Impact of Comorbidities on the Mortality Benefits of Lung Cancer Screening: A Post-Hoc Analysis of the PLCO and NLST Trials.

Abstract

Objectives: To evaluate how comorbidities affect mortality benefits of lung cancer screening (LCS) with low-dose computed tomography.

Methods: We developed a comorbidity index (Prostate, Lung, Colorectal, and Ovarian comorbidity index [PLCO-ci]) using LCS-eligible participants' data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial (training set) and the National Lung Screening Trial (NLST) (validation set). PLCO-ci predicts five-year non-lung cancer (LC) mortality using a regularized Cox model; with performance evaluated using the area under the receiver operating characteristics curve. In NLST, LC mortality (per original publication) was compared between low-dose computed tomography and chest radiograph arms across the PLCO-ci quintile (Q1-5) using a cause-specific hazard ratio (csHR) with 95% confidence intervals (CIs).

Results: Analyses included 34,690 PLCO and 53,452 NLST participants (mean age: 62 y [±5 y] and 61 y [±5 y], 58% and 59% male individuals, and 39% and 41% active smokers, respectively). PLCO-ci predicted five-year non-LC mortality with an area under the receiver operating characteristics curve of 0.72 (95% CI: 0.71-0.74) in PLCO and 0.69 (95% CI: 0.67-0.70) in NLST. In NLST, at a median follow-up of 6.5 years, LC mortality was significantly reduced for participants with intermediate comorbidity (Q2, Q3, and Q4): csHR 0.62 (95% CI: 0.41-0.95), 0.68 (95% CI: 0.48-0.96), and 0.72 (95% CI: 0.54-0.96) respectively, with a nonstatistically significant reduction for Q1 (csHR = 0.72, 95% CI: 0.45-1.17) and no reduction for Q5 participants (csHR = 0.99, 95% CI: 0.79-1.23). Participants in Q2, Q3, and Q4 (60%) accounted for 89% of LC deaths averted among all NLST participants. Q1 participants had low LC incidence, whereas Q5 had higher localized LC lethality, more squamous cell carcinomas, and untreated LC.

Conclusions: The PLCO-ci developed in this work shows that individuals with intermediate comorbidity benefited the most from LCS, highlighting the need of addressing comorbidities to achieve LC mortality benefits.