The utility of ground-glass attenuation score for anticancer treatment-related acute exacerbation of interstitial lung disease among lung cancer patients with interstitial lung disease

  • Naoki Nishiyama
  • Takayuki Honda
  • Manabu Sema
  • Tatsuo Kawahara
  • Yasuto Jin
  • Ichiro Natsume
  • Tomoshige Chiaki
  • Takaaki Yamashita
  • Yoshikazu Tsukada
  • Reiko Taki
  • Yoshihiro Miyashita
  • Kazuhito Saito
  • Tomoya Tateishi
  • Hiroyuki Sakashita
  • Yasunari MiyazakiEmail author
Original Article



Acute exacerbation (AE) of interstitial lung disease (ILD) is a fatal adverse event in the treatment of lung cancer patients with ILD. The value of pre-treatment radiological findings obtained by high-resolution computed tomography for the detection of anticancer treatment-related AE of ILD has not been established.


Two medical record-based retrospective studies were performed. The chemotherapy cohort included 105 lung cancer patients with ILD who received chemotherapy at Tokyo Medical and Dental University between October 2008 and December 2017. The immune checkpoint inhibitor (ICI) cohort included 48 advanced non-small cell lung cancer patients with ILD treated with ICIs at nine institutions between January 2016 and September 2018. Variables were compared between AE-positive and -negative groups. Candidate variables were analyzed by multivariate logistic regression. A P value < 0.05 was considered statistically significant.


Anticancer treatment-related AE of ILD occurred in 12 patients (11.4%) in the chemotherapy cohort and seven patients (14.5%) in the ICI cohort. In the multivariate logistic regression analysis, ground-glass attenuation (GGA) score was the only factor significantly associated with the development of AE of ILD in both cohorts (P = 0.037 and 0.01 in the chemotherapy and ICI cohorts, respectively).


Evaluation of GGA may help predict anticancer treatment-related AE of ILD.


Acute exacerbation Chemotherapy HRCT score Interstitial pneumonia Immune checkpoint inhibitor 



The authors would like to thank Y Sakakibara, Y Wakai, Y Watanabe, T Tsutsui, T Yagi, S Yamashita, and M Doi for cooperation in collecting data. We also thank T Mitsumura and R Sakakibara for useful comments and suggestions.

Compliance with ethical standards

Conflict of interest

Yasunari Miyazaki received lecture fees from Nippon Boehringer Ingelheim Co., Ltd.

Supplementary material

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Supplementary file2 (PDF 7366 kb)
10147_2019_1576_MOESM3_ESM.docx (24 kb)
Supplementary file3 (DOCX 24.1 kb)


  1. 1.
    Raghu G, Nyberg F, Morgan G (2004) The epidemiology of interstitial lung disease and its association with lung cancer. Br J Cancer 91:S3. CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Le Jeune I, Gribbin J, West J et al (2007) The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med 101(12):2534–2540. CrossRefPubMedGoogle Scholar
  3. 3.
    Sato T, Teramukai S, Kondo H et al (2014) Impact and predictors of acute exacerbation of interstitial lung diseases after pulmonary resection for lung cancer. J Thorac Cardiovasc Surg 147(5):1604–1611.e1603. CrossRefPubMedGoogle Scholar
  4. 4.
    Omori T, Tajiri M, Baba T et al (2015) Pulmonary resection for lung cancer in patients with idiopathic interstitial pneumonia. Ann Thorac Surg 100(3):954–960. CrossRefPubMedGoogle Scholar
  5. 5.
    Kenmotsu H, Naito T, Kimura M et al (2011) The risk of cytotoxic chemotherapy-related exacerbation of interstitial lung disease with lung cancer. J Thorac Oncol 6(7):1242–1246. CrossRefPubMedGoogle Scholar
  6. 6.
    Kanai O, Kim YH, Demura Y et al (2018) Efficacy and safety of nivolumab in non-small cell lung cancer with preexisting interstitial lung disease. Thorac Cancer 9(7):847–855. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hanibuchi M, Kakiuchi S, Atagi S et al (2018) A multicenter, open-label, phase II trial of S-1 plus carboplatin in advanced non-small cell lung cancer patients with interstitial lung disease. Lung Cancer 125:93–99. CrossRefPubMedGoogle Scholar
  8. 8.
    Kakiuchi S, Hanibuchi M, Tezuka T et al (2017) Analysis of acute exacerbation of interstitial lung disease associated with chemotherapy in patients with lung cancer: a feasibility of S-1. Respir Investig 55(2):145–152. CrossRefPubMedGoogle Scholar
  9. 9.
    Chen YJ, Chen LX, Han MX et al (2015) The efficacy and safety of chemotherapy in patients with nonsmall cell lung cancer and interstitial lung disease: a prisma-compliant bayesian meta-analysis and systematic review. Medicine (Baltimore) 94(36):e1451. CrossRefGoogle Scholar
  10. 10.
    Ott PA, Bang YJ, Piha-Paul SA et al (2019) T-Cell-Inflamed gene-expression profile, programmed death ligand 1 expression, and tumor mutational burden predict efficacy in patients treated with pembrolizumab across 20 cancers: KEYNOTE-028. J Clin Oncol 37(4):318–327. CrossRefPubMedGoogle Scholar
  11. 11.
    Yamaguchi T, Shimizu J, Hasegawa T et al (2018) Pre-existing pulmonary fibrosis is a risk factor for anti-PD-1-related pneumonitis in patients with non-small cell lung cancer: a retrospective analysis. Lung Cancer 125:212–217. CrossRefPubMedGoogle Scholar
  12. 12.
    Shibaki R, Murakami S, Matsumoto Y et al (2019) Tumor expression and usefulness as a biomarker of programmed death ligand 1 in advanced non-small cell lung cancer patients with preexisting interstitial lung disease. Medical Oncol (Northwood, Lond, Engl) 36(6):49. CrossRefGoogle Scholar
  13. 13.
    Fujimoto D, Morimoto T, Ito J et al (2017) A pilot trial of nivolumab treatment for advanced non-small cell lung cancer patients with mild idiopathic interstitial pneumonia. Lung Cancer 111:1–5. CrossRefPubMedGoogle Scholar
  14. 14.
    Raghu G, Remy-Jardin M, Myers JL et al (2018) Diagnosis of idiopathic pulmonary fibrosis. An Official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med 198(5):e44–e68CrossRefGoogle Scholar
  15. 15.
    Masuda T, Hirano C, Horimasu Y et al (2018) The extent of ground-glass attenuation is a risk factor of chemotherapy-related exacerbation of interstitial lung disease in patients with non-small cell lung cancer. Cancer Chemother Pharmacol 81(1):131–139. CrossRefPubMedGoogle Scholar
  16. 16.
    Mirsadraee S, Oswal D, Alizadeh Y et al (2012) The 7th lung cancer TNM classification and staging system: review of the changes and implications. World J Radiol 4(4):128–134. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Travis WD, Brambilla E, Nicholson AG et al (2015) The 2015 world health organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol 10(9):1243–1260. CrossRefPubMedGoogle Scholar
  18. 18.
    Enomoto Y, Inui N, Kato T et al (2016) Low forced vital capacity predicts cytotoxic chemotherapy-associated acute exacerbation of interstitial lung disease in patients with lung cancer. Lung Cancer 96:63–67. CrossRefPubMedGoogle Scholar
  19. 19.
    Kazerooni EA, Martinez FJ, Flint A et al (1997) Thin-section CT obtained at 10-mm increments versus limited three-level thin-section CT for idiopathic pulmonary fibrosis: correlation with pathologic scoring. AJR Am J Roentgenol 169(4):977–983. CrossRefPubMedGoogle Scholar
  20. 20.
    Goddard PR, Nicholson EM, Laszlo G et al (1982) Computed tomography in pulmonary emphysema. Clin Radiol 33(4):379–387CrossRefGoogle Scholar
  21. 21.
    Suzuki H, Sekine Y, Yoshida S et al (2011) Risk of acute exacerbation of interstitial pneumonia after pulmonary resection for lung cancer in patients with idiopathic pulmonary fibrosis based on preoperative high-resolution computed tomography. Surg Today 41(7):914–921. CrossRefPubMedGoogle Scholar
  22. 22.
    Collard HR, Ryerson CJ, Corte TJ et al (2016) Acute exacerbation of idiopathic pulmonary fibrosis. An International Working Group Report. Am J Respir Crit Care Med 194(3):265–275. CrossRefPubMedGoogle Scholar
  23. 23.
    Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48(3):452–458. CrossRefGoogle Scholar
  24. 24.
    Ryerson CJ, Vittinghoff E, Ley B et al (2014) Predicting survival across chronic interstitial lung disease: The ILD-GAP model. Chest 145(4):723–728. CrossRefPubMedGoogle Scholar
  25. 25.
    Singh S, Collins BF, Sharma BB et al (2017) Interstitial lung disease in India. Results of a prospective registry. Am J Respir Crit Care Med 195(6):801–813. CrossRefPubMedGoogle Scholar
  26. 26.
    Usui Y, Kenmotsu H, Mori K et al (1438PA) 1438PA multicenter single-arm phase II study of nab-paclitaxel/carboplatin for non-small cell lung cancer patients with interstitial lung disease. Ann Oncol. CrossRefGoogle Scholar
  27. 27.
    Reck M, Rodriguez-Abreu D, Robinson AG et al (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(7):537–546. CrossRefPubMedGoogle Scholar
  28. 28.
    Socinski MA, Bondarenko I, Karaseva NA et al (2012) Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol 30(17):2055–2062. CrossRefPubMedGoogle Scholar
  29. 29.
    Kenmotsu H, Naito T, Mori K et al (2015) Effect of platinum-based chemotherapy for non-small cell lung cancer patients with interstitial lung disease. Cancer Chemother Pharmacol 75(3):521–526. CrossRefPubMedGoogle Scholar
  30. 30.
    Horn L, Spigel DR, Vokes EE et al (2017) Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III Trials (CheckMate 017 and CheckMate 057). J Clin Oncol 35(35):3924–3933. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Fujimoto D, Sato Y, Morimoto T et al (2018) Programmed cell death ligand 1 expression in non-small-cell lung cancer patients with interstitial lung disease: a matched case-control study. Clin Lung Cancer. CrossRefPubMedGoogle Scholar
  32. 32.
    Rizvi NA, Hellmann MD, Snyder A et al (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science (New York) 348(6230):124–128. CrossRefPubMedCentralGoogle Scholar
  33. 33.
    Honda T, Sakashita H, Masai K et al (2018) Deleterious pulmonary surfactant system gene mutations in lung adenocarcinomas associated with usual interstitial pneumonia. JCO Precis Oncol 2:1–24. CrossRefGoogle Scholar
  34. 34.
    Isobe K, Kaburaki K, Kobayashi H et al (2018) New risk scoring system for predicting acute exacerbation of interstitial pneumonia after chemotherapy for lung cancer associated with interstitial pneumonia. Lung Cancer 125:253–257. CrossRefPubMedGoogle Scholar
  35. 35.
    Isobe K, Hata Y, Sakamoto S et al (2010) Clinical characteristics of acute respiratory deterioration in pulmonary fibrosis associated with lung cancer following anti-cancer therapy. Respirology (Carlton, Vic) 15(1):88–92. CrossRefGoogle Scholar
  36. 36.
    Nakao A, Hasegawa Y, Tsuchiya Y et al (1995) Expression of cell adhesion molecules in the lungs of patients with idiopathic pulmonary fibrosis. Chest 108(1):233–239. CrossRefPubMedGoogle Scholar
  37. 37.
    Strieter RM (2005) Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel. Chest 128(5 Suppl 1):526s–532s. CrossRefPubMedGoogle Scholar
  38. 38.
    Balestro E, Calabrese F, Turato G et al (2016) Immune inflammation and disease progression in idiopathic pulmonary fibrosis. PLoS One 11(5):e0154516. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Parra ER, Kairalla RA, Ribeiro de Carvalho CR et al (2007) Inflammatory cell phenotyping of the pulmonary interstitium in idiopathic interstitial pneumonia. Respiration 74(2):159–169. CrossRefPubMedGoogle Scholar
  40. 40.
    Leuschner G, Behr J (2017) Acute exacerbation in interstitial lung disease. Frontiers in medicine 4:176. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Vuga LJ, Tedrow JR, Pandit KV et al (2014) C-X-C motif chemokine 13 (CXCL13) is a prognostic biomarker of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 189(8):966–974. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Cocconcelli E, Balestro E, Biondini D et al (2019) High-resolution computed tomography (hrct) reflects disease progression in patients with idiopathic pulmonary fibrosis (IPF): relationship with lung pathology. J Clin Med. CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Kim TS, Lee KS, Chung MP et al (1998) Nonspecific interstitial pneumonia with fibrosis: high-resolution CT and pathologic findings. AJR Am J Roentgenol 171(6):1645–1650. CrossRefPubMedGoogle Scholar

Copyright information

© Japan Society of Clinical Oncology 2019

Authors and Affiliations

  • Naoki Nishiyama
    • 1
  • Takayuki Honda
    • 1
  • Manabu Sema
    • 1
  • Tatsuo Kawahara
    • 1
  • Yasuto Jin
    • 2
  • Ichiro Natsume
    • 3
  • Tomoshige Chiaki
    • 4
  • Takaaki Yamashita
    • 5
  • Yoshikazu Tsukada
    • 6
  • Reiko Taki
    • 7
  • Yoshihiro Miyashita
    • 8
  • Kazuhito Saito
    • 9
  • Tomoya Tateishi
    • 1
  • Hiroyuki Sakashita
    • 1
    • 3
    • 10
  • Yasunari Miyazaki
    • 1
    Email author
  1. 1.Department of Respiratory MedicineTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department of Respiratory MedicineHiratsuka Kyosai HospitalHiratsuka-shiJapan
  3. 3.Department of Respiratory MedicineYokosuka Kyosai HospitalYokosuka-shiJapan
  4. 4.Department of Respiratory MedicineHokushin General HospitalNaganoJapan
  5. 5.Department of Respiratory MedicineJapan Agricultural Cooperatives Toride Medical CenterIbarakiJapan
  6. 6.Department of Respiratory MedicineSoka Municipal HospitalSaitamaJapan
  7. 7.Department of Respiratory MedicineJapanese Red Cross Musashino HospitalTokyoJapan
  8. 8.Department of Respiratory MedicineYamanashi Prefectural Central HospitalYamanashiJapan
  9. 9.Department of Respiratory MedicineTsuchiura Kyodo General HospitalIbarakiJapan
  10. 10.Department of ChemotherapyYokosuka Kyosai HospitalYokosuka-shiJapan

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