3 Evolution of Lung Cancer Screening

Peter M.J. Lee, Samira Shojaee, and Mark S. Parker

Summary

This chapter discusses the evolution of initial unsuccessful early-detection lung cancer-screening programs with sputum cytology and chest radiography and the reasons for their failure to the current state-of-the-art early detection with LDCT (low-dose computed tomography). The natural history of lung cancer, the National Lung Screening Trials (NLST) results, and the endorsement of lung cancer screening for eligible high-risk persons by the U.S. Preventive Services Task Forces (USPSTF) and the Centers for Medicare & Medicaid Services (CMS) are also addressed.

Keywords: lung cancer, screening, cancer growth, chest radiography, sputum cytology, PLCO, NLST, USPSTF, CMS

3.1 What Is Screening?

Screening means testing for diseases, such as lung cancer, while the individual is still healthy, that is, when there are no symptoms or clinical signs of disease. The purpose of the screen is to find disease early on, when treatment options may be more successful, and individuals may have a much better chance of cure. The intent of lung cancer screening is to detect the disease at its earliest possible stage, while it is small, confined to the thorax and before it invades adjacent tissues, extends beyond the lung, and/or causes symptoms, at which point the chance for cure dramatically diminishes and treatment is less successful. The early detection of lung cancer when it is still small and localized is of paramount importance in mortality reduction. Individuals not infrequently undergo other forms of screening for similar purposes (e.g., blood pressure or cholesterol checks; annual mammography; PAP smear; colonoscopy; PSA; etc.).

3.2 Natural History of Lung Cancer

Unfortunately, lung cancer is a “sneaky” disease. It may harbor in the body for years, growing in size and volume, before becoming large enough to be detectable on a conventional radiograph or before it causes symptoms such as cough, hemoptysis, or weight loss ( Fig.3.1). In the absence of screening, most patients already have locally advanced or metastatic disease when they first see their primary care doctor with these or similar symptoms. Only 15 to 25% of patients have potentially resectable, early-stage disease confined to the chest at that time. Over the years, screening for the early detection of lung cancer has included miniature chest photofluorography, conventional chest radiography, sputum cytology, and more recently low-dose helical computed tomography (CT).

3.3 Chest Radiography

The possibility of tobacco as a primary cause for the increasing incidence of lung cancer was introduced in the early 1900s. The first case control study to highlight this association was from a German scholar, Franz Hermann Müller, in 1939. By the 1950s, several epidemiologic studies further supported this link, concluding smoking 35 cigarettes or more per day increased the odds of death by lung cancer by a factor of 40. Concurrently, in the 1940s, mass screening for tuberculosis began using miniature chest photofluorography or abreugraphy. These early X-ray images were a miniature 50- to 100-mm photograph of the screen of an X-ray fluoroscopy of the thorax and were typically viewed on a projector. Screening with chest radiography was instrumental in the early detection of tuberculosis, leading to early appropriate antimicrobial treatment and improved prognosis. As most thoracic tumors were visible on photofluorography, there was a potential for reducing mortality through screening and early treatment with this modality. Early efforts at screening in the 1950s with several large uncontrolled studies showed mixed results. The earliest U.S.-led studies conducted in the 1950s were the Philadelphia Pulmonary Neoplasm Research Project (PNRP) and a cooperative pilot study between the American Cancer Society and the Veterans Administration (VA). Combined, these two studies enrolled 20,743 males older than 45 years to undergo screening with chest radiography every 6 months with a questionnaire regarding smoking habits, occupation, and respiratory symptoms. A total of 194 screen-detected lung cancers were discovered, but only 35% were resectable. Five-year survival in the PNRP and 32-month survival in the VA cooperative were a disappointing 8% and 17%, respectively. The PNRP was also notable for high (24%) 30-day postoperative mortality rates.

Fig. 3.1 Natural history of lung cancer cell growth (Adapted with permission from J. Surg Oncol 1997;65(4):284–297.)

Despite the proportion of earlier screen-detected lung cancers and apparent survival advantage, these early RCTs were flawed and ultimately incapable of determining whether screening for lung cancer is better than no screening at all. They did not have a proper control group, excluded women, lacked power, and did not consistently report operative morbidity and mortality. The lack of mortality benefit in the MLP and Czechoslovakian studies was likely influenced by the above factors in addition to biases such as lead time and overdiagnosis. Furthermore, a Cochrane meta-analysis found a relative mortality increase of 11% attributed to frequent lung cancer screening and determined, based on available data, that there was insufficient evidence to recommend lung cancer screening with chest radiography or sputum cytology.

Fig. 3.2 A 40-year-old male patient with hemoptysis. Posteroanterior chest radiograph reveals a 3.0cm right perihilar mass with welldefined borders. (Reproduced with permission from Hamartoma. In: Parker MS, Rosado-de-Christenson ML, Abbott GF, eds. Chest Imaging Case Atlas. 2nd ed. New York, NY: Thieme; 2012:406-409.)

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