Semin Respir Crit Care Med 2022; 43(06): 887-898
DOI: 10.1055/s-0042-1755569
Review Article

Imaging of Drug-Related Pneumonitis in Oncology

Shu-Chi Tseng
1   Department of Radiology, Brigham and Women's Hospital and Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts
,
Ho Yun Lee
2   Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-Gu, Seoul, Korea
,
Mizuki Nishino
1   Department of Radiology, Brigham and Women's Hospital and Department of Imaging, Dana-Farber Cancer Institute, Boston, Massachusetts
› Author Affiliations

Abstract

Clinical applications of novel anticancer agents in the past few decades brought marked advances in cancer treatment, enabling remarkable efficacy and effectiveness; however, these novel agents are also associated with toxicities. Among various toxicities, drug-related pneumonitis is one of the major clinical challenges in the management of cancer patients. Imaging plays a key role in detection, diagnosis, and monitoring of drug-related pneumonitis during cancer treatment. In the current era of precision oncology, pneumonitis from molecular targeted therapy and immune-checkpoint inhibitors (ICI) has been recognized as an event of clinical significance. Additionally, further advances of therapeutic approaches in cancer have brought several emerging issues in diagnosis and monitoring of pneumonitis. This article will describe the computed tomography (CT) pattern-based approach for drug-related pneumonitis that has been utilized to describe the imaging manifestations of pneumonitis from novel cancer therapies. Then, we will discuss pneumonitis from representative agents of precision cancer therapy, including mammalian target of rapamycin inhibitors, epidermal growth factor receptor inhibitors, and ICI, focusing on the incidence, risk factors, and the spectrum of CT patterns. Finally, the article will address emerging challenges in the diagnosis and monitoring of pneumonitis, including pneumonitis from combination ICI and radiation therapy and from antibody conjugate therapy, as well as the overlapping imaging features of drug-related pneumonitis and coronavirus disease 2019 pneumonia. The review is designed to provide a practical overview of drug-related pneumonitis from cutting-edge cancer therapy with emphasis on the role of imaging.

Note

M.N. was supported by grants, grant nos.: R01CA203636, U01CA209414, R01HL111024, and R01CA240592.




Publication History

Article published online:
28 October 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 
  • References

  • 1 Erasmus JJ, McAdams HP, Rossi SE. High-resolution CT of drug-induced lung disease. Radiol Clin North Am 2002; 40 (01) 61-72
  • 2 Nishino M, Hatabu H, Sholl LM, Ramaiya NH. Thoracic complications of precision cancer therapies: a practical guide for radiologists in the new era of cancer care. Radiographics 2017; 37 (05) 1371-1387
  • 3 Johkoh T, Lee KS, Nishino M. et al. Chest CT diagnosis and clinical management of drug-related pneumonitis in patients receiving molecular targeting agents and immune checkpoint inhibitors: a Position Paper from the Fleischner Society. Radiology 2021; 298 (03) 550-566
  • 4 Nishino M, Hatabu H, Hodi FS, Ramaiya NH. Drug-related pneumonitis in the era of precision cancer therapy. JCO Precis Oncol 2017; 1: 1
  • 5 Müller NL, White DA, Jiang H, Gemma A. Diagnosis and management of drug-associated interstitial lung disease. Br J Cancer 2004; 91 (Suppl. 02) S24-S30
  • 6 Min JH, Lee HY, Lim H. et al. Drug-induced interstitial lung disease in tyrosine kinase inhibitor therapy for non-small cell lung cancer: a review on current insight. Cancer Chemother Pharmacol 2011; 68 (05) 1099-1109
  • 7 Nishino M. Imaging of oncologic treatment-related pneumonitis: a focused review on emerging issues of immune-checkpoint inhibitor pneumonitis, from the AJR special series on inflammation. AJR Am J Roentgenol 2022; 218 (01) 19-27
  • 8 Nishino M, Sholl LM, Hodi FS, Hatabu H, Ramaiya NH. Anti-PD-1-related pneumonitis during cancer immunotherapy. N Engl J Med 2015; 373 (03) 288-290
  • 9 Nishino M, Ramaiya NH, Awad MM. et al. PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res 2016; 22 (24) 6051-6060
  • 10 Nishino M, Brais LK, Brooks NV, Hatabu H, Kulke MH, Ramaiya NH. Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with neuroendocrine tumors: a radiographic pattern-based approach. Eur J Cancer 2016; 53: 163-170
  • 11 Sears CR, Peikert T, Possick JD. et al. Knowledge gaps and research priorities in immune checkpoint inhibitor-related pneumonitis. an Official American Thoracic Society Research Statement. Am J Respir Crit Care Med 2019; 200 (06) e31-e43
  • 12 Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009; 122 (pt 20): 3589-3594
  • 13 Wysocki PJ. mTOR in renal cell cancer: modulator of tumor biology and therapeutic target. Expert Rev Mol Diagn 2009; 9 (03) 231-241
  • 14 Dabydeen DA, Jagannathan JP, Ramaiya N. et al. Pneumonitis associated with mTOR inhibitors therapy in patients with metastatic renal cell carcinoma: incidence, radiographic findings and correlation with clinical outcome. Eur J Cancer 2012; 48 (10) 1519-1524
  • 15 White DA, Camus P, Endo M. et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 2010; 182 (03) 396-403
  • 16 Yao JC, Shah MH, Ito T. et al; RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group. Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364 (06) 514-523
  • 17 Campone M, Bachelot T, Gnant M. et al. Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study. Eur J Cancer 2013; 49 (12) 2621-2632
  • 18 Soria JC, Shepherd FA, Douillard JY. et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors. Ann Oncol 2009; 20 (10) 1674-1681
  • 19 Nishino M, Boswell EN, Hatabu H, Ghobrial IM, Ramaiya NH. Drug-related pneumonitis during mammalian target of rapamycin inhibitor therapy: radiographic pattern-based approach in Waldenström Macroglobulinemia as a Paradigm. Oncologist 2015; 20 (09) 1077-1083
  • 20 Deutsch E, Le Péchoux C, Faivre L. et al. Phase I trial of everolimus in combination with thoracic radiotherapy in non-small-cell lung cancer. Ann Oncol 2015; 26 (06) 1223-1229
  • 21 Albiges L, Chamming's F, Duclos B. et al. Incidence and management of mTOR inhibitor-associated pneumonitis in patients with metastatic renal cell carcinoma. Ann Oncol 2012; 23 (08) 1943-1953
  • 22 Ko B, Paucar D, Halmos B. EGFR T790M: revealing the secrets of a gatekeeper. Lung Cancer (Auckl) 2017; 8: 147-159
  • 23 Park H, Sholl LM, Hatabu H, Awad MM, Nishino M. Imaging of precision therapy for lung cancer: current state of the art. Radiology 2019; 293 (01) 15-29
  • 24 Gemma A, Kudoh S, Ando M. et al. Final safety and efficacy of erlotinib in the phase 4 POLARSTAR surveillance study of 10 708 Japanese patients with non-small-cell lung cancer. Cancer Sci 2014; 105 (12) 1584-1590
  • 25 Mok TS, Wu YL, Papadimitrakopoulou VA. Osimertinib in EGFR T790M-positive lung cancer. N Engl J Med 2017; 376 (20) 1993-1994
  • 26 Qi WX, Sun YJ, Shen Z, Yao Y. Risk of interstitial lung disease associated with EGFR-TKIs in advanced non-small-cell lung cancer: a meta-analysis of 24 phase III clinical trials. J Chemother 2015; 27 (01) 40-51
  • 27 Suh CH, Park HS, Kim KW, Pyo J, Hatabu H, Nishino M. Pneumonitis in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitor: meta-analysis of 153 cohorts with 15,713 patients: meta-analysis of incidence and risk factors of EGFR-TKI pneumonitis in NSCLC. Lung Cancer 2018; 123: 60-69
  • 28 Gemma A, Kusumoto M, Sakai F. et al. Real-world evaluation of factors for interstitial lung disease incidence and radiologic characteristics in patients with EGFR T790M-positive NSCLC treated with osimertinib in Japan. J Thorac Oncol 2020; 15 (12) 1893-1906
  • 29 Soria JC, Ohe Y, Vansteenkiste J. et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378 (02) 113-125
  • 30 Kudoh S, Kato H, Nishiwaki Y. et al; Japan Thoracic Radiology Group. Interstitial lung disease in Japanese patients with lung cancer: a cohort and nested case-control study. Am J Respir Crit Care Med 2008; 177 (12) 1348-1357
  • 31 Oshima Y, Tanimoto T, Yuji K, Tojo A. EGFR-TKI-associated interstitial pneumonitis in nivolumab-treated patients with non-small cell lung cancer. JAMA Oncol 2018; 4 (08) 1112-1115
  • 32 Noonan SA, Sachs PB, Camidge DR. Transient asymptomatic pulmonary opacities occurring during osimertinib treatment. J Thorac Oncol 2016; 11 (12) 2253-2258
  • 33 Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12 (04) 252-264
  • 34 Ott PA, Hodi FS, Robert C. CTLA-4 and PD-1/PD-L1 blockade: new immunotherapeutic modalities with durable clinical benefit in melanoma patients. Clin Cancer Res 2013; 19 (19) 5300-5309
  • 35 Phan GQ, Yang JC, Sherry RM. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 2003; 100 (14) 8372-8377
  • 36 Hodi FS, Mihm MC, Soiffer RJ. et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A 2003; 100 (08) 4712-4717
  • 37 Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. Cancers (Basel) 2020; 12 (03) 12
  • 38 Wang DY, Salem JE, Cohen JV. et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol 2018; 4 (12) 1721-1728
  • 39 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
  • 40 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 (02) 271-281
  • 41 Su Q, Zhu EC, Wu JB. et al. Risk of pneumonitis and pneumonia associated with immune checkpoint inhibitors for solid tumors: a systematic review and meta-analysis. Front Immunol 2019; 10: 108
  • 42 Cadranel J, Canellas A, Matton L. et al. Pulmonary complications of immune checkpoint inhibitors in patients with nonsmall cell lung cancer. Eur Respir Rev 2019; 28 (153) 28
  • 43 Park H, Hatabu H, Ricciuti B, Aijazi SJ, Awad MM, Nishino M. Immune-related adverse events on body CT in patients with small-cell lung cancer treated with immune-checkpoint inhibitors. Eur J Radiol 2020; 132: 109275
  • 44 Kanai O, Kim YH, Demura Y. et al. Efficacy and safety of nivolumab in non-small cell lung cancer with preexisting interstitial lung disease. Thorac Cancer 2018; 9 (07) 847-855
  • 45 Ahn MJ, Gandhi L, Hamid O. et al. 459P risk of pneumonitis in patients with advanced NSCLC treated with pembrolizumab in KEYNOTE-001. Ann Oncol 2015; 26: ix125
  • 46 Delaunay M, Cadranel J, Lusque A. et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir J 2017; 50 (02) 50
  • 47 Asher N, Marom EM, Ben-Betzalel G. et al. Recurrent pneumonitis in patients with melanoma treated with immune checkpoint inhibitors. Oncologist 2019; 24 (05) 640-647
  • 48 Brahmer JR, Lacchetti C, Thompson JA. Management of Immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline Summary. J Oncol Pract 2018; 14 (04) 247-249
  • 49 Kalisz KR, Ramaiya NH, Laukamp KR, Gupta A. Immune checkpoint inhibitor therapy-related pneumonitis: patterns and management. Radiographics 2019; 39 (07) 1923-1937
  • 50 Deng L, Liang H, Burnette B. et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest 2014; 124 (02) 687-695
  • 51 Gong X, Li X, Jiang T. et al. Combined radiotherapy and anti-PD-L1 antibody synergistically enhances antitumor effect in non-small cell lung cancer. J Thorac Oncol 2017; 12 (07) 1085-1097
  • 52 Gong J, Le TQ, Massarelli E, Hendifar AE, Tuli R. Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. J Immunother Cancer 2018; 6 (01) 46
  • 53 Antonia SJ, Villegas A, Daniel D. et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med 2018; 379 (24) 2342-2350
  • 54 Antonia SJ, Villegas A, Daniel D. et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med 2017; 377 (20) 1919-1929
  • 55 Schoenfeld JD, Nishino M, Severgnini M, Manos M, Mak RH, Hodi FS. Pneumonitis resulting from radiation and immune checkpoint blockade illustrates characteristic clinical, radiologic and circulating biomarker features. J Immunother Cancer 2019; 7 (01) 112
  • 56 Park KJ, Chung JY, Chun MS, Suh JH. Radiation-induced lung disease and the impact of radiation methods on imaging features. Radiographics 2000; 20 (01) 83-98
  • 57 Thomas R, Chen YH, Hatabu H, Mak RH, Nishino M. Radiographic patterns of symptomatic radiation pneumonitis in lung cancer patients: Imaging predictors for clinical severity and outcome. Lung Cancer 2020; 145: 132-139
  • 58 Chen X, Sheikh K, Nakajima E. et al. Radiation versus immune checkpoint inhibitor associated pneumonitis: distinct radiologic morphologies. Oncologist 2021; 26 (10) e1822-e1832
  • 59 Chari RV. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res 2008; 41 (01) 98-107
  • 60 Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res 2014; 16 (02) 209
  • 61 Verma S, Miles D, Gianni L. et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012; 367 (19) 1783-1791
  • 62 von Minckwitz G, Huang CS, Mano MS. et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 2019; 380 (07) 617-628
  • 63 Lewis Phillips GD, Li G, Dugger DL. et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibody-cytotoxic drug conjugate. Cancer Res 2008; 68 (22) 9280-9290
  • 64 Dieci MV, Miglietta F, Griguolo G, Guarneri V. Biomarkers for HER2-positive metastatic breast cancer: beyond hormone receptors. Cancer Treat Rev 2020; 88: 102064
  • 65 Ogitani Y, Aida T, Hagihara K. et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res 2016; 22 (20) 5097-5108
  • 66 Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci 2016; 107 (07) 1039-1046
  • 67 Modi S, Saura C, Yamashita T. et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med 2020; 382 (07) 610-621
  • 68 Rugo HS, Im SA, Cardoso F. et al; SOPHIA Study Group. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol 2021; 7 (04) 573-584
  • 69 Shitara K, Bang YJ, Iwasa S. et al; DESTINY-Gastric01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 2020; 382 (25) 2419-2430
  • 70 Kumagai K, Aida T, Tsuchiya Y, Kishino Y, Kai K, Mori K. Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys. Cancer Sci 2020; 111 (12) 4636-4645
  • 71 Tarantino P, Modi S, Tolaney SM. et al. Interstitial lung disease induced by Anti-ERBB2 antibody-drug conjugates: a review. JAMA Oncol 2021; 7 (12) 1873-1881
  • 72 Akira M, Ishikawa H, Yamamoto S. Drug-induced pneumonitis: thin-section CT findings in 60 patients. Radiology 2002; 224 (03) 852-860
  • 73 Salehi S, Abedi A, Balakrishnan S, Gholamrezanezhad A. Coronavirus disease 2019 (COVID-19): a systematic review of imaging findings in 919 patients. AJR Am J Roentgenol 2020; 215 (01) 87-93
  • 74 Simpson S, Kay FU, Abbara S. et al. Radiological Society of North America Expert Consensus Document on reporting chest CT findings related to COVID-19: endorsed by the Society of Thoracic Radiology, the American College of Radiology, and RSNA. Radiol Cardiothorac Imaging 2020; 2 (02) e200152