Journal of General Internal Medicine | 2021
Low-Dose Computed Tomographic Screening for Lung Cancer: Time to Implement or Unresolved Questions?
Abstract
prostate, colorectal, and brain cancers. Since most lung cancer patients are identified at advanced stages, with a 5-year survival of <15%, the prospect of screening has garnered much attention. Yet, early results were disappointing. Trials investigating the utility of chest radiography (CXR) and sputum cytology for screening failed to demonstrate a mortality benefit. However, more recent studies assessing low-dose computed tomography (LDCT) have yielded promising results, spurring enthusiasm. These trials also have quantified the magnitude of potential benefit, but also suggest continued unresolved questions. In 2011, the National Lung Screening Trial (NLST) demonstrated a 20% (95% CI, 6.8 to 26.7; P = 0.004) relative reduction in mortality from lung cancer, as well as improved all-cause mortality by 6.7% (95% CI, 1.2 to 13.6; P = 0.02) with LDCT over CXR. Concerns were raised however that the trials’ non-standard control arm may mask potential harms, as well as the fact that the significance of overall mortality in the initial publication was contingent on a numerical imbalance in non-lung cancer deaths. In other words, a difference in nonlung cancer deaths that happened to favor the CT screening arm was necessary for the NSLT to have an overall mortality benefit. For this reason, it is not surprising that in an extended follow-up, the overall mortality benefit is no longer significant (RR 0.97 (95% CI: 0.94–1.01); the difference in the number dying (per 1000) is 4.2 (95% CI: –2.6 to 10.9, p =0.18). Despite these caveats, the United States Preventive Service Task Force (USPSTF) and Canadian Task Force on Preventive Health Care endorsed annual screening LDCT for lung cancer in adults aged 55 to 80 years with a 30 pack-year smoking history who currently smoke or have quit within the past 15 years. Additional evidence from trials like DANTE, ITALUNG, and LUSI (Table 1) failed to demonstrate a significant lung cancer mortality benefit with LDCT. Additionally, no allcause mortality benefit was seen among the screening cohorts. Against this backdrop, the recent publication of the NELSON trial was keenly anticipated. NELSON compared a strategy of four annual screenings with LDCT to no screening among male smokers 50–74 years old, with >15 cigarettes a day for >25 years or >10 cigarettes a day for >30 years and have quit less than 10 years ago. The average number of screening CT scans in the intervention arm was 3.43. At a median follow-up of 10 years, NELSON found that lung cancer mortality was significantly lower among atrisk individuals who underwent LDCT compared with no screening among high-risk patients (2.43% vs 3.17%). At the same time, NELSON raises important concerns. Lung cancer mortality requires adjudication, and attribution of death is not an exact science. An endpoint less prone to interpretation is death from any cancer. In NELSON, this endpoint occurred in 499 of 6612 (7.54%) control arm participants and 478 of 6583 (7.26%) intervention arm participants, a difference that fails to meet nominal significance. All-cause mortality is resistant to observer interpretations, and here too NELSON provides a cautionary note. Despite the 0.74% reduction in lung cancer death, no difference was seen in all-cause mortality between the two groups (13.76% (control) vs 13.93% (screened)) [RR: 1.01 (0.92–1.11)]. Although not powered to assess all-cause mortality, the numerical difference in lung cancer death was not preserved in the all-cause mortality statistic. This result has been observed in other cancer screening trials such as the Minnesota Colon Cancer Control Study. It is important to clarify what this result means. A common misconception is that all-cause mortality is unchanged in cancer screening trials because death is inevitable. While it is true we all die, NELSON suggests that when approximately one in 7 individuals has experienced the event of interest, there was no suggestion death is delayed in the screening arm. At the same time, the study lacks power to render a final verdict on this outcome, so residual uncertainty is present. One notable comparison between the NELSON trial and the NLST is the markedly reduced rate of a positive screening LDCT result in NELSON (2.1% vs 24.2%). This may be explained by what the trials considered as “positive.” The Received November 17, 2020 Accepted April 3, 2021 JGIM