Lung Cancer Section Prepared by:
Edward Patz, M.D.
Department of Radiology
Duke Medical Center
September 22, 1998
Lung cancer is the leading cause of cancer death for men and women in the United States, and more people die annually of lung cancer than of colon cancer, breast cancer, and prostate cancer combined. Screening trials with chest radiographs and/or sputum cytology, even targeted at high risk individuals, has so far been ineffectual. It is becoming increasingly clear that effective screening will depend not only on early detection, but a complimentary understanding of the biology of this disease. Even very small tumors can metastasize early and ultimately lead to death in most patients. This reflects the tremendous spectrum of biologic behavior of lung cancer, even among tumors with identical histologic classification. To believe that only larger and undifferentiated tumors metastasize is naive. Tumor cells are directly contiguous with "leaky" abnormal blood vessels and are probably continuously shed into the blood. The ability to seed distant sites and grow is likely dependent on genes which control cell adhesion, migration, and invasion, most of which are yet unknown or poorly characterized.
The most common early radiologic manifestation of lung cancer is a pulmonary nodule, and now with the requisite resolution of CT, very small lesions ( ~ 1mm; representing ~1,000,000 tumor cells) can be seen. This results in a significantly improvement over chest radiographs which typically identifies 1 cm lesions (~1 billion cells; much later in the biology of this disease).
Although CT is an extremely sensitive non-invasive study used to identify and localize lung cancer, the specificity is less than optimal. Differentiating benign from malignant lesions can be difficult because of the overlap in radiographic manifestations. Many small nodules remain indeterminate despite thorough radiological evaluation. In these cases, patients may be followed which might lead to progression of disease, or they may proceed to an invasive procedure for a tissue diagnosis because of the concern for cancer. These invasive procedures, including percutaneous, bronchoscopic or surgical biopsy, always have associated morbidity and expense. A non-invasive functional study which could compliment anatomic imaging would have tremendous clinical significance.
The Task Force discussed two basic issues confronting screening and early detection trials:
If studies are to be constructed then both of these issues need to be addressed. It was decided that justification of a high-risk population was required. At this time it would probably include those who are smokers and possibly individuals with emphysema. Unfortunately, an increasing proportion of lung cancer patients are nonsmokers but until a better way of constructing trials and identifying high risk individuals is established, this appears to be the most logical group of individuals to screen.
The second issue discussed focused on the methods for screening. It is apparent that cost-effective, easy, noninvasive, readily available methods are essential for mass screening programs. Although some trials have included bronchoscopy particularly with the LIFE bronchoscope, this realistically will not be acceptable for mass screening. These invasive tools may be helpful for diagnostic purposes only.
At this time it appears there are three potential areas where noninvasive studies might be developed:
As above, imaging with CT can detect very small lesions, but CT lacks specificity and alone probably will not be able to provide the requisite information for a screening test. CT needs to be complimented with other noninvasive studies. This may include the development of tumor specific imaging agents which is a difficult but promising area of research with tremendous potential. If the appropriate targets could be identified, then imaging agents could not only localize sites of tumor, but produce a "tumor profile", correlating to the biologic behavior.
Another potential method would be to use currently available techniques (CT), in combination with blood or sputum biomarkers to predict the probability and then the behavior of lung cancer. While there multiple biomarkers have been tested, none so far have been used in the appropriate trials demonstrating clinical applicability. However, integration of biomarkers with imaging studies may serve as a new model system for screening trials. This will not only provide us with increased specificity but hopefully we will be able to create a "tumor profile" thus determining some of the biologic activity and possible therapeutic strategies for treating these patients.
If we are to move forward with creating early detection screening trials we must integrate imaging with understanding of molecular medicine. There are studies which can be constructed at this time with the appropriate modeling systems and statistical design.
Methodology and Modeling Section Prepared by:
Constantine Gatsonis, PhD
Center for Biostatistics
April 27, 1998