Inflammatory status and lung function predict mortality in lung cancer screening participants

Ugo Pastorino, Daniele Morelli, Alfonso Marchianò, Stefano Sestini, Paola Suatoni, Francesca Taverna, Mattia Boeri, Gabriella Sozzi, Anna Cantarutti, Giovanni Corrao, Ugo Pastorino, Daniele Morelli, Alfonso Marchianò, Stefano Sestini, Paola Suatoni, Francesca Taverna, Mattia Boeri, Gabriella Sozzi, Anna Cantarutti, Giovanni Corrao

Abstract

Low-dose computed tomography (LDCT) screening trials have based their risk selection algorithm on age and tobacco exposure, but never on pulmonary risk-related biomarkers. In the present study, the baseline inflammatory status, measured by C-reactive protein (CRP) level, and lung function, measured by forced expiratory volume in 1 s (FEV1), were tested as independent predictors of all-cause mortality in LDCT-screening participants. Between 2000 and 2010, 4413 volunteers were enrolled in two LDCT-screening trials, with evaluable baseline CRP and FEV1 values: 2037 were included in the discovery set and 2376 were included in the validation set. The effect of low FEV1 or high CRP alone or combined was evaluated by Kaplan-Meier mortality curves and hazard ratio (HR) with 95% confidence interval (CI) by fitting Cox proportional hazards models. The overall mortality risk was significantly higher in participants with FEV1 of up to 90% (HR: 2.13, CI: 1.43-3.17) or CRP more than 2 mg/l (HR: 3.38, CI: 1.60-3.54) and was still significant in the fully adjusted model. The cumulative 10-year probability of death was 0.03 for participants with FEV1 of more than 90% and CRP up to 2 mg/l, 0.05 with only FEV1 of up to 90% or CRP above 2 mg/l, and 0.12 with FEV1 of up to 90% and CRP above 2 mg/l. This predictive performance was confirmed in the two external validation cohorts with 10-year mortality rates of 0.06, 0.12, and 0.14, and 0.03, 0.07, and 0.14, respectively. Baseline inflammatory status and lung function reduction are independent predictors of all-cause long-term mortality in LDCT-screening participants. CRP and FEV1 could be used to select higher-risk individuals for future LDCT screening and preventive programs.

Figures

Fig. 1
Fig. 1
Cumulative 10-year probabilities of death for participants who had no [forced expiratory volume in 1 s (FEV1)>90% and C-reactive protein (CRP) ≤2 mg/l], one (FEV1≤90% or CRP>2 mg/l), or two (FEV1≤90% and CRP>2 mg/l) predictors. All the 2037 participants of the low-dose computed tomography arms of the Multicentric Italian Lung Detection (MILD) trial are included in the discovery set.
Fig. 2
Fig. 2
Cumulative 10-year probabilities of death of the 1001 participants in the pilot low-dose computed tomography cohort (a) and of the 1375 participants in the Multicentre Italian Lung Detection (MILD) control cohort (b) who had no [forced expiratory volume in 1 s (FEV1)>90% and C-reactive protein (CRP)≤2 mg/l], one (FEV1≤90% or CRP>2 mg/l), or two (FEV1≤90% and CRP>2 mg/l) predictors. LDCT, low-dose computed tomography.
Fig. 3
Fig. 3
Cumulative 10-year probabilities of lung cancer death for patients who had 0 [forced expiratory volume in 1 s (FEV1)>90% and C-reactive protein (CRP)≤2 mg/l], one (FEV1≤90% or CRP>2 mg/l), or two (FEV1≤90% and CRP>2 mg/l) predictors.

References

    1. Ake CF, Carpenter AL. Survival analysis with PHREG: using MI and MIANALYZE to accommodate missing data. Available at: ; 2010.
    1. Bach PB, Mirkin JN, Oliver TK, Azzoli CG, Berry DA, Brawley OW, et al. (2012). Benefits and harms of CT screening for lung cancer: a systematic review. JAMA 307:2418–2429.
    1. Calabro E, Randi G, La Vecchia C, Sverzellati N, Marchianò A, Villani M, et al. (2010). Lung function predicts lung cancer risk in smokers: a tool for targeting screening programmes. Eur Respir J 35:146–151.
    1. Carter BD, Abnet CC, Feskanich D, Freedman ND, Hartge P, Lewis CE, et al. (2015). Smoking and mortality – beyond established causes. N Engl J Med 372:631–640.
    1. Cozlea DL, Farcas DM, Nagy A, Keresztesi AA, Tifrea R, Cozlea L, Caraca E. (2013). The impact of C reactive protein on global cardiovascular risk on patients with coronary artery disease. Curr Health Sci J 39:225–231.
    1. Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. (2007). C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 175:250–255.
    1. Esfahanian F, Zamani MM, Heshmat R, Moininia F. (2013). Effect of metformin compared with hypocaloric diet on serum C-reactive protein level and insulin resistance in obese and overweight women with polycystic ovary syndrome. J Obstet Gynaecol Res 39:806–813.
    1. Field JK, Duffy SW, Baldwin DR, Whynes DK, Devaraj A, Brain KE, et al. (2016). UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening. Thorax 71:161–170.
    1. Ford ES, Cunningham TJ, Mannino DM. (2015). Inflammatory markers and mortality among US adults with obstructive lung function. Respirology 20:587–593.
    1. Harris JE, Thun MJ, Mondul AM, Calle EE. (2004). Cigarette tar yields in relation to mortality from lung cancer in the cancer prevention study II prospective cohort, 1982–8. BMJ 328:72.
    1. Infante M, Sestini S, Galeone C, Marchianò A, Lutman FR, Angeli E, et al. (2016). Lung cancer screening with low-dose spiral computed tomography: evidence from a pooled analysis of two Italian randomized trials. Eur J Cancer Prev [Epub ahead of print].
    1. Kaplan EL, Meier P. (1958). Nonparametric estimation from incomplete observations. J Am Statist Assoc 53:457–481.
    1. Kawashima M, Murakawa T, Shinozaki T, Ichinose J, Hino H, Konoeda C, et al. (2015). Significance of the Glasgow Prognostic Score as a prognostic indicator for lung cancer surgery. Interact Cardiovasc Thorac Surg 21:637–643.
    1. Kim HT. (2007). Cumulative incidence in competing risks data and competing risks regression analysis. Clin Cancer Res 13:559–565.
    1. Lahousse L, Loth DW, Joos GF, Hofman A, Leufkens HGM, Brusselle GG, Stricker BH. (2013). Statins, systemic inflammation and risk of death in COPD: the Rotterdam study. Pulm Pharmacol Ther 26:212e–217e.
    1. Lahousse L, Loth DW, Joos GF, Hofman A, Leufkens HG, Brusselle GG, Stricker BH. (2013). Statins, systemic inflammation and risk of death in COPD: the Rotterdam study. Pulm Pharmacol Ther 26:212–217.
    1. Lee TM, Lin MS, Chang NC. (2008). Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. Am J Cardiol 101:530–535.
    1. Leuzzi G, Galeone C, Gisabella M, Duranti L, Taverna F, Suatoni P, et al. (2016). Baseline C-reactive protein level predicts survival of early-stage lung cancer: evidence from a systematic review and meta-analysis. Tumori 102:441–449.
    1. Leuzzi G, Galeone C, Taverna F, Suatoni P, Morelli D, Pastorino U. (2017). C-reactive protein level predicts mortality in COPD: a systemic review and meta-analysis. Eur Respir Rev 26:160070.
    1. Marsik C, Kazemi-Shirazi L, Schickbauer T, Winkler S, Joukhadar C, Wagner OF, Endler G. (2008). C-reactive protein and all-cause mortality in a large hospital-based cohort. Clin Chem 54:343–349.
    1. Muezzinler A, Mons U, Gellert C, Schöttker B, Jansen E, Kee F, et al. (2015). Smoking and all-cause mortality in older adults: results from the CHANCES consortium. Am J Prev Med 49:e53–e63.
    1. National Lung Screening Trial Research Team, Aberle DR, Adams AM, Berg CD, Black WC, Clapp JD, Fagerstrom RM, et al. (2011). Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med 365:395–409.
    1. Park ER, Gareen IF, Japuntich S, Lennes I, Hyland K, DeMello S, et al. (2015). Primary care provider-delivered smoking cessation interventions and smoking cessation among participants in the national lung screening trial. JAMA Intern Med 175:1509–1516.
    1. Pastorino U, Bellomi M, Landoni C, De Fiori E, Arnaldi P, Picchio M, et al. (2003). Early lung-cancer detection with spiral CT and positron emission tomography in heavy smokers: 2-year results. Lancet 362:593–597.
    1. Pastorino U, Rossi M, Rosato V, Marchiano A, Sverzellati N, Morosi C, et al. (2012). Annual or biennial CT screening versus observation in heavy smokers: 5-year results of the MILD trial. Eur J Cancer Prev 21:308–315.
    1. Pastorino U, Boffi R, Marchiano A, Sestini S, Munarini E, Calareso G, et al. (2016). Stopping smoking reduces mortality in low-dose computed tomography screening participants. J Thorac Oncol 11:693–699.
    1. Pozzi P, Munarini E, Bravi F, Rossi M, La Vecchia C, Boffi R, Pastorino U. (2015). A combined smoking cessation intervention within a lung cancer screening trial: a pilot observational study. Tumori 101:306–311.
    1. Ridker PM. (2003). Cardiology Patient Page. C-reactive protein: a simple test to help predict risk of heart attack and stroke. Circulation 108:e81–e85.
    1. Ridker PM. (2008). High-sensitivity C-reactive protein as a predictor of all-cause mortality: implications for research and patient care. Clin Chem 54:234–237.
    1. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. (2005). C-Reactive protein levels and outcomes after statin therapy. N Engl J Med 352:20–28.
    1. Shrotriya S, Walsh D, Bennani-Baiti N, Thomas S, Lorton C. (2015). C-reactive protein is an important biomarker for prognosis tumor recurrence and treatment response in adult solid tumors: a systematic review. PLoS One 10:e0143080.
    1. Sozzi G, Boeri M, Rossi M, Verri C, Suatoni P, Bravi F, et al. (2014). Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD trial study. J Clin Oncol 32:768–773.
    1. Tammemagi MC. (2015). Application of risk prediction models to lung cancer screening: a review. J Thorac Imaging 30:88–100.
    1. Tanner NT, Kanodra NM, Gebregziabher M, Payne E, Halbert CH, Warren GW, et al. (2016). The association between smoking abstinence and mortality in the national lung screening trial. Am J Respir Crit Care Med 193:534–541.
    1. Thun MJ, Carter BD, Feskanich D, Freedman ND, Prentice R, Lopez AD, et al. (2013). 50-year trends in smoking-related mortality in the United States. N Engl J Med 368:351–364.
    1. Wang L, Zhang LF, Wu J, Xu SJ, Xu YY, Li D, et al. (2014). IL-1beta-mediated repression of microRNA-101 is crucial for inflammation-promoted lung tumorigenesis. Cancer Res 74:4720–4730.
    1. Wille MM, Dirksen A, Ashraf H, Saghir Z, Bach KS, Brodersen J, et al. (2016). Results of the randomized Danish lung cancer screening trial with focus on high-risk profiling. Am J Respir Crit Care Med 193:542–551.
    1. Young RP, Hopkins R, Eaton TE. (2009). Pharmacological actions of statins: potential utility in COPD. Eur Respir Rev 18:222–232.
    1. Young RP, Hopkins RJ, Targeted BN, Image CT. (2013). Screening and its effect on lung cancer detection rate. Chest 144:1419–1420.
    1. Young RP, Duan F, Greco E, Hopkins RJ, Chiles C, Gamble GD, Aberle D. (2016). Lung cancer-specific mortality reduction with CT screening: outcomes according to airflow limitation in the ACRIN NLST sub-study (n=18 475). Am J Respir Crit Care Med 193:A6166.
    1. Zacho J, Tybjaerg-Hansen A, Nordestgaard BG. (2010). C-reactive protein and all-cause mortality – the Copenhagen City Heart Study. Eur Heart J 31:1624–1632.
    1. Zhang XL, Chi YH, Wang LF, Wang HS, Lin XM. (2014). Systemic inflammation in patients with chronic obstructive pulmonary disease undergoing percutaneous coronary intervention. Respirology 19:723–729.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere