Tobacco Smoking and Risk of Second Primary Lung Cancer

Abstract

Introduction: Lung cancer survivors are at high risk of developing a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined the risk factors for SPLC across multiple epidemiologic cohorts and evaluated the impact of smoking cessation on reducing SPLC risk.

Methods: We analyzed data from 7059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 3423 IPLC cases) and European Prospective Investigation into Cancer and Nutrition (N = 4731 IPLC cases) cohorts and pooled the SPLC risk estimates using random effects meta-analysis.

Results: Overall, 163 MEC cases (2.3%) developed SPLC. Smoking pack-years (hazard ratio [HR] = 1.18 per 10 pack-years, p < 0.001) and smoking intensity (HR = 1.30 per 10 cigarettes per day, p < 0.001) were significantly associated with increased SPLC risk. Individuals who met the 2013 U.S. Preventive Services Task Force's screening criteria at IPLC diagnosis also had an increased SPLC risk (HR = 1.92; p < 0.001). Validation studies with the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and European Prospective Investigation into Cancer and Nutrition revealed consistent results. Meta-analysis yielded pooled HRs of 1.16 per 10 pack-years (p_meta < 0.001), 1.25 per 10 cigarettes per day (p_meta < 0.001), and 1.99 (p_meta < 0.001) for meeting the U.S. Preventive Services Task Force's criteria. In MEC, smoking cessation after IPLC diagnosis was associated with an 83% reduction in SPLC risk (HR = 0.17; p < 0.001).

Conclusions: Tobacco smoking is a risk factor for SPLC. Smoking cessation may reduce the risk of SPLC. Additional strategies for SPLC surveillance and screening are warranted.

Keywords: Screening; Second primary lung cancer; Smoking cessation; Surveillance; Tobacco smoking.

Figure 1.. Forest Plots of Associations Between Smoking-Related Factors and Second Primary Lung Cancer in the Multiethnic Cohort.

The smoking-SPLC associations were evaluated among (A) all IPLC cases (N=7,059) and (B) early-stage (I-III) IPLC cases (N=2,806). Smoking-related data were collected from the baseline questionnaire or 10-year follow-up questionnaire prior to IPLC diagnosis, if available. Meeting the 2013 USPSTF criteria was determined at IPLC diagnosis. All variables were evaluated in individual cause-specific proportional hazards models accounting for the competing risk of death. Models for all-stage IPLC cases adjusted for age at IPLC diagnosis, IPLC histology, and IPLC stage; models for early-stage IPLC cases adjusted for age at IPLC diagnosis and IPLC histology. Abbreviations: SPLC second primary lung cancer, IPLC initial primary lung cancer, N sample size, USPSTF United States Preventive Services Task Force, HR hazard ratio, CI confidence interval, vs. versus.

Figure 2.. Sensitivity Analyses for Associations Between Categorical (A) Smoking Pack-Years and (B) Cigarettes Per Day and Second Primary Lung Cancer in the Multiethnic Cohort.

All risk estimates were generated from cause-specific proportional hazards models adjusting for age at IPLC diagnosis, IPLC histology, and IPLC stage and accounting for the competing risk of death. Abbreviation: CI confidence interval.

Figure 3.. Meta-Analyses of Associations Between Smoking-Related Factors and Second Primary Lung Cancer Across MEC, PLCO, and EPIC.

Cause-specific proportional hazards models accounting for the competing risk of death from all causes were used to evaluate the risk of second primary lung cancer by (A) smoking per 10 pack-years, (B) smoking per 10 cigarettes per day, and (C) meeting the 2013 USPSTF screening criteria, adjusting for IPLC age at diagnosis, stage, and histology in MEC and PLCO and by IPLC age at diagnosis and histology in EPIC. Abbreviations: MEC Multiethnic Cohort; PLCO Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; EPIC European Prospective Investigation into Cancer and Nutrition; USPSTF United States Preventive Services Task Force; IPLC initial primary lung cancer; SE standard error; HR hazard ratio; CI confidence interval.

Figure 4.. Smoking Cessation and Risk of Second Primary Lung Cancer in the Multiethnic Cohort (N=156).

Participants in this subset analysis were current smoking at baseline, had 10-year follow-up smoking data, and were diagnosed with an initial primary lung cancer before follow-up. Participants who reported that they were “former” smoking at 10-year follow-up were classified as undergoing smoking cessation (“yes”), whereas those who reported that they were “current” smoking at 10-year follow-up were classified as not undergoing smoking cessation (“no”). Participants were followed for the development of SPLC after 10-year follow-up. This cumulative incidence plot was generated using Gray’s method, accounting for the competing risk of death from all causes. Abbreviations: N sample size, SPLC second primary lung cancer, IPLC initial primary lung cancer.