Clinical and Radiological Features and Treatment of Pulmonary Toxicity Associated with Using Immune Checkpoint Inhibitors in Cancer Treatment: A Single-Center Experience
Received Date : 14 Feb 2023
Accepted Date : 05 Apr 2023
Available Online : 04 May 2023
Doi: 10.37047/jos.2023-95972 - Article's Language: EN
J Oncol Sci. 2023;9(2):62-71
This is an open access article under the CC BY-NC-ND license
Objective: Immune checkpoint inhibitor-related pneumonitis (ICI-P), as a rare, immune-related adverse event, is difficult to diagnose and treat for clinicians because of its life-threatening adverse events and nonspecific clinical and laboratory findings. Material and Methods: Patients with newly developed pulmonary infiltrates receiving ICI for cancer treatment were included in this study, and their images were re-evaluated by a radiologist. Results: In this study, 32 (88.9%) male and four (11.3%) female patients with a median age of 62 years (range: 20-70 years) were enrolled, of whom 26 patients (72.3%) were diagnosed with non-small cell lung cancer. The most frequent ICI-P-related symptom was cough (63.9%). The median time to the occurrence of ICI-P was 3.5 months (range: 0.3-20 months), and the median number of cycles was four (range: 1-25). Ten patients needed hospitalization, 13 patients were found with permanent termination of ICI therapy, and ICI-P recurred in six patients (16.7%). Other immunosuppressive treatments, such as using mycophenolate mofetil and infliximab, were required in three steroid-refractory patients. No patient died due to uncontrolled ICI-P. Conclusion: In our study, consolidation was the most common radiological finding of ICI-P, which may involve the contralateral side as well as the tumor margin, possibly mimicking lymphangitic spread. Although ICI-P diagnosis is based on the exclusion of other differential diagnoses, it can mimic many other clinical conditions. Empirical use of steroids should not be avoided if there is clinical suspicion because of the risk of mortality.
  1. Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022;19(4):254-267. [Crossref]  [PubMed]  [PMC] 
  2. Dine J, Gordon R, Shames Y, Kasler MK, Barton-Burke M. Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer. Asia Pac J Oncol Nurs. 2017;4(2):127-135. [Crossref]  [PubMed]  [PMC] 
  3. Spiers L, Coupe N, Payne M. Toxicities associated with checkpoint inhibitors-an overview. Rheumatology (Oxford). 2019;58(Suppl 7):vii7-vii16. [Crossref]  [PubMed]  [PMC] 
  4. Ciccarese C, Alfieri S, Santoni M, et al. New toxicity profile for novel immunotherapy agents: focus on immune-checkpoint inhibitors. Expert Opin Drug Metab Toxicol. 2016;12(1):57-75. [Crossref]  [PubMed] 
  5. Haslam A, Gill J, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs. JAMA Netw Open. 2020;3(3):e200423. [Crossref]  [PubMed]  [PMC] 
  6. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139-148. [Crossref]  [PubMed] 
  7. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: american society of clinical oncology clinical practice guideline. J Clin Oncol. 2018;36(17):1714-1768. [PubMed]  [PMC] 
  8. Naidoo J, Wang X, Woo KM, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017;35(7):709-717. Erratum in: J Clin Oncol. 2017;35(22):2590. [Crossref]  [PubMed]  [PMC] 
  9. Suresh K, Naidoo J, Lin CT, Danoff S. Immune checkpoint immunotherapy for non-small cell lung cancer: benefits and pulmonary toxicities. Chest. 2018;154(6):1416-1423. [Crossref]  [PubMed]  [PMC] 
  10. Khunger M, Rakshit S, Pasupuleti V, et al. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials. Chest. 2017;152(2):271-281. [Crossref]  [PubMed] 
  11. Kato T, Masuda N, Nakanishi Y, et al. Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer. Lung Cancer. 2017 Feb;104:111-118. [Crossref]  [PubMed] 
  12. Nishino M, Giobbie-Hurder A, Hatabu H, Ramaiya NH, Hodi FS. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis. JAMA Oncol. 2016;2(12):1607-1616. [Crossref]  [PubMed] 
  13. Haanen JBAG, Carbonnel F, Robert C, et al; ESMO Guidelines Committee. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017 1;28(suppl_4):iv119-iv142. Erratum in: Ann Oncol. 2018;29(Suppl 4):iv264-iv266. [Crossref]  [PubMed] 
  14. Beattie J, Rizvi H, Fuentes P, et al. Success and failure of additional immune modulators in steroid-refractory/resistant pneumonitis related to immune checkpoint blockade. J Immunother Cancer. 2021;9(2):e001884. [Crossref]  [PubMed]  [PMC] 
  15. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. [Crossref]  [PubMed]  [PMC] 
  16. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373(17):1627-1639. [Crossref]  [PubMed]  [PMC] 
  17. Reck M, Rodríguez-Abreu D, Robinson AG, et al; KEYNOTE-024 Investigators. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823-1833. [Crossref]  [PubMed] 
  18. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540-1550. [Crossref]  [PubMed] 
  19. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920. [PubMed]  [PMC] 
  20. Fehrenbacher L, Spira A, Ballinger M, et al; POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387(10030):1837-1846. [Crossref]  [PubMed] 
  21. Hassanzadeh C, Sita T, Savoor R, et al. Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer. J Thorac Dis. 2020;12(11):6690-6700. [Crossref]  [PubMed]  [PMC] 
  22. Zhai X, Zhang J, Tian Y, et al. The mechanism and risk factors for immune checkpoint inhibitor pneumonitis in non-small cell lung cancer patients. Cancer Biol Med. 2020;17(3):599-611. [Crossref]  [PubMed]  [PMC] 
  23. Hindocha S, Campbell D, Ahmed M, et al. Immune checkpoint inhibitor and radiotherapy-related pneumonitis: an informatics approach to determine real-world incidence, severity, management, and resource implications. Front Med (Lausanne). 2021 Nov;8:764563. [Crossref]  [PubMed]  [PMC] 
  24. Suresh K, Voong KR, Shankar B, et al. Pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors. J Thorac Oncol. 2018;13(12):1930-1939. [Crossref]  [PubMed] 
  25. Wang H, Zhao Y, Zhang X, et al. Clinical characteristics and management of immune checkpoint inhibitor-related pneumonitis: a single-institution retrospective study. Cancer Med. 2021;10(1):188-198. [Crossref]  [PubMed]  [PMC] 
  26. Delaunay M, Cadranel J, Lusque A, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir J. 2017;50(2):1700050. Erratum in: Eur Respir J. 2017;50(5). [PubMed] 
  27. Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785-792. [Crossref]  [PubMed] 
  28. Chennamadhavuni A, Abushahin L, Jin N, Presley CJ, Manne A. Risk factors and biomarkers for immune-related adverse events: a practical guide to identifying high-risk patients and rechallenging immune checkpoint inhibitors. Front Immunol. 2022;13:779691. [Crossref]  [PubMed]  [PMC] 
  29. Mark NM, Kargl J, Busch SE, et al. Chronic obstructive pulmonary disease alters immune cell composition and immune checkpoint inhibitor efficacy in non-small cell lung cancer. Am J Respir Crit Care Med. 2018;197(3):325-336. [Crossref]  [PubMed]  [PMC] 
  30. Shaverdian N, Lisberg AE, Bornazyan K, et al. Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Lancet Oncol. 2017;18(7):895-903. Erratum in: Lancet Oncol. 2017;18(7):e371. [Crossref]  [PubMed]  [PMC] 
  31. Banavasi H, Kim S, Alkassis S, et al. Immune checkpoint inhibitor-induced pneumonitis: incidence, clinical characteristics, and outcomes. Hematol Oncol Stem Cell Ther. 2021. [Crossref]  [PubMed] 
  32. Raghu G, Remy-Jardin M, Myers JL, et al; American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society. Diagnosis of idiopathic pulmonary fibrosis. An official ATS/ERS/JRS/ALAT clinical practice guideline. Am J Respir Crit Care Med. 2018;198(5):e44-e68. [PubMed] 
  33. Andruska N, Mahapatra L, Hebbard C, Patel P, Paul V. Severe pneumonitis refractory to steroids following anti-PD-1 immunotherapy. BMJ Case Rep. 2018;2018:bcr2018225937. [Crossref]  [PubMed]  [PMC] 
  34. Nobashi TW, Nishimoto Y, Kawata Y, et al. Clinical and radiological features of immune checkpoint inhibitor-related pneumonitis in lung cancer and non-lung cancers. Br J Radiol. 2020;93(1115):20200409. [Crossref]  [PubMed]  [PMC] 
  35. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN guidelines insights: management of immunotherapy-related toxicities, version 1.2020. J Natl Compr Canc Netw. 2020;18(3):230-241. [PubMed] 
  36. Weber JS, Postow M, Lao CD, Schadendorf D. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist. 2016;21(10):1230-1240. [Crossref]  [PubMed]  [PMC] 
  37. Delaunay M, Prévot G, Collot S, Guilleminault L, Didier A, Mazières J. Management of pulmonary toxicity associated with immune checkpoint inhibitors. Eur Respir Rev. 2019;28(154):190012. [Crossref]  [PubMed]  [PMC] 
  38. Sun Y, Shao C, Li S, et al. Programmed cell death 1 (PD-1)/PD-ligand 1(PD-L1) inhibitors-related pneumonitis in patients with advanced non-small cell lung cancer. Asia Pac J Clin Oncol. 2020;16(6):299-304. [Crossref]  [PubMed]  [PMC] 
  39. Shannon VR. Pneumonitis associated with immune checkpoint inhibitors among patients with non-small cell lung cancer. Curr Opin Pulm Med. 2020;26(4):326-340. [Crossref]  [PubMed] 
  40. Brahmer JR, Govindan R, Anders RA, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018;6(1):75. [Crossref]  [PubMed]  [PMC] 
  41. Ortega Sanchez G, Jahn K, Savic S, Zippelius A, Läubli H. Treatment of mycophenolate-resistant immune-related organizing pneumonia with infliximab. J Immunother Cancer. 2018;6(1):85. [Crossref]  [PubMed]  [PMC] 
  42. Youssef J, Novosad SA, Winthrop KL. Infection risk and safety of corticosteroid use. Rheum Dis Clin North Am. 2016;42(1):157-76, ix-x. [Crossref]  [PubMed]  [PMC] 
  43. Zhao Q, Zhang J, Xu L, et al. Safety and efficacy of the rechallenge of immune checkpoint inhibitors after immune-related adverse events in patients with cancer: a systemic review and meta-analysis. Front Immunol. 2021 Sep;12:730320. [Crossref]  [PubMed]  [PMC] 
  44. Wang H, Guo X, Zhou J, et al. Clinical diagnosis and treatment of immune checkpoint inhibitor-associated pneumonitis. Thorac Cancer. 2020;11(1):191-197. [Crossref]  [PubMed]  [PMC] 
  45. de Jong C, Peters BJM, Schramel FMNH. Recurrent episodes of nivolumab-induced pneumonitis after nivolumab discontinuation and the time course of carcinoembryonic antigen levels: a case of a 58-year-old woman with non-small cell lung cancer. Chemotherapy. 2018;63(5):272-277. [Crossref]  [PubMed] 
  46. Tao H, Li F, Wu D, et al. Rate and risk factors of recurrent immune checkpoint inhibitor-related pneumonitis in patients with lung cancer. Transl Lung Cancer Res. 2022;11(3):381-392. [Crossref]  [PubMed]  [PMC] 
  47. Wang W, Wang Q, Xu C, et al. Chinese expert consensus on the multidisciplinary management of pneumonitis associated with immune checkpoint inhibitor. Thorac Cancer. 2022;13(23):3420-3430. [PubMed]  [PMC]