leaving 48 patients in the first group and seven in the second.
Each patient underwent both WLB and LIFE procedures, with the order of the examination being randomized with regard to whether the LIFE or the WLB examination was performed first. Each of the two bronchoscopists was randomly assigned to only one procedure per patient. The bronchoscopists performed their examinations independently of each other and recorded areas of visual abnormalities. The results of the bronchoscopy made by each examiner were blinded for the other. Randomization was done by the study statistician using a random-number generator in Microsoft Excel (Microsoft Corp., Redland, WA). Patients and bronchoscopists were blinded to these assignments before the examination.
Both bronchoscopy procedures used the same equipment, the Xillix LIFE system (Xillix Technologies Corp., Richmond, BC, Canada) and an Olympus BF20D fiberoptic bronchoscope (Olympus America Inc., Melville, NY). The only equipment difference used in the procedures was the light source and the camera attachment. A white-light camera and a xenon lamp were used for WLB, and a fluorescence camera and helium-cadmium laser (442-nm wavelength) were used for LIFE.
A bronchoscopic examination was carried out on the patients after they had fasted overnight (medication was allowed) for 8 hours before the procedure. During the bronchoscopies, the patients were under local anesthesia with or without sedation (e.g., midazolam and/or fentanyl). All of the accessible areas in the tracheobronchial tree were examined. Normal and abnormal areas with visually suspicious moderate or severe dysplasia, CIS, or invasive carcinoma were recorded within the LIFE unit in both digital form and on S-VHS video in real time with a video camera.
After both examinations, the bronchoscopists jointly collected biopsy specimens by forceps from all of the lesions identified as suspicious by either modality. Two additional biopsy specimens were taken at random from apparently normal areas identified during both LIFE and WLB procedures (usually the left and right upper lobar orifices). If no suspicious areas were identified during the WLB or LIFE procedures, then we attempted to collect a total of four biopsy specimens from random sites. Biopsy specimens were formalin fixed, paraffin embedded, sectioned, and stained with hematoxylin–eosin.
Histopathologic Examinations
The bronchial specimens were examined histopathologically by one of the authors (W. A. Franklin), who was blinded to the results of the bronchoscopy examinations. Histology results were graded according to a modification of the World Health Organization classification (24), with the following diagnostic scheme: 1) normal, 2) reserve cell hyperplasia, 3) squamous metaplasia, 4) low-grade dysplasia (mild dysplasia), 5) high-grade dysplasia (moderate or severe dysplasia), 6) CIS, and 7) invasive carcinoma (delineated by cell type). Angiogenic squamous dysplasia (Fig. 1
) was diagnosed according to criteria described elsewhere (25). Only those specimens that could be interpreted adequately were included in the analysis.
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On the basis of the histopathologic examination, the primary comparative analyses of the patients or the biopsy specimens were done for two major categories: Patients or biopsy specimens with normal cellular morphology, reserve cell hyperplasia, squamous metaplasia, or low-grade dysplasia were analyzed as one group (considered to be negative), and patients or biopsy specimens with the diagnosis of moderate or severe dysplasia, CIS, or invasive carcinoma were analyzed as the other group (considered to be positive). We also analyzed separately the diagnostic ability of the two procedures to detect metaplasia, dysplasia (mild, moderate, and severe), or CIS. Multiple biopsy specimens (range, two to 14) were taken from all of the patients, and the histopathologic evaluation often revealed different diagnoses at different sites. The final diagnosis for each patient was based on the biopsy specimen with the highest degree of dysplasia or malignancy, regardless of which modality was used when the biopsy specimen was taken. With that site establishing the actual diagnosis for the patient, we compared the WLB and LIFE diagnostic performances.
Statistical Methods
The sensitivity and specificity of both bronchoscopy procedures were calculated in the standard manner (26). Thus, the sensitivity was defined as the ratio (visually suspicious and histologically positive/total number of histologically positive), and the specificity was defined as the ratio (visually normal and histologically negative/total number of histologically negative). Positive predictive values and negative predictive values were also calculated for both WLB and LIFE (26) in a similar manner.
Because one analytic objective was to determine whether LIFE provides any additional benefit when used as an adjunct to WLB, relative sensitivity and relative specificity were also calculated. The relative sensitivity was defined as the ratio of the sensitivity of LIFE alone or WLB and LIFE combined divided by the sensitivity of WLB alone. The relative specificity was defined as the ratio of the specificity of LIFE alone or WLB and LIFE combined divided by the specificity of WLB alone. The detection ratio (DR) was calculated as DR = sensitivity/(1 – specificity). The DR, which is the same as the epidemiologic risk ratio, indicates how much more likely it is to get a positive result in a sample with dysplasia than in a sample without it. It incorporates both the false-positive and the false-negative behaviors of the test in a single statistic, and confidence intervals (CIs) can be calculated for DR in the same way that they can be calculated for the risk ratio (27). SAS version 6.12 (SAS Institute, Cary, NC) was used for all analyses. All statistical tests were two-sided.
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RESULTS |
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TopNotesAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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To compare the WLB and LIFE procedures in a randomized trial, we first selected patients from a pool of subjects at high risk for dysplasia. The study included 42 men and 13 women with a mean cigarette smoking history of 71 pack-years (range, 28–183). There were no differences in the demographic characteristics between individuals who entered the study on the basis of cellular atypia on sputum cytology alone (n = 48) and those who entered on the basis of additional suspicious chest x-ray or CT scan (n = 7) (data not shown). Thus, these groups were combined in all further analyses.
Preneoplastic lesions were detected at high frequency in the study patients. The mean number of sites per patient from which biopsy specimens were taken was 7.2 (range, two to 14). The patients' histologic categorizations were based on the worst histologic diagnosis of the individual biopsy specimens identified by WLB or LIFE (Table 1). Only five patients (9%) of 55 patients had no abnormal biopsy specimens in any of the specimens taken from them. Thirty-two (58%) of 55 patients and 78 (20%) of 391 biopsy specimens had high-grade (moderate or severe) dysplasia or worse. Nineteen (35%) of 55 patients were current smokers, and they contributed 151 (39%) of 391 biopsy specimens. Of the 32 patients with high-grade dysplasia, 11 (34%) were current smokers. Current and former smokers did not differ substantially in the percentage of patients with high-grade dysplasia (21 [58%] of 36 former smokers versus 11 [58%] of 19 current smokers).
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Invasive carcinoma was diagnosed in three patients, one of whom had only microinvasive disease (Fig. 2
). Of note, two of these three patients had been enrolled in the study on the basis of sputum cytology with moderate cellular atypia or worse, with no clinical evidence of cancer before the bronchoscopy procedure (i.e., no clinical signs of cancer and chest radiography without suspicion for malignancy). The other patient had a CT scan that was suspicious for malignancy after the sputum examination but before the bronchoscopy procedure. One patient who was diagnosed with CIS during the bronchoscopy did not have any radiologic evidence of malignancy.
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We next compared the diagnoses made on biopsy specimens identified by either WLB or LIFE or by both procedures. The patients' diagnoses were based on the worst histologic diagnosis of the individual biopsy specimens identified by either procedure and are stratified by WLB or LIFE (Table 2
). LIFE (alone or combined with WLB) detected high-grade dysplasia or worse in 22 (69%; 95% CI == 50% to 84%) of 32 patients Table 2) and in 57 (73%) of 78 biopsy specimens (data not shown). WLB alone detected high-grade dysplasia or worse in seven (22%; 95% CI = 9% to 40%) of 32 patients and in 14 (18%) of 78 biopsy specimens (data not shown). The number of biopsy specimens sampled because of visual abnormalities detected by LIFE alone was 199, it was 58 by WLB alone, and it was 26 by both LIFE and WLB combined. The number of biopsy specimens sampled without any abnormalities detected by LIFE or WLB was 108; in this group, six patients (19%) of a total of 32 and 16 biopsy specimens (15%) had high-grade dysplasia or worse. In conclusion, the LIFE procedure detected more of the high-grade dysplasias in both patients and biopsy specimens.
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We then determined the sensitivity and specificity for diagnosing high-grade dysplasia (Table 3
). The sensitivity of LIFE was statistically significantly better than that of WLB, 68.8% versus 21.9% (difference = 46.9%; 95% CI = 25% to 68%; P<.001 ). The sensitivity of LIFE and WLB combined was statistically significantly better than that of WLB, 81.3% versus 21.9% (difference = 59.4%; 95% CI = 40% to 79%; P<.001). Although the specificity of LIFE was lower than that of WLB, 69.6% versus 78.3%, the difference was not statistically significant (P = .45). However, the specificity of LIFE and WLB combined (47.8%) was statistically significantly less than the specificity of WLB alone (difference = 30.5%; 95% CI = 5% to 60%; P = .02).
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Because of the increase in sensitivity and the decrease in specificity for the LIFE procedure, we next examined the DRs of the bronchoscopy procedures (Table 3
). The DRs when we considered the patient as the unit of analysis were WLB = 1.01 (95% CI = 0.36 to 2.78), LIFE = 2.26 (95% CI = 1.17 to 4.37), and LIFE and WLB combined = 1.56 (95% CI = 1.02 to 2.38). We also determined the relative sensitivities of LIFE alone and of LIFE and WLB combined, which were 3.1 (95% CI = 1.6 to 6.3) and 3.7 (95% CI = 1.9 to 7.3), respectively. The relative specificities of LIFE and of LIFE and WLB combined were 0.9 (95% CI = 0.6 to 1.3) and 0.6 (95% CI = 0.4 to 1.0), respectively—both lower than that of WLB alone. The analyses considering the biopsy specimens as the unit of analysis showed similar trends (data not shown). In conclusion, when the data were analyzed on a per-subject or a per-biopsy basis, LIFE increased the sensitivity for diagnosing high-grade dysplasia or worse over that of the WLB, but it decreased the specificity. However, both LIFE and LIFE combined with WLB had statistically significant DRs, whereas WLB did not.
To determine whether the severity of the abnormalities influenced the sensitivity and specificity, we analyzed the DRs for WLB and LIFE for diagnoses of metaplasia, metaplasia or worse, mild dysplasia or worse, and severe dysplasia or worse by using the biopsy data (Table 4). Too few observations were available to perform this analysis with the patient as the unit of analysis. The DRs were greater for LIFE than for WLB for all categories of disease, except for severe dysplasia (Table 4). For severe dysplasia or worse, the DR for LIFE was 1.66 (95% CI = 0.52 to 5.30), which was similar to that for WLB (1.62; 95% CI = 0.51 to 5.14). However, there were only 16 biopsy specimens with severe dysplasia or worse. Thus, the severity of the lesion did not appear to influence the results because use of the LIFE procedure increased the ability to detect abnormal lesions over use of WLB in all categories, except for severe dysplasia or worse.
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We then evaluated the effect of the order of the bronchoscopy procedure. When the data were analyzed with the biopsy specimens as the units of analysis, there was no difference in the sensitivity, specificity, or DR for either WLB or LIFE, regardless of the order of the procedures (Table 5
, A). The data were also analyzed to determine whether the order of the procedure influenced the individual bronchoscopists. The sensitivities, specificities, and DRs were analyzed for each bronchoscopist, taking into account whether the procedure was done as the first or the second procedure (Table 5, B). For each bronchoscopist, the LIFE procedure had a greater sensitivity and lower specificity than the WLB procedure and, as indicated by the DR, a better overall ability than WLB to detect high-grade dysplasia or worse. Therefore, LIFE and WLB had the same relationship to one another, regardless of the order of the procedures or the operator.
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Finally, the presence of angiogenic squamous dysplasia was associated with the visual bronchoscopic findings and the histopathologic diagnosis. Among 71 biopsy sites with evidence of angiogenic squamous dysplasia, LIFE detected 53 (75%) and WLB detected 11 (16%). However, of the 320 biopsy sites with no evidence of angiogenic squamous dysplasia, 173 were identified as suspicious for dysplasia by LIFE (false-positive rate = 54%) compared with 74 by WLB (false-positive rate = 23%). The sensitivities of LIFE and WLB were 75% and 16%, respectively; when the two procedures were combined, the sensitivity was 90%. However, the specificities of LIFE and WLB were 46% and 77%, respectively; when the two procedures were combined, the specificity was 23%. The positive predictive values were 24% for LIFE, 13% for WLB, and 21% when the procedures were combined. The negative predictive values were 89% for LIFE, 80% for WLB, and 91% when the procedures were combined. The DRs were 1.39 (95% CI = 1.17 to 1.65) for LIFE and 0.67 (95% CI = 0.38 to 1.21) for WLB; when the procedures were combined, the DR was 1.18 (95% CI = 1.07 to 1.3). Thus, LIFE was better than WLB at identifying lesions with angiogenic squamous dysplasia, despite its higher false-positive rate.
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DISCUSSION |
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TopNotesAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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There are no established means for the screening for or the early detection of lung cancer, which is critically important because the majority of patients present with metastatic disease. There are no established biomarkers for use as end points in early detection or chemoprevention trials, and acquisition and analysis of premalignant dysplastic lesions would be an essential requirement for the development of biomarker end points.
A recent study (23) has demonstrated that carcinogens in tobacco produce a field cancerization effect, with progressive genetic and histologic changes in the preneoplastic epithelium. These genetic abnormalities are present even many years after quitting smoking (28). Advances in understanding the cellular and molecular biology of lung cancer should allow for the development of new methods for early intervention with surveillance and chemoprevention strategies that rely on proven biomarkers. In this study, we showed that LIFE increased the ability to detect premalignant changes in the bronchial epithelium of high-risk patients when compared with WLB.
It is well known that standard bronchoscopy (i.e., WLB) is ineffective in detecting premalignant changes in the bronchial epithelium and in detecting early lung cancers (14). This result from the literature is consistent with our finding that WLB has a DR close to 1.0. LIFE has been reported to increase the sensitivity for detecting moderate dysplasia or worse (19,21,22) but not for detecting metaplasia or hyperplasia (20) (Table 6). In most of the studies shown in Table 6, LIFE increased the sensitivity for detecting high-grade lesions, most obviously in those studies reporting a high incidence of dysplasia (19,21,22) and least obviously in those studies reporting a low incidence of dysplasia (20). Several questions were raised by these studies: 1) Does the order of the bronchoscopy procedures and/or the experience of the bronchoscopist affect the results? 2) Does the number of biopsy specimens sampled affect the sensitivity of the procedure? 3) Does LIFE increase the sensitivity only for detecting dysplasia or worse?
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In a study by Lam et al. (19), WLB was done before the LIFE procedure, and the same bronchoscopist performed both examinations. Such a study design may have biased the results in favor of LIFE because knowledge of WLB-identified abnormalities might influence the bronchoscopist to also call a LIFE-identified abnormality in a given area. Furthermore, if a bronchoscopist was biased in favor of LIFE, WLB might be underestimated. To avoid this potential bias, we randomly assigned a single procedure to each bronchoscopist. Differences in the performance of the bronchoscopists did not affect the overall increased sensitivity of LIFE compared with that of WLB. We found that LIFE was more sensitive for detecting all grades of bronchial atypia, including metaplasia, but not for detecting severe dysplasia or worse. The reason for the lack of statistical significance for detecting severe dysplasia or worse was probably due to the small number of patients in this category. Thus, neither the order nor the individual bronchoscopist affected the overall conclusion that LIFE was better able to detect bronchial metaplasia and dysplasia. The results of our study are supported by those of Venmans et al. (21), who also found that the sensitivity of LIFE was greater than that of WLB and not affected by the sequence of the two bronchoscopy procedures. Our study, however, differed from the study by Venmans et al. (21), in that we studied a larger number of patients and biopsy specimens and different bronchoscopists were used for the two procedures.
More biopsy specimens were taken on the basis of abnormalities detected by LIFE than by WLB. This over-sampling could lead to increased sensitivity at the expense of specificity. To address this issue, we used the DRs, which incorporate both sensitivity and specificity, as the statistic for determining the effectiveness of each procedure. Because the number of samples taken and the biopsy results from a patient are not independent, test statistics for the biopsy data should be considered as only descriptive. The per-subject data provide an independent assessment of the results. Therefore, the DRs calculated per subject are our best measure of the effectiveness of the procedure. Taking these statistics into account should adjust for the effect of the increased number of samples because it extracts a penalty for the increased number of false-positive results. Analyses of the DRs demonstrated that LIFE had a better diagnostic ability to detect high-grade dysplasia, irrespective of the number of biopsy specimens taken per subject. For example, 69% of the patients with high-grade dysplasia or worse were identified by LIFE compared with 22% identified by WLB and 19% identified by random sampling.
Although a previous study (29) showed that sputum cytology atypia is a reasonable way to assess risk of lung cancer and is a specific test for establishing a diagnosis of invasive lung carcinoma, it is considered to be a poor screening test (23). However, in a previous screening study (17), 10% of patients with mild to moderate atypia and more than 40% of patients with severe atypia subsequently developed invasive lung cancer. We, therefore, used moderate or worse dysplasia as an end point based on these findings. Clearly, LIFE was better than WLB in the detection of high-grade premalignant changes with respect to overall sensitivity and DRs. In contrast to a study by Kurie et al. (20), we also found that LIFE was superior to WLB in detecting metaplasia or mild dysplasia. The reason for the difference in results might be that, in the study by Kurie et al. (20), relatively few patients had dysplasia and most of the bronchial abnormalities were metaplasias. Moreover, because smoking history and sputum atypia are useful in establishing lung cancer risk, a high-risk population was selected for our study on the basis of a cigarette smoking history of more than 30 pack-years, air-flow obstruction, sputum cytology result of cellular atypia, and/or an abnormal x-ray or CT scan. Our selection of a high-risk population seemed to be effective because 55% of the patients had severe dysplasia or worse and 7% had CIS or invasive cancer. Differences in the study results may also reflect differences in histopathologic evaluation and/or the subjectivity in the interpretation of the bronchoscopy findings. The LIFE was developed originally to detect moderate dysplasia or worse (18) because lesions with hyperplasia or metaplasia often regress spontaneously, whereas lesions with more severe degrees of dysplasia seldom regress (30,31).
Angiogenic squamous dysplasia is a newly recognized morphologic entity commonly found in preneoplastic tissue (25). LIFE detected 75% of the lesions with angiogenic squamous dysplasia. In contrast, WLB detected only 15%. This substantial difference may be explained by the fact that the angiogenic lesions contain hemoglobin, which affects the autofluorescence. To our knowledge, this is the first report that LIFE is superior to WLB for the detection of lesions with angiogenic squamous dysplasia. However, the prognostic implication of this finding—i.e., whether or not this lesion is an indicator of tumor progression—remains undetermined. Ongoing follow-up studies will address this question. These lesions might also be an important target for antiangiogenic chemoprevention therapy.
LIFE may be useful in providing biomarker end points for chemoprevention trials. Previous chemoprevention trials that used the development of lung cancer as an end point required thousands of patients and many years of follow-up to reach definitive answers. The explosion of new molecular and biologic markers and targeted therapies is leading to new targeted chemoprevention studies with biomarker end points (32). LIFE is being incorporated into these trials to assist in the evaluation of the therapies. The morbidity associated with the LIFE procedure is low and does not exceed that for conventional bronchoscopy, therefore making the technique acceptable for early detection and chemoprevention studies. We have not made any cost-effectiveness analyses with the LIFE because we currently use the procedure only as a scientific tool. It remains to be determined whether LIFE will aid in the identification of patients with early-stage disease and will increase the survival rates and/or reduce lung cancer mortality. These issues should be addressed through larger studies with longer follow-up. We did, however, identify three early invasive cancers and one CIS among the 55 patients in this study. Using the LIFE procedure, we identified a patient with microinvasive carcinoma (Fig. 2), a lesion that is hard to identify by conventional bronchoscopy. Thus, we believe that the use of LIFE in the future will allow more frequent identification of patients with microinvasive cancer, which should make curative treatment possible.
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NOTES |
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Editor's note: None of the authors have had any financial interest in Xillix Technologies Corp., Richmond, BC, Canada, the company producing the LIFE, or in Olympus America Inc., Melville, NY, which markets the LIFE bronchoscope.
Supported by Specialized Program of Research Excellence (SPORE) in Lung Cancer, Public Health Service grant P50CA58187, from the National Cancer Institute (NCI), National Institutes of Health, Department of Health and Human Services; by HealthOne Alliance, Denver, CO; by the International Association for the Study of Lung Cancer/Cancer Research Foundation of America Career Development Award to F. R. Hirsch; and by a Preventive Oncology Career Development Award to S. A. Prindiville, Public Health Service grant KO7CA75159 from the NCI.
We thank Susan Proudfoot, Sharolene Goodman, and William W. Moore (Lung Cancer Institute of Colorado/HealthOne Alliance, Denver) and Pam Rosse (University of Colorado Cancer Center, Denver) for data collection and patient care management.
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