Pitfalls and Immune-Related Adverse Events

  • Amir IravaniEmail author
  • Rodney J. Hicks


The role of imaging including FDG PET/CT in response assessment, identification, and monitoring of immune-related adverse events (irAEs) is becoming more important given recent accelerated approvals of immunotherapeutic agents for several tumor types that previously had an extremely poor prognosis and lack of therapeutic options. However, the occurrence of irAEs presents challenges for distinction from progressive malignancy. Prompt and accurate imaging diagnosis of irAEs is important given their clinical impact. Due to ever-increasing the number of immunomodulatory agents with different modes of action and their expanding clinical indications, it is vital that clinicians are aware of various and emerging patterns of response and nonmalignant findings that can be associated with their use. It is therefore critical to systematically document the imaging features of irAEs that can be identified during immunotherapy, either as part of routine therapeutic response assessment or to investigate symptoms.


Immune-related adverse event Immune checkpoint inhibitor Immunotherapy FDG PET/CT 18F-FDG PET 


  1. 1.
    Weber JS, Hodi FS, Wolchok JD, Topalian SL, Schadendorf D, Larkin J, et al. Safety profile of nivolumab monotherapy: a pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785–92.CrossRefGoogle Scholar
  2. 2.
    Krummel MF, Allison JP. CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J Exp Med. 1996;183(6):2533–40.CrossRefGoogle Scholar
  3. 3.
    Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N Engl J Med. 2016;375(18):1767–78.CrossRefGoogle Scholar
  4. 4.
    Abdel-Rahman O, ElHalawani H, Fouad M. Risk of endocrine complications in cancer patients treated with immune check point inhibitors: a meta-analysis. Future Oncol. 2016;12(3):413–25.CrossRefGoogle Scholar
  5. 5.
    Naidoo J, Wang X, Woo KM, Iyriboz T, Halpenny D, Cunningham J, et al. Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy. J Clin Oncol. 2017;35(7):709–17.CrossRefGoogle Scholar
  6. 6.
    Morganstein DL, Lai Z, Spain L, Diem S, Levine D, Mace C, et al. Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clin Endocrinol. 2017;86(4):614–20.CrossRefGoogle Scholar
  7. 7.
    Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68.CrossRefGoogle Scholar
  8. 8.
    Weber JS, Kahler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691–7.CrossRefGoogle Scholar
  9. 9.
    Wang PF, Chen Y, Song SY, Wang TJ, Ji WJ, Li SW, et al. Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Front Pharmacol. 2017;8:730.CrossRefGoogle Scholar
  10. 10.
    Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017;389(10066):255–65.CrossRefGoogle Scholar
  11. 11.
    Bronstein Y, Ng CS, Hwu P, Hwu WJ. Radiologic manifestations of immune-related adverse events in patients with metastatic melanoma undergoing anti-CTLA-4 antibody therapy. AJR Am J Roentgenol. 2011;197(6):W992–W1000.CrossRefGoogle Scholar
  12. 12.
    Tirumani SH, Ramaiya NH, Keraliya A, Bailey ND, Ott PA, Hodi FS, et al. Radiographic profiling of immune-related adverse events in advanced melanoma patients treated with ipilimumab. Cancer Immunol Res. 2015;3(10):1185–92.CrossRefGoogle Scholar
  13. 13.
    Weber JS, Dummer R, de Pril V, Lebbe C, Hodi FS, Investigators MDX. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer. 2013;119(9):1675–82.CrossRefGoogle Scholar
  14. 14.
    van der Hiel B, Blank CU, Haanen JB, Stokkel MP. Detection of early onset of hypophysitis by (18)F-FDG PET-CT in a patient with advanced stage melanoma treated with ipilimumab. Clin Nucl Med. 2013;38(4):e182–4.CrossRefGoogle Scholar
  15. 15.
    Lyall A, Vargas HA, Carvajal RD, Ulaner G. Ipilimumab-induced colitis on FDG PET/CT. Clin Nucl Med. 2012;37(6):629–30.CrossRefGoogle Scholar
  16. 16.
    Raad RA, Pavlick A, Kannan R, Friedman KP. Ipilimumab-induced hepatitis on 18F-FDG PET/CT in a patient with malignant melanoma. Clin Nucl Med. 2015;40(3):258–9.CrossRefGoogle Scholar
  17. 17.
    Bacanovic S, Burger IA, Stolzmann P, Hafner J, Huellner MW. Ipilimumab-induced adrenalitis: a possible pitfall in 18F-FDG-PET/CT. Clin Nucl Med. 2015;40(11):e518–9.CrossRefGoogle Scholar
  18. 18.
    Wachsmann JW, Ganti R, Peng F. Immune-mediated disease in ipilimumab immunotherapy of melanoma with FDG PET-CT. Acad Radiol. 2017;24(1):111–5.CrossRefGoogle Scholar
  19. 19.
    Kaira K, Higuchi T, Naruse I, Arisaka Y, Tokue A, Altan B, et al. Metabolic activity by (18)F-FDG-PET/CT is predictive of early response after nivolumab in previously treated NSCLC. Eur J Nucl Med Mol Imaging. 2018;45(1):56–66.CrossRefGoogle Scholar
  20. 20.
    Sachpekidis C, Larribere L, Pan L, Haberkorn U, Dimitrakopoulou-Strauss A, Hassel JC. Predictive value of early 18F-FDG PET/CT studies for treatment response evaluation to ipilimumab in metastatic melanoma: preliminary results of an ongoing study. Eur J Nucl Med Mol Imaging. 2015;42(3):386–96.CrossRefGoogle Scholar
  21. 21.
    Cho SY, Lipson EJ, Im HJ, Rowe SP, Gonzalez EM, Blackford A, et al. Prediction of response to immune checkpoint inhibitor therapy using early-time-point (18)F-FDG PET/CT imaging in patients with advanced melanoma. J Nucl Med. 2017;58(9):1421–8.CrossRefGoogle Scholar
  22. 22.
    Sachpekidis C, Anwar H, Winkler J, Kopp-Schneider A, Larribere L, Haberkorn U, et al. The role of interim (18)F-FDG PET/CT in prediction of response to ipilimumab treatment in metastatic melanoma. Eur J Nucl Med Mol Imaging. 2018;45(8):1289–96.CrossRefGoogle Scholar
  23. 23.
    Anwar H, Sachpekidis C, Winkler J, Kopp-Schneider A, Haberkorn U, Hassel JC, et al. Absolute number of new lesions on (18)F-FDG PET/CT is more predictive of clinical response than SUV changes in metastatic melanoma patients receiving ipilimumab. Eur J Nucl Med Mol Imaging. 2018;45(3):376–83.CrossRefGoogle Scholar
  24. 24.
    Kong BY, Menzies AM, Saunders CA, Liniker E, Ramanujam S, Guminski A, et al. Residual FDG-PET metabolic activity in metastatic melanoma patients with prolonged response to anti-PD-1 therapy. Pigment Cell Melanoma Res. 2016;29(5):572–7.CrossRefGoogle Scholar
  25. 25.
    Grizzi F, Castello A, Lopci E. Is it time to change our vision of tumor metabolism prior to immunotherapy? Eur J Nucl Med Mol Imaging. 2018;45(6):1072–5.CrossRefGoogle Scholar
  26. 26.
    Breki CM, Dimitrakopoulou-Strauss A, Hassel J, Theoharis T, Sachpekidis C, Pan L, et al. Fractal and multifractal analysis of PET/CT images of metastatic melanoma before and after treatment with ipilimumab. EJNMMI Res. 2016;6(1):61.CrossRefGoogle Scholar
  27. 27.
    Shozushima M, Tsutsumi R, Terasaki K, Sato S, Nakamura R, Sakamaki K. Augmentation effects of lymphocyte activation by antigen-presenting macrophages on FDG uptake. Ann Nucl Med. 2003;17(7):555–60.CrossRefGoogle Scholar
  28. 28.
    Wong ANM, McArthur GA, Hofman MS, Hicks RJ. The advantages and challenges of using FDG PET/CT for response assessment in melanoma in the era of targeted agents and immunotherapy. Eur J Nucl Med Mol Imaging. 2017;44(Suppl 1):67–77.CrossRefGoogle Scholar
  29. 29.
    Aide N, Hicks RJ, Le Tourneau C, Lheureux S, Fanti S, Lopci E. FDG PET/CT for assessing tumour response to immunotherapy: report on the EANM symposium on immune modulation and recent review of the literature. Eur J Nucl Med Mol Imaging. 2019;46(1):238–50. Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Cancer ImagingPeter MacCallum Cancer CentreMelbourneAustralia
  2. 2.Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneAustralia

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