The Future

While current screening trials rely primarily on imaging studies, other methodologies of early diagnosis are being pursued, although none has been tested in a large trial. Positron emission tomography (PET) with 18-fluorodeoxyglucose identifies malignant tumours on the basis of their increased metabolic rate.^42,43 A 2003 study investigated the efficacy of repeated yearly LDCT and selective use of PET (non-calcified nodules ≥7mm) in 1,035 volunteers for five years. The subjects, aged ≥50 years, had smoked for ≥20 pack-years. By year two, a total of 411 (284 at baseline and 127 at two years) non-calcified nodules were identified, of which 22 (11 in prevalence and 11 in incidence) were lung cancers (17 stage I). PET scans were positive in 18 identified lung cancers – the main reason for biopsy in three of five benign lesions. The authors found selective use of PET to be helpful in replacing fine-needle aspiration biopsy for differential diagnosis.⁴⁴

Mucosal dysplasia, angiogenic squamous dysplasia and carcinoma in situ are considered pre-malignant conditions and to be early stages of invasive lung cancer.⁴⁵ These lesions originate from the mucosal surface and are too small to be detected by any radiographic techniques, but can be visualised by flexible bronchoscopy. Light-induced fluorescence endoscopy (LIFE) employs a blue light rather than a white light for illumination, and pre-malignant and malignant tissue are distinguished from normal tissue by a change in colour.^46,47 While normal bronchial mucosa appears green, pre-malignant and malignant tissue appears brown–red.⁴⁸ Conflicting results were reported about the real advantage of LIFE in detecting abnormal bronchial tissue, so further trials are needed to define its role in the surveillance of patients with a history of lung cancer or with dysplastic cells in their sputum or screened because they are at high risk of lung cancer.^49–52

Sputum immunocytology promises much greater sensitivity than conventional sputum cytology. There is a series of both genetic and molecular alterations found in lung cancers and pre-neoplastic lesions. Polymerase chain reaction and microarray analysis have enabled rapid analysis of DNA isolated from sputum cells to detect genetic changes. The presence of these genetic and molecular changes may be clinically useful in identifying patients with cancer or those at high risk of developing cancer. Identified changes in lung cancer include the detection of loss of heterozygosity, microsatellite alterations or instability, mutations in specific genes, cancer-specific methylation changes and the detection of mutant gene products.^53–55 This suggests that chromosomal analysis may allow for the detection of pre-malignant changes in the airway epithelium long before they would be apparent on CT, and may serve as a high-risk marker for lung cancer. Experiments with the monoclonal antibody 703D4 have shown that overexpression of heterogeneous nuclear ribonucleoprotein A2/B1, a ribonucleic-acid-binding protein, is a powerful predictor of early subclinical cancer in high-risk groups.⁵⁶ The University of Colorado Specialized Program Of Research Excellence is conducting a cohort study to assess sputum cytological and molecular biomarkers in subjects at high risk of lung cancer (≥30 pack-years and chronic obstructive pulmonary disease defined by spirometry). Preliminary results showed that severe atypia or worse cytological changes in the sputum represent a high risk of developing lung cancer within a short time.⁵⁷

Circulating tumour DNA in blood seems a promising way to study biomarkers for early detection of lung cancer. In fact, its presence could appear at the first stage of the disease before a metastasis process. In a study assessing the sensitivity and specificity of a quantitative molecular assay of circulating DNA to identify patients with lung cancer and to monitor their disease, the median concentration of circulating plasma DNA in patients was almost eight times the value detected in controls.⁵⁸ This suggests that plasma-DNA elevation is a strong risk factor for lung cancer.⁵⁹

The role of the biomarkers may be important either to select a population that would require radiological or endoscopic screening programmes, or to recommend more aggressive diagnostic procedures or therapeutic interventions when radiological or endoscopic lesions have been found. Biomarkscan and Depiscan are ongoing protocols to evaluate the role of these biomarkers.⁶⁰

Conclusion

The most effective treatment for lung cancer remains surgical resection of early-stage disease. Lung cancer screening is able to increase the percentage of early-stage disease diagnosis; however, to date no trials have reported a change in lung cancer mortality, the main outcome of screening studies. A recent recommendation statement for lung cancer screening concluded that the current evidence does not support screening for lung cancer with any method. However, these data are also insufficient to conclude that screening does not work.^61,62 From the first screening trials, conducted in the 1950s, which failed to show any benefit in the use of chest X-ray,^14,15,63,64 through to the progression in imaging techniques, molecular biology knowledge and increasing sophistication in trial design, methodologies for future lung cancer screening programmes are promising (see Table 1).

In conclusion, considering that the risk of lung cancer increases with the number of cigarettes smoked, years of smoking duration, earlier age at onset of smoking, degree of inhalation, tar and nicotine content, the use of unfiltered cigarettes and passive smoking, and that it decreases in proportion to the number of years after smoking cessation,⁶⁵ while waiting and hoping for current and future improved lung cancer screening results, it is best to increase the primary prevention – promoting smoking cessation.