Lung Cancer Screening: Adjuncts and Alternatives to Low-Dose CT Scans

Rolando Sanchez Sanchez 0 Nichole T. Tanner 0 Nasar A. Siddiqi 0 Gerard A. Silvestri 0 0 R. S. Sanchez N. T. Tanner N. A. Siddiqi G. A. Silvestri (&) Division of Pulmonary and Critical Care, Department of Internal Medicine, Allergy and Sleep Medicine, Medical University of South Carolina , 96 Jonathan Lucas Street, Suite 812-G, Charleston, SC 29425, USA Lung cancer (LC) is the leading cause of cancer related mortality in US. The National Lung Screening Trial has demonstrated a mortality benefit of using low-dose computed tomography (LDCT) in the screening of LC in high-risk individuals. The US Preventive Service Task Force has given screening for LC with LDCT a grade B recommendation; however, it recognizes gaps in generalizability to the population that would qualify for screening. There are a number of new tests in various stages of evaluation and development that hold promise as adjuncts or alternatives to LDCT. The following is a review of these novel diagnostic tests. - Lung cancer (LC) is the leading cause of cancer-related mortality in the US, causing more deaths than breast, prostate and colon cancer combined [1]. The median 5-year survival for all comers in US is *16 % [1]. The median 5-year survival for stage I and II LC, however, ranges from 50 to 70 %, making early detection desirable for decreasing LC mortality [1]. Investigations into effective screening with methods including chest radiograph (CXR) and sputum cytology alone and in combination were unable to demonstrate any impact on LC mortality [2, 3]. In 2011, the results from the National Lung Screening Trial (NLST) were published. This was the first large scale multicenter randomized trial that convincingly demonstrated a mortality benefit by screening high-risk individuals with low-dose computed tomography (LDCT) scans [4]. The following reviews the evidence and limitations of LC screening with LDCT, and describes the potential use of new techniques in LC screening as adjuncts and alternatives to LDCT. Low Dose Helical Computed Tomography (LDCT) Over the last two decades, technical advances have improved the quality of image acquisition and diagnostic yield of computed tomography (CT). The multidetector helical CT, for example, is able to image the entire lung during a single breath hold, using a lower radiation dose than standard CT. The initial studies demonstrated an increased rate of lung nodule detection and higher percentage of detected early-stage LCs with LDCT compared to CXR. Study design, however, precluded conclusions as to the impact of the use of LDCT in LC mortality, because the studies either lacked a control group, were underpowered, or did not have adequate follow-up time [511]. The NLST [4] was designed to detect a 20 % reduction in mortality by LDCT LC screening, with a 90 % power. It included 33 centers across the US, and enrolled 53,454 current or former smokers aged 5574 years, with a minimum 30-pack-year smoking history. Former smokers had quit within the past 15 years. The participants were randomly assigned to screening with LDCT (n = 26,722) or CXR (n = 26,732) annually for three screens. The LDCT screenings were consider positive if they revealed a noncalcified nodule measuring at least 4 mm in longest diameter, and CXR screens were positive if they revealed any noncalcified nodule or mass. The median follow-up period was over 6.5 years. The LDCT-screened group had a higher rate of positive screening tests compared with the CXR group (24.2 vs. 6.9 %). However, the rate of false positive results was high (96.4 % in the LDCT group and 94.5 % in the CXR group). LDCT detected more LC compared to CXR (1,060 vs. 941). Among the patients diagnosed with LC, the LDCT group had significantly more stage I cancers (63 vs. 47.6 %). There were also fewer patients with stage III and IV LCs in the LDCT group compared to the CXR group (29.8 vs. 43.2 %). At the end of the follow-up period, there were 354 LC deaths in the LDCT group and 442 deaths in the CXR group. The LC rate mortality was 247 per 100,000 person-years in the LDCT group, and 309 per 100,000 person-years in the CXR group (a 20 % reduction in mortality in the LDCT group). The overall mortality was reduced by 6.7 %, largely due to the reduction in deaths from LC. The number needed to screen with low-dose CT to prevent one death from LC was 320 [4], which is comparable to the number of women needed to screen with mammography to save one life from breast cancer [12]. Potential Shortcomings of LDCT Screening Generalizability of NLST Results Although randomized controlled studies are considered the most robust method to assess efficacy (performance under ideal conditions), one of their main limitations is their ability to evaluate effectiveness (performance under real conditions). Randomized controlled trials require more standardized and higher levels of medical care than occurs in real practice. In addition, the trial participants are usually not fully representative of the eventual target group [13]. Such is true for the NLST cohort that, when compared to the US population eligible for screening based on trial entry criteria, was younger, healthier, better educated, and more frequently former smokers [4]. It is therefore unclear if the same mortality benefit will be recognized with large-scale LC screening implementation. In the NSLT, screening with LDCT had a high rate of false positive results (96 %) and low positive predicted value (\ 4 %). Despite this, few medical complications occurred during diagnostic evaluation for positive screens (*1.4 %). This may be due in some part to the location of care in the NLST. Participants were enrolled in urban, tertiary care hospitals with expertise in all aspects of cancer care, including dedicated thoracic radiologists. The majority of positive screens were followed with serial imaging without need for invasive testing. In contrast, community practice gives rise to the potential for considerable variation in the management of solitary pulmonary nodules identified by screening LDCT. One study demonstrated a two-fold variation among geographic regions in the use of CT-guided biopsy, ranging from 14.7 to 36.2 per 100,000 adults [14, 15]. This variation in management of solitary pulmonary nodules may lead to an increased number of invasive procedures with risk of harm. In addition, the psychological harms of a positive test result should not be underestimated. Studies of breast and prostate cancer screening showed that false-positive screening results were associated with depression and change in selfperception of health status [16, 17]. There are, however, ways to decrease the high falsepositive rate from screening with LDCT. Investigators from the NELSON study [18] improved the sensitivity, specificity, positive and negative predictive value of the LDCT for LC screening through the use of semi-automated volumetric software to measure diameter and volume doubling time (VDT). Gr (...truncated)