Thermodetection of Lung Cancer-Hot Stuff?

In the hopes of improving on the dismal 15% 5-year survival rates of lung cancer, early detection has been a focus of much study, discussion and debate over the past 30 years. Following the disappointing results of several large trials with chest x-ray screening in the 1970s,1-4 renewed interest in lung cancer screening has emerged in view of advancements in diagnostic tools such as autofluorescence bronchoscopy,5 low dose CT scans6,7 and sputum analysis.8 The study presented by Votruba and Bruha in this issue of the Journal of Bronchology describes a novel approach to detection of endobronchial malignancies.9 The authors used a contact thermometer to measure temperature of mucosa involved with tumor or overlying enlarged lymph nodes seen on CT scans and compared them with temperature of normal mucosa. They found that mean temperature overlying cancerous mucosa was 0.78°C higher than normal mucosa. As well, the mucosal temperature adjacent to enlarged lymph nodes was 0.52°C higher than normal. Mean differences across patients may not discriminate between malignant and normal areas given substantial overlap in temperature measurements as seen in Figure 1. Redefining abnormal areas as those demonstrating increased temperature in a given patient would appear to be more promising as there is no overlap in the 95% confidence intervals of temperature differences of ipsilateral normal mucosa vs. malignant areas as compared to normal contralateral sites (Fig. 2). This suggests that temperature differences between sites in a given individual are more discriminating than absolute temperature cutoffs.FIGURE 1: Mean temperature at 4 sites.FIGURE 2: Temperature differences between sites.The authors theorize that differences in temperature could be exploited to design new instruments aimed at improving early lung cancer diagnosis or to direct transbronchial sampling of lymph nodes. Although these findings are intriging enough to warrant proceeding with further studies, this must be seen as a very early phase in a long course of investigation. Using a contact probe to scan a large area of the tracheobronchial tree would be cumbersome at best and may be better served, as suggested by the authors, by a visual “infrared bronchoscope” with which the airway could be scanned visually analogous to autofluorescence devices. The interest of such devices in lung cancer screening would be to detect early lesions (ie, carcinoma-in-situ or high grade dysplasias) although this did not appear to have been the focus of this study. It remains to be seen whether these early lesions also demonstrate measurable temperature differences. As far as using temperature changes to guide lymph node biopsies, the authors will need to confirm malignant involvement of the lymph nodes, as CT is known to have only moderate specificity in determining if an enlarged node is malignant or reactive.10 One could easily theorize that mucosa overlying reactive lymph nodes would also have increased temperature. This technique to guide transbronchial needle biopsy of mediastinal nodes would also have to show advantages over real time endobronchial ultrasound which has recently been shown to be highly sensitive.11 These early findings suggest that thermodetection may now be added to the list of tools in development to assist bronchoscopist in the detection of lung malignancies. As new bronchoscopic technology continues to evolve in this field, two major scientific challenges will continue to be debated. The first and most important issue relates to the implications and overall impact of early diagnosis of lung cancer and its influence on outcomes. We disagree with the authors' statement that the detection of lung cancer in the early stages necessarily improves survival. Previous randomized screening studies did in fact detect more early stage cancers but this did not lead to an improvement in mortality from this disease.12 The uncertainty over this issue is even larger when dealing with endobronchial detection of high grade dysplasia and CIS lesions for which the natural history and treatment options are still under investigation.13,14 We are not aware of any studies even considering the impact of detection and treatment of early lesions on lung cancer mortality, although investigators using AFB are beginning to study other clinically significant outcomes such as pre-operative lung cancer staging.15 It would seem unethical to recommend to the billions of citizens at risk for lung cancer worldwide to undergo invasive tests for early detection of lung cancer prior to demonstrating a positive impact on a meaningful clinical outcome. The second issue relates specifically to endobronchial detection and the lack of gold standards for comparing new devices. The only currently approved device specifically aimed at early endobronchial diagnosis is AFB which may seem the natural benchmark for comparing upcoming technologies as it is proven to have increased relative sensitivity over white light bronchoscopy in the detection of early lesions.5 The relative sensitivity of autofluorescence has been based on comparisons with fiberoptic bronchoscopy, no longer the standard of care in many institutions. It remains to be proven whether autofluorescence bronchoscopy has a similar increased sensitivity over video bronchoscopy. We also question the use of relative sensitivity as primary endpoint in the evaluation of these devices. White light and video bronchoscopes have never been touted to be useful devices for early detection of lung cancer, have an unknown sensitivity to do so, and as such are an inappropriate control group for new devices for this indication. The relative sensitivity of a test has little meaning if nothing is known of the actual sensitivity of the device it is being compared to. Given that AFB is the first device designed for the detection of endobronchial dysplasia and CIS, the initial question which needs to be answered is its true sensitivity. The true sensitivity of AFB remains unclear despite many years of study. We are aware of only one study which attempted to determine the true sensitivity of AFB by performing careful pathological examination of specimens obtained from lung cancer resection surgery.16 These investigators found that AFB detected only 50% of dysplastic lesions within the reach of the bronchoscope, suggesting that a large number of lesions will be missed by AFB. That many lesions are missed with AFB is confirmed by the frequent finding of high grade lesions in normal appearing “control” biopsies.5 Given that ideal screening tests should be highly sensitive, AFB would not seem to be well suited to the task and its use may be better suited for other indications such as staging and evaluation of patients with abnormal sputum cytology. That industry is not willing or able to fund large prospective trials of new medical technologies with significant clinical outcome measures as primary endpoints is not surprising given that this type of data is not required for regulatory approval of medical devices. The responsibility then falls on the bronchoscopy community to carry out this research prior to recommending new technology to our patients and colleagues or implementing them into our own general clinical practice.

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