Abstract
Background and aim
Many pieces of literature have evaluated the predictive value of pre-existing lung interstitial changes for immunotherapy-related pneumonia in patients with non-small cell lung cancer (NSCLC), but the results of studies are still controversial. The purpose of this article is to explore whether pre-existing lung interstitial changes can predict the occurrence of immunotherapy-related pneumonia.
Methods
PubMed, Web of Science, and Embase were used to search for relevant documents. Two investigators respectively carried out literature screening, quality evaluation, and data extraction strictly according to the inclusion criteria. Odds ratios (ORs) and the corresponding 95% CIs were applied to assess the predictive value of interstitial lung disease (ILD), interstitial lung abnormalities (ILA), and radiation pneumonitis (RP). Stata 12.0 software was used for the statistical analysis of data.
Results
Seventeen studies involving 2758 patients were included in the final analysis. NSCLC patients with pulmonary interstitial changes were more likely to develop immune-related pneumonia after immunotherapy (OR = 3.68, 95% CI: 2.49–5.44). Subgroup analysis revealed that ILD (OR = 3.59, 95% CI: 2.22–5.82), RP (OR = 3.63, 95% CI: 1.80–7.30), and ILA (OR = 6.64, 95% CI: 1.78–24.8) were all predictors of immune-related pneumonia. As the preliminary screening of other risk factors, gender, neutrophilic lymphocyte ratio (NLR), actual eosinophil count (AEC), and drug type may have potential predictive value for immunotherapy-related pneumonia. There was no significant statistical heterogeneity and publication bias in our study. Further research is needed to update and validate our results.
Conclusion
Pulmonary interstitial changes can be considered as a predictive factor of immune-related pneumonia after immunotherapy in NSCLC patients.
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References
Ascierto PA, Del Vecchio M, Mandalá M, Gogas H, Arance AM, Dalle S, Cowey CL, Schenker M, Grob JJ, Chiarion-Sileni V, Márquez-Rodas I, Butler MO, Maio M, Middleton MR, de la Cruz-Merino L, Arenberger P, Atkinson V, Hill A, Fecher LA, Millward M, Khushalani NI, Queirolo P, Lobo M, de Pril V, Loffredo J, Larkin J, Weber J (2020) Adjuvant nivolumab versus ipilimumab in resected stage IIIB-C and stage IV melanoma (CheckMate 238): 4-year results from a multicentre, double-blind, randomised, controlled, phase 3 trial. Lancet Oncol 21:1465–1477
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin 68:394–424
Cho JY, Kim J, Lee JS, Kim YJ, Kim SH, Lee YJ, Cho YJ, Yoon HI, Lee JH, Lee CT, Park JS (2018) Characteristics, incidence, and risk factors of immune checkpoint inhibitor-related pneumonitis in patients with non-small cell lung cancer. Lung Cancer (Amsterdam, Netherlands) 125:150–156
Chu X, Zhao J, Zhou J, Zhou F, Jiang T, Jiang S, Sun X, You X, Wu F, Ren S, Zhou C, Su C (2020) Association of baseline peripheral-blood eosinophil count with immune checkpoint inhibitor-related pneumonitis and clinical outcomes in patients with non-small cell lung cancer receiving immune checkpoint inhibitors. Lung Cancer (Amsterdam, Netherlands) 150:76–82
Ettinger DS, Wood DE, Aggarwal C, Aisner DL, Akerley W, Bauman JR, Bharat A, Bruno DS, Chang JY, Chirieac LR, D’Amico TA, Dilling TJ, Dobelbower M, Gettinger S, Govindan R, Gubens MA, Hennon M, Horn L, Lackner RP, Lanuti M, Leal TA, Lin J, Loo BW Jr, Martins RG, Otterson GA, Patel SP, Reckamp KL, Riely GJ, Schild SE, Shapiro TA, Stevenson J, Swanson SJ, Tauer KW, Yang SC, Gregory K, Hughes M (2019) NCCN guidelines insights: non-small cell lung cancer, Version 1.2020. J Nat Comprehens Cancer Network: JNCCN 17:1464–1472
Fujimoto D, Yomota M, Sekine A, Morita M, Morimoto T, Hosomi Y, Ogura T, Tomioka H, Tomii K (2019) Nivolumab for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia: A multicenter, open-label single-arm phase II trial. Lung Cancer (Amsterdam, Netherlands) 134:274–278
Fukihara J, Sakamoto K, Koyama J, Ito T, Iwano S, Morise M, Ogawa M, Kondoh Y, Kimura T, Hashimoto N, Hasegawa Y (2019) Prognostic impact and risk factors of immune-related pneumonitis in patients with non-small-cell lung cancer who received programmed death 1 inhibitors. Clin Lung Cancer 20:442-450.e444
Gomatou G, Tzilas V, Kotteas E, Syrigos K, Bouros D (2020) Immune checkpoint inhibitor-related pneumonitis. Respiration 99:932–942
Hata H, Mio T, Yamashita D, Matsumura C, Chisaki Y, Motohashi H, Yano Y (2020) Factors associated with efficacy and nivolumab-related interstitial pneumonia in non-small cell lung cancer: a retrospective survey. Cancer Control 27:1073274820977200
Hatabu H, Hunninghake GM, Lynch DA (2019) Interstitial lung abnormality: recognition and perspectives. Radiology 291:1–3
Hatabu H, Hunninghake GM, Richeldi L, Brown KK, Wells AU, Remy-Jardin M, Verschakelen J, Nicholson AG, Beasley MB, Christiani DC, San José Estépar R, Seo JB, Johkoh T, Sverzellati N, Ryerson CJ, Graham Barr R, Goo JM, Austin JHM, Powell CA, Lee KS, Inoue Y, Lynch DA (2020) Interstitial lung abnormalities detected incidentally on CT: a Position Paper from the Fleischner Society. Lancet Respir Med 8:726–737
Hayden JA, Côté P, Bombardier C (2006) Evaluation of the quality of prognosis studies in systematic reviews. Ann Intern Med 144:427–437
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ (Clin Res ed) 327:557–560
Hubbard R, Venn A, Lewis S, Britton J (2000) Lung cancer and cryptogenic fibrosing alveolitis A population-based cohort study. Am J Respir Critic Care Med 161:5–8
Ikeda S, Kato T, Kenmotsu H, Ogura T, Iwasawa S, Iwasawa T, Kasajima R, Miyagi Y, Misumi T, Yamanaka T, Okamoto H (2020) A phase II study of atezolizumab for pretreated advanced/recurrent non-small cell lung cancer with idiopathic interstitial pneumonias: rationale and design for the TORG1936/AMBITIOUS study. Therapeut Adv Med Oncol 12:1758835920922022
Isono T, Kagiyama N, Takano K, Hosoda C, Nishida T, Kawate E, Kobayashi Y, Ishiguro T, Takaku Y, Kurashima K, Yanagisawa T, Takayanagi N (2021) Outcome and risk factor of immune-related adverse events and pneumonitis in patients with advanced or postoperative recurrent non-small cell lung cancer treated with immune checkpoint inhibitors. Thorac cancer 12:153–164
Kanai O, Kim YH, Demura Y, Kanai M, Ito T, Fujita K, Yoshida H, Akai M, Mio T, Hirai T (2018) Efficacy and safety of nivolumab in non-small cell lung cancer with preexisting interstitial lung disease. Thoracic Cancer 9:847–855
Komiya K, Nakamura T, Abe T, Ogusu S, Nakashima C, Takahashi K, Kimura S, Sueoka-Aragane N (2019) Discontinuation due to immune-related adverse events is a possible predictive factor for immune checkpoint inhibitors in patients with non-small cell lung cancer. Thoracic Cancer 10:1798–1804
Lederer DJ, Martinez FJ (2018) Idiopathic pulmonary fibrosis. N Engl J Med 378:1811–1823
Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr, Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G (2019) Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, phase 3 trial. Lancet (London, England) 393:1819–1830
Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, Chaft JE, Segal NH, Callahan MK, Lesokhin AM, Rosenberg J, Voss MH, Rudin CM, Rizvi H, Hou X, Rodriguez K, Albano M, Gordon RA, Leduc C, Rekhtman N, Harris B, Menzies AM, Guminski AD, Carlino MS, Kong BY, Wolchok JD, Postow MA, Long GV, Hellmann MD (2017) Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol 35:709–717
Nakahama K, Tamiya A, Isa SI, Taniguchi Y, Shiroyama T, Suzuki H, Inoue T, Tamiya M, Hirashima T, Imamura F, Atagi S (2018) Association between imaging findings of airway obstruction adjacent to lung tumors and the onset of interstitial lung disease after nivolumab. In Vivo (Athens, Greece) 32:887–891
Nakanishi Y, Masuda T, Yamaguchi K, Sakamoto S, Horimasu Y, Nakashima T, Miyamoto S, Tsutani Y, Iwamoto H, Fujitaka K, Miyata Y, Hamada H, Okada M, Hattori N (2019) Pre-existing interstitial lung abnormalities are risk factors for immune checkpoint inhibitor-induced interstitial lung disease in non-small cell lung cancer. Respir Investig 57:451–459
Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS (2016) Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncology 2:1607–1616
Okada N, Matsuoka R, Sakurada T, Goda M, Chuma M, Yagi K, Zamami Y, Nishioka Y, Ishizawa K (2020) Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: a single-institution retrospective study. Scientif Rep 10:13773
Omori T, Tajiri M, Baba T, Ogura T, Iwasawa T, Okudela K, Takemura T, Oba MS, Maehara T, Nakayama H, Tsuboi M, Masuda M (2015) Pulmonary resection for lung cancer in patients with idiopathic interstitial pneumonia. Ann Thorac Surg 100:954–960
Raghu G, Nyberg F, Morgan G (2004) The epidemiology of interstitial lung disease and its association with lung cancer. Br J Cancer 91(Suppl 2):S3-10
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M, Rao S, Hotta K, Vandormael K, Riccio A, Yang J, Pietanza MC, Brahmer JR (2019) Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol 37:537–546
Shibaki R, Murakami S, Matsumoto Y, Yoshida T, Goto Y, Kanda S, Horinouchi H, Fujiwara Y, Yamamoto N, Kusumoto M, Yamamoto N, Ohe Y (2020) Association of immune-related pneumonitis with the presence of preexisting interstitial lung disease in patients with non-small lung cancer receiving anti-programmed cell death 1 antibody. Cancer Immunol, Immunother 69:15–22
Shimoji K, Masuda T, Yamaguchi K, Sakamoto S, Horimasu Y, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Takeno S, Hide M, Teishima J, Ohdan H, Hattori N (2020) Association of preexisting interstitial lung abnormalities with immune checkpoint inhibitor-induced interstitial lung disease among patients with nonlung cancers. JAMA Network Open 3:e2022906–e2022906
Shimoji K, Masuda T, Yamaguchi K, Sakamoto S, Horimasu Y, Nakashima T, Miyamoto S, Iwamoto H, Fujitaka K, Hamada H, Takeno S, Hide M, Teishima J, Ohdan H, Hattori N (2021) Association of pre-existing interstitial lung abnormalities with immune checkpoint inhibitor-induced interstitial lung disease among patients with non-lung cancers. Ann Oncol 32:S302–S302
Suazo-Zepeda E, Bokern M, Vinke PC, Hiltermann TJN, de Bock GH, Sidorenkov G (2021) Risk factors for adverse events induced by immune checkpoint inhibitors in patients with non-small-cell lung cancer: a systematic review and meta-analysis Cancer Immunol Immunother 70(11):3069–3080
Sugano T, Seike M, Saito Y, Kashiwada T, Terasaki Y, Takano N, Hisakane K, Takahashi S, Tanaka T, Takeuchi S, Miyanaga A, Minegishi Y, Noro R, Kubota K, Gemma A (2020) Immune checkpoint inhibitor-associated interstitial lung diseases correlate with better prognosis in patients with advanced non-small-cell lung cancer. Thorac Cancer 11:1052–1060
Tamiya A, Tamiya M, Nakahama K, Taniguchi Y, Shiroyama T, Isa SI, Inoue T, Okishio K, Nishino K, Kumagai T, Suzuki H, Hirashima T, Imamura F, Atagi S (2017) Correlation of radiation pneumonitis history before nivolumab with onset of interstitial lung disease and progression-free survival of patients with pre-treated advanced non-small cell lung cancer. Anticancer Res 37:5199–5205
Tasaka Y, Honda T, Nishiyama N, Tsutsui T, Saito H, Watabe H, Shimaya K, Mochizuki A, Tsuyuki S, Kawahara T, Sakakibara R, Mitsumura T, Okamoto T, Kobayashi M, Chiaki T, Yamashita T, Tsukada Y, Taki R, Jin Y, Sakashita H, Natsume I, Saitou K, Miyashita Y, Miyazaki Y (2021) Non-inferior clinical outcomes of immune checkpoint inhibitors in non-small cell lung cancer patients with interstitial lung disease. Lung Cancer (Amsterdam, Netherlands) 155:120–126
Tzilas V, Bouros D (2019) Interstitial lung abnormalities: a word of caution. Chest 156:1037–1038
Washko GR, Hunninghake GM, Fernandez IE, Nishino M, Okajima Y, Yamashiro T, Ross JC, Estépar RS, Lynch DA, Brehm JM, Andriole KP, Diaz AA, Khorasani R, D’Aco K, Sciurba FC, Silverman EK, Hatabu H, Rosas IO (2011) Lung volumes and emphysema in smokers with interstitial lung abnormalities. N Engl J Med 364:897–906
Weber JS, D’Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH Jr, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J (2015) Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol 16:375–384
Whittaker Brown S-A, Padilla M, Mhango G, Powell C, Salvatore M, Henschke C, Yankelevitz D, Sigel K, de-Torres JP, Wisnivesky J (2019) Interstitial lung abnormalities and lung cancer risk in the national lung screening trial. Chest 156:1195–1203
Yamaguchi O, Kaira K, Shinomiya S, Mouri A, Hashimoto K, Shiono A, Miura Y, Akagami T, Imai H, Kobayashi K, Kagamu H (2021) Pre-existing interstitial lung disease does not affect prognosis in non-small cell lung cancer patients with PD-L1 expression ≥50% on first-line pembrolizumab. Thoracic Cancer 12:304–313
Yamaguchi T, Shimizu J, Hasegawa T, Horio Y, Inaba Y, Hanai N, Muro K, Hida T (2021) Pre-existing interstitial lung disease is associated with onset of nivolumab-induced pneumonitis in patients with solid tumors: a retrospective analysis. BMC cancer 21:924
Yu X, Zhang X, Yao T, Zhang Y, Zhang Y (2021) Fatal adverse events associated with immune checkpoint inhibitors in non-small cell lung cancer: a systematic review and meta-analysis. Front Med 8:627089
Funding
This present research was funded by the National Natural Science Foundation of China (to Richeng Jiang) (No. 81372517) and the Nature Science Foundation of Tianjin City (to Richeng Jiang) (No. 18JCZDJC 98800).
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X. Q. and R. C. designed and performed the study, and wrote the manuscript. Z. N. and X. Y. extracted the information and assisted in information collection and analysis. Z. J. and Q. H. revised the manuscript critically and confirmed correct data analysis.
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Fig. S1
Sensitivity analysis plot for 14 studues considering ILD and ICI-pneumonia. (PNG 526 kb)
Fig. S2
Forest plot of odds ratios for the association between other risk factors and ICI-pneumonia. (A). association between age and ICI-pneumonia. (B). association between gender and ICI-pneumonia. (C). association between ECOG and ICI-pneumonia. (D). association between smoking and ICI-pneumonia. (E). association between pathology and ICI-pneumonia. (F). association between treatment line and ICI-pneumonia. (G). association between chest radiation and ICI-pneumonia. (H). association between drug type and ICI-pneumonia. (I). association between CRP and ICI-pneumonia. (J). association between WBC and ICI-pneumonia. (K). association between NLR and ICI-pneumonia. (L). association between AEC and ICI-pneumonia. (M). association between LDH and ICI-pneumonia. (N). association between ALB and ICI-pneumonia. (PNG 1939 kb)
Fig. S3
Forest plot of odds ratios for subgroup analysis of the association between lung interstitial changes and ICI-pneumonia according to study type. (PNG 48 kb)
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Chen, X., Li, Z., Wang, X. et al. Association of pre-existing lung interstitial changes with immune-related pneumonitis in patients with non-small lung cancer receiving immunotherapy. Support Care Cancer 30, 6515–6524 (2022). https://doi.org/10.1007/s00520-022-07005-6
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DOI: https://doi.org/10.1007/s00520-022-07005-6