to continue standard of care that did not include any form of screening (control group). After 10 years of follow-up, screening with LDCT resulted in a 24% reduction in lung cancer mortality. Whether volumetric analysis of lung nodules is a superior method of nodule management requires validation in future studies [16]. The MILD trial, an Italian randomized controlled trial comparing LDCT screening with no intervention, reported a 39% reduction in lung cancer mortality at 10 years in the LDCT arm [17]. This trial also compared annual to biannual screening and found no differences, suggesting a less intensive regimen of screening may be as effective. However, this trial was smaller than the other randomized controlled trials and it’s results will have to be validated in further studies.

Benefts and Risks of Lung Cancer

Screening

The bene ts and risks of lung cancer screening using annual LDCT have been summarized by the National Comprehensive Cancer Network (NCCN) guidelines and are shown in Table 17.1 [18]. The major bene t of screening is to reduce mortality by detecting the disease in early stages when curative surgery is still feasible. The main risks include overdiagnosis, false positives, false negatives, radiation, and risk of complications [18].

Table 17.1  Risks and bene ts of lung cancer screening

Overdiagnosis

The large IELCAP study published in 2006 consisted of a single arm, observational study in which all participants underwent screening. Four hundred eighty four out of 59,023 participants were diagnosed with lung cancer, and 85% of them were diagnosed in stage 1. The estimated 10-year survival rate regardless of treatment was 88% (95% CI, 84–91). Critics argued that such positive results were likely due to overdiagnosis, that is, the diagnosis of cancers that would not result in the death of an individual if not detected, and that without a control group to show reduction in mortality it was not possible to accept the effectiveness of lung cancer screening. As previously mentioned, three randomized controlled trials comparing screening with LDCT with a control arm have reported similar results showing signi cant reductions in mortality with the use of LDCT. Although there might be some degree of overdiagnosis, the reduction in lung cancer-­ speci c mortality con rms that lung cancer screening with LDCT is bene cial and that the very signi cant improvements seen in long-term survival rates in observational studies are not due to overdiagnosis.

Furthermore, more than 25 years of research have advanced the understanding of lung nodule subtypes to a point where the radiologic characteristics on LDCT allow for a better distinction

between nodules that are more likely to be cancer from those that are more likely benign. And among those that are likely to be cancer, certain radiologic characteristics such as a ground glass appearance on CT are generally indicative of a more indolent type of tumor that can be managed mostly by close observation (see non-solid nodules below) [19].

Traditionally, the consensus among lung cancer specialists has been that untreated lung cancer­ is universally fatal [18]. However, recent advances in knowledge of the biological behavior of the different subtypes of adenocarcinomas have been translated into different management recommendations of suspicious lung nodules. Low-grade lung cancers known as adenocarcinoma in situ (AIS), formerly known as bronchoalveolar carcinoma, and minimally invasive adenocarcinoma (MIA), are easily identi able on LDCT as they typically present as non-solid nodules. After complete resection, patients with these types of tumors have 100% 5-year disease-­ free survival rates [18, 20, 21]. Most guidelines now recommend follow-up of non-solid nodules even if they are growing. The appearance in fol- low-­up LDCTs of a new solid component in a previously detected non-solid nodule, or the growth of a previously known solid component, should alert to the possibility of invasive adenocarcinoma and prompt a different management strategy.

False Positives

LDCT detects nodules in a high proportion of individuals. In NLST, 27% of participants had non-calci ed nodules of 4 mm or more in diameter [15]. In the IELCAP study, 13% of participants had a positive LDCT, de ned by the presence of one or more non-calci ed nodules of at least 5 mm in diameter [14]. The great majority of nodules detected by LDCT in participants in lung cancer screening programs are considered false positives because they are benign, raising the concern of unnecessary invasive procedures, including surgery. However, after screening numerous participants, the pro-

tocols for the management of nodules used in these studies have resulted in few unnecessary procedures. In the IELCAP study, more than 90% of all invasive diagnostic procedures done resulted in a diagnosis of cancer [12]. In a recent analysis of surgeries performed on participants of the IELCAP cohort, 89% of patients who underwent surgery had a histologic diagnosis of cancer. These low gures of surgical interventions for benign disease have been con rmed by other studies [22].

The American Cancer Society has developed Lung-RADS to standardize LDCT lung examinations (Fig. 17.3). This reporting system has been shown to increase the detection rate of lung cancer while decreasing the rate of false positives to approximately 10% and 5% in baseline and subsequent annual screening rounds, respectively [15, 18]. To expand on this concept and to minimize risks, the NCCN guidelines incorporate recommendations from three of the major protocols: I-ELCAP, NLST, and Lung-RADS [18].

Radiation

In the LDCT studies conducted between 2000 and 2011, the dose of radiation patients received with each screening ranged between 0.8 and 1.5 mSv, about 7 times less than common doses for conventional diagnostic chest CTs at that time, and approximately 10 times that of chest radiography [23]. A study published shortly after the initial lung cancer screening trial results were known, estimated that in the US population, lung cancer screening with LDCT of 50% of the population at risk between the ages of 50 and 75, could result in an increase in the number of cancers induced by radiation by 1.8% [24]. The modelling in this study assumed higher doses of radiation than those currently used with LDCT, and estimated risks of cancer from radiation by extrapolating data from exposures to radiation in survivors of the atomic bombs. Studies that are more recent have suggested that lower doses of radiation result in favorable bene t to risk ratios with greater effects on mortality reduction than on risk of radiation exposure [25, 26].