Low-dose CT for lung cancer screening: opportunities and challenges

Abstract

Lung cancer is among the most frequently diagnosed cancers worldwide and the leading cause of cancer death in both males and females. Screening for lung cancer coupled with earlier intervention has long been studied as an approach to mortality reduction. However, minimal progress was achieved until recently, when low-dose spiral computed tomography (LDCT) screening demonstrated a 20% reduction in mortality from lung cancer in a randomized controlled trial (RCT), the National Lung Screening Trial, from the United States. On the basis of this finding, LDCT has been recommended for lung cancer screening in high-risk populations by several clinical guidelines. However, results from the following independent RCTs in Europe failed to show consistent conclusions. In addition, intractable problems gradually emerged with the progress of LDCT screening. This paper summarizes and discusses the main observations and challenges of LDCT screening for lung cancer. Before spreading implementation of LDCT screening, challenges, including high false-positive rates, overdiagnosis, enormous costs, and radiation risk, must be addressed. Complementary biomarkers and technical improvement are expected in the field of lung cancer screening in the near future.

Keywords

lung cancer / low-dose computerized tomography / early detection / opportunities / challenges

Introduction

Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer death for males and females combined around the world, with an estimation of 1.8 million new cases and 1.59 million deaths in 2012 [1,2]. Notably, more than one-third of newly diagnosed lung cancer and related deaths occurred in China [3]. Although biomedical technologies have undergone considerable development in the past decades, the five-year survival rate for lung cancer remains around 18% [4]. This sobering outlook primarily results from the fact that the majority of patients have already reached advanced stages at the time of diagnosis.

From the 1970s, several studies have evaluated the benefits of screening for lung cancer by using chest radiograph (CXR) with or without sputum cytology [5,6]. However, these methods showed limited efficacy in reduction of lung cancer mortality. Computerized tomography (CT) has been clinically used since the mid-1970s [7], and advances in CT technology that followed allowed for scanning of the entire chest in a single breath-hold with spiral low-dose CTs (LDCTs), reviving the interest in imaging-based lung cancer screening [8]. In the early 1990s, single-arm trials from Japan and the United States (US) showed that screening for lung cancer with LDCT may detect not only more cancers but also the stage shift toward earlier and resectable cancer types, and related results can possibly improve lung cancer survival [9,10].

To adjust inherent biases of screening and to provide direct evidence of effectiveness for lung cancer screening with LDCT, several randomized controlled trials (RCT) have been initiated since the beginning of the 2000s (Table 1) [11–21]. Among these trials, the National Lung Screening Trial (NLST) was the most influential project with the largest sample size of 53 454 high-risk participants between September 2002 and April 2004 [20]. Eligible participants in the NLST were 55–74 years of age at the time of randomization and presented smoking history of at least 30 pack-years. In a follow-up after approximately six years, 356 lung cancer deaths occurred among the 26 722 subjects in the LDCT arm versus 443 deaths among 26 732 subjects in the CXR arm. These numbers indicated a reduction of 20% (95% confidence interval, 6.8 to 26.7; P = 0.004) in the LDCT group. On the basis of favorable findings from this study, the American Cancer Society, the American College of Chest Physicians, the American Society of Clinical Oncology, and the National Comprehensive Cancer Network (NCCN) recommended that LDCT for lung cancer screening should be offered to those who meet the NLST criteria [22]. Notably, the NLST criteria are not immutable and completely accepted by all professional societies or organizations. For example, the US Preventive Services Task Force expanded the recommendation to persons up to age 80 years who meet other criteria for screening based on the evaluation model for benefits and harms of screening programs [23]. NCCN recommended that persons featuring an additional lung cancer risk factor (such as asbestos exposure, pulmonary fibrosis, and chronic obstructive pulmonary disease) should also be included in this screening even when they claim a smoking history of less than 30 pack-years [24].

However, several other RCTs (such as the DANTE Trial, DLCST, and MILD) in Europe showed no contribution to mortality reduction, although more early-stage cancers were detected in the LDCT arm [11,13,17]. The inconsistent results probably resulted from the small sample size, inadequate follow-up, or heterogeneity of inclusion criteria [25]. A few RCTs with relatively large sample sizes are still ongoing in Europe and Asia; these RCTs include the Nederlands–Leuvens Longkanker Screenings Onderzoek trial in the Netherlands and Belgium, with 7557 participants randomized to receive CT screening [18] and the Japanese randomized trial, which aimed to recruit 17 500 subjects for each arm [26]. In the near future, these trails will provide more evidence and reference for the public, doctors, and policy makers. In China, a demonstration program of lung cancer screening, which recruited participants based on their smoking history, age distribution, and other risk factors (such as indoor air pollution in Xuanwei), was initiated in 2010 [27]. This program will help in evaluating the feasibility of conducting population-based LDCT screening in the Chinese context.

While the prospects of LDCT in lung cancer screening may be promising, several challenges exist for implementation of LDCT screening in populations.

High rates of false-positive screens

In the NLST trial, which defined a positive screen as any noncalcified nodule with a diameter of at least 4 mm in any radiographic images, 96.4% of positive screening results in the LDCT group and 94.5% in the CXR group yielded false-positive results [20]. Similar results were also reported in other studies, with more than 90% of nodules finally confirmed to be benign [11,14–16]. Tests that distinguish malignant nodules from the benign are imperfect and can subject patients to unnecessary procedures and anxiety. In the reports, 1.2% of patients without lung cancer underwent an unnecessary biopsy or bronchoscopy in the NLST trial [22]. In recent years, several studies have demonstrated that utility of Lung Imaging Reporting and Data System criteria can significantly decrease false-positive rates. Aside from this method, using three-dimensional volume measurements in addition to nodule diameter and constructing risk stratification models by using clinical characteristics and nodule characteristics may also aid in reducing false-positive rates [19,28,29].

Overdiagnosis

The concept of overdiagnosis remains confusing to date, yet it mainly refers to histologically confirmed lung cancers identified through screening that will not affect the patient’s lifetime if left untreated [22]. LDCT screening mainly saves the lives of patients with fast-growing cancers (usually doubling times of 50–150 days), whereas about 27% of the detected cancers exhibited doubling times over 400 days in the Mayo CT trial [30]. For these patients, avoidance of diagnosis and treatment may be appropriate when other clinical factors are more likely to affect life expectancy. Within the CT arm of the NLST, overdiagnosis rate of lung cancer was estimated to be 18.5% [31]. Similar findings were also observed in the DLCST 13. Management of pulmonary nodule, considering growth rate through follow-up (e.g., three months), may be helpful in reducing overdiagnosis rate [18]. The author expect that awareness of this issue will help reduce unnecessary surgery for these indolent cancers.

Cost effectiveness

Cost effectiveness is the major consideration for policy makers before expanding the use of LDCT screening. Results from the NLST showed that screening with LDCT cost an additional $1631 per person and provided an additional 0.032 life-year and 0.020 quality-adjusted life-year (QALY) per person. This finding indicated that cost per life-year and per QALY reaches $52 000 and $81 000, respectively [32]. This cost is far more expensive than that in colon cancer (approximately $56 800 per QALY) but less than the cost for breast cancer screening (approximately $107 346 per QALY) [33–35]. However, incremental cost-effectiveness ratio showed a prominent decrease in females ($46 000 per QALY), patients 60–69 years old ($48 000–$52 000 per QALY), and those in the two highest-risk quintiles of lung cancer ($32 000–$52 000 per QALY), according to NLST results [32]. Considering the potential enormous high-risk population, the cost will enlarge when we spread implementation of LDCT screening nationally. A total of 320 people must be screened to avoid one lung cancer death based on the NLST program [20]. These findings highlighted the opportunity of LDCT in public use outside the trial, given that we can refine the definition of high-risk population appropriately. Aside from age and cigarette smoking, which are the only two factors used in the NLST, genetic susceptibility variants of lung cancer from genome-wide association studies may be significant in building risk stratification models in the future [36].

Radiation risks

Risk of radiation exposure is another concern widely discussed in LDCT screening. Comparatively, a standard dose of diagnosed CT usually approximates 7 mSv, and an LDCT scan delivers approximately 1.5 mSv of radiation, whereas ambient radiation exposure associated with inhabiting planet Earth is estimated at 3 mSv per year [37,38]. The threshold radiation dose potentially associated with carcinogenesis is estimated at 50 mSv, and approximately 1–3 lung cancer deaths are induced by radiation risk per 10 000 people scanned in the NLST [20]. This potential harm further emphasized the necessity of RCT in LDCT screening and gave rise to consideration of whether every person in high-risk populations should continue with their annual scans and how to reduce radiation exposure resulting from false positives. In the future, RCT with different intervals and improved nodule evaluation protocols will probably provide more suggestions in determining optimal screening frequency and follow-up pattern. Fortunately, ultra LDCT (ULDCT), which is usually defined as CT with an effective dose of less than 1 mSv, has been recently shown to feature comparable quality with lower noise and streak artifacts than LDCT or common CT [39]. Independent RCT based on ULDCT may provide valuable suggestions in the near future.

Other challenges

In addition to abnormal opacities detected in the lungs, LDCT scans may also identify abnormalities, such as coronary calcifications, aneurysms, and mediastinal tumors, in other organs [38,40]. Such findings may cause anxiety and lead to additional testing and intervention. On the way to expanding LDCT screening outside of clinical trials, numerous obstacles must be cleared. Robust resources and an eligible medical team are the basic guarantees for a clinical screening program. To date, most RCTs are performed in large medical centers of excellence, whereas most screenings will be done in primary hospitals in the future when recommended. The expertise of radiologists will probably affect screening results and lead to more complicated conditions [41]. In addition, whether the medical insurance can cover costs of LDCT screening also poses a challenge for some developing countries, including China.

The aforementioned debates on whether the implementation of LDCT screening should be spread may continue in the years to come when these uncertainties cannot be resolved. LDCT screening aims to detect early lung cancer patients who are suited for curative treatment. However, promoting smoking cessation should not be overlooked as it is the most cost-effective preventive measure in reducing deaths from lung cancer. More importantly, new biomarkers in the blood, urine, sputum, or mucosa are currently under development [42]. These harmless biomarkers will probably be utilized for initial screening test in high-risk populations to reduce the number of individuals who must undergo LDCT screenings in the future.

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