Korean Journal of Radiology

The Korean Society of Radiology (대한영상의학회)
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Immunotherapy-Related Imaging Findings in Patients with Gynecological Malignancies: What Radiologists Need to Know

  • Luca Russo (UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS) ;
  • Giacomo Avesani (UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS) ;
  • Benedetta Gui (UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS) ;
  • Charlotte Marguerite Lucille Trombadori (Dipartimento Universitario di Scienze Radiologiche ed Ematologiche, Universita Cattolica del Sacro Cuore) ;
  • Vanda Salutari (UOC Ginecologia Oncologica, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS) ;
  • Maria Teresa Perri (Istituto di Ginecologia e Ostetricia, Universita Cattolica del Sacro Cuore) ;
  • Valerio Di Paola (UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS) ;
  • Elena Rodolfino (UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS) ;
  • Giovanni Scambia (UOC Ginecologia Oncologica, Dipartimento per la Salute della Donna e del Bambino e della Salute Pubblica, Fondazione Policlinico Universitario A. Gemelli IRCCS) ;
  • Riccardo Manfredi (UOC Radiologia Generale ed Interventistica Generale, Dipartimento Diagnostica per Immagini, Radioterapia Oncologica ed Ematologia, Area Diagnostica per Immagini, Fondazione Policlinico Universitario A. Gemelli IRCCS)
  • Received : 2020.08.14
  • Accepted : 2021.03.05
  • Published : 2021.08.01
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Abstract

Immunotherapy is an effective treatment option for gynecological malignancies. Radiologists dealing with gynecological patients undergoing treatment with immune checkpoint inhibitors should be aware of unconventional immune-related imaging features for the evaluation of tumor response and immune-related adverse events. In this paper, immune checkpoint inhibitors used for gynecological malignancies and their mechanisms of action are briefly presented. In the second part, patterns of pseudoprogression are illustrated, and different forms of immune-related adverse events are discussed.

Keywords

References

  1. Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R. Cancer of the cervix uteri. Int J Gynaecol Obstet 2018;143 Suppl 2:22-36  https://doi.org/10.1002/ijgo.12611
  2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-E386  https://doi.org/10.1002/ijc.29210
  3. Mihor A, Tomsic S, Zagar T, Lokar K, Zadnik V. Socioeconomic inequalities in cancer incidence in Europe: a comprehensive review of population-based epidemiological studies. Radiol Oncol 2020;54:1-13  https://doi.org/10.2478/raon-2020-0008
  4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin 2018;68:7-30  https://doi.org/10.3322/caac.21442
  5. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-723  https://doi.org/10.1056/NEJMoa1003466
  6. Massari F, Di Nunno V, Ciccarese C, Graham J, Porta C, Comito F, et al. Adjuvant therapy in renal cell carcinoma. Cancer Treat Rev 2017;60:152-157  https://doi.org/10.1016/j.ctrv.2017.09.004
  7. Pishko A, Nasta SD. The role of novel immunotherapies in non-Hodgkin lymphoma. Transl Cancer Res 2017;6:93-103  https://doi.org/10.21037/tcr.2017.01.08
  8. Ramos JD, Yu EY. Immuno-oncology in urothelial carcinoma: who or what will ultimately sit on the iron throne? Immunotherapy 2017;9:951-954  https://doi.org/10.2217/imt-2017-0109
  9. Lee HW, Cho KJ, Park JY. Current status and future direction of immunotherapy in hepatocellular carcinoma: what do the data suggest? Immune Netw 2020;20:e11 
  10. Grywalska E, Sobstyl M, Putowski L, Rolin' ski J. Current possibilities of gynecologic cancer treatment with the use of immune checkpoint inhibitors. Int J Mol Sci 2019;20:4705 
  11. Lynam S, Lugade AA, Odunsi K. Immunotherapy for gynecologic cancer: current applications and future directions. Clin Obstet Gynecol 2020;63:48-63  https://doi.org/10.1097/GRF.0000000000000513
  12. Green AK, Feinberg J, Makker V. A review of immune checkpoint blockade therapy in endometrial cancer. Am Soc Clin Oncol Educ Book 2020;40:1-7  https://doi.org/10.1200/EDBK_280503
  13. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18:e143-e152  https://doi.org/10.1016/S1470-2045(17)30074-8
  14. Disis ML, Taylor MH, Kelly K, Beck JT, Gordon M, Moore KM, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol 2019;5:393-401  https://doi.org/10.1001/jamaoncol.2018.6258
  15. Shih K, Arkenau HT, Infante JR. Clinical impact of checkpoint inhibitors as novel cancer therapies. Drugs 2014;74:1993-2013  https://doi.org/10.1007/s40265-014-0305-6
  16. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol 2005;23:515-548  https://doi.org/10.1146/annurev.immunol.23.021704.115611
  17. Wang DH, Guo L, Wu XH. Checkpoint inhibitors in immunotherapy of ovarian cancer. Tumour Biol 2015;36:33-39  https://doi.org/10.1007/s13277-014-2848-2
  18. Pedoeem A, Azoulay-Alfaguter I, Strazza M, Silverman GJ, Mor A. Programmed death-1 pathway in cancer and autoimmunity. Clin Immunol 2014;153:145-152  https://doi.org/10.1016/j.clim.2014.04.010
  19. Eskander RN, Tewari KS. Immunotherapy: an evolving paradigm in the treatment of advanced cervical cancer. Clin Ther 2015;37:20-38  https://doi.org/10.1016/j.clinthera.2014.11.010
  20. Liu YL, Zamarin D. Combination immune checkpoint blockade strategies to maximize immune response in gynecological cancers. Curr Oncol Rep 2018;20:94 
  21. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A 2007;104:3360-3365  https://doi.org/10.1073/pnas.0611533104
  22. Matulonis UA, Shapira-Frommer R, Santin AD, Lisyanskaya AS, Pignata S, Vergote I, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol 2019;30:1080-1087  https://doi.org/10.1093/annonc/mdz135
  23. Ledermann JA, Colombo N, Oza AM, Fujiwara K, Birrer MJ, Randall LM, et al. Avelumab in combination with and/or following chemotherapy vs chemotherapy alone in patients with previously untreated epithelial ovarian cancer: results from the phase 3 javelin ovarian 100 trial. Gynecol Oncol 2020;159:13-14  https://doi.org/10.1016/j.ygyno.2020.06.025
  24. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med 2012;366:2517-2519  https://doi.org/10.1056/NEJMe1205943
  25. Frenel JS, Le Tourneau C, O'Neil B, Ott PA, Piha-Paul SA, Gomez-Roca C, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol 2017;35:4035-4041  https://doi.org/10.1200/JCO.2017.74.5471
  26. Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 2019;37:1470-1478  https://doi.org/10.1200/JCO.18.01265
  27. Naumann RW, Hollebecque A, Meyer T, Devlin MJ, Oaknin A, Kerger J, et al. Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial. J Clin Oncol 2019;37:2825-2834  https://doi.org/10.1200/JCO.19.00739
  28. Herzog TJ, Arguello D, Reddy SK, Gatalica Z. PD-1, PD-L1 expression in 1599 gynecological cancers: implications for immunotherapy. Gynecol Oncol 2015;137:204-205  https://doi.org/10.1016/j.ygyno.2015.01.514
  29. Gargiulo P, Della Pepa C, Berardi S, Califano D, Scala S, Buonaguro L, et al. Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: new candidates for checkpoint blockade immunotherapy? Cancer Treat Rev 2016;48:61-68  https://doi.org/10.1016/j.ctrv.2016.06.008
  30. Kasherman L, Ahrari S, Lheureux S. Dostarlimab in the treatment of recurrent or primary advanced endometrial cancer. Future Oncol 2021;17:877-892  https://doi.org/10.2217/fon-2020-0655
  31. Makker V, Taylor MH, Aghajanian C, Oaknin A, Mier J, Cohn AL, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. J Clin Oncol 2020;38:2981-2992  https://doi.org/10.1200/JCO.19.02627
  32. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247  https://doi.org/10.1016/j.ejca.2008.10.026
  33. Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009;15:7412-7420  https://doi.org/10.1158/1078-0432.CCR-09-1624
  34. Dromain C, Beigelman C, Pozzessere C, Duran R, Digklia A. Imaging of tumour response to immunotherapy. Eur Radiol Exp 2020;4:2 
  35. Hodi FS, Hwu WJ, Kefford R, Weber JS, Daud A, Hamid O, et al. Evaluation of immune-related response criteria and RECIST v1. 1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 2016;34:1510-1517  https://doi.org/10.1200/JCO.2015.64.0391
  36. Katz SI, Hammer M, Bagley SJ, Aggarwal C, Bauml JM, Thompson JC, et al. Radiologic pseudoprogression during anti-PD-1 therapy for advanced non-small cell lung cancer. J Thorac Oncol 2018;13:978-986  https://doi.org/10.1016/j.jtho.2018.04.010
  37. Nishino M, Dahlberg SE, Adeni AE, Lydon CA, Hatabu H, Janne PA, et al. Tumor response dynamics of advanced non- small cell lung cancer patients treated with PD-1 inhibitors: imaging markers for treatment outcome. Clin Cancer Res 2017;23:5737-5744  https://doi.org/10.1158/1078-0432.CCR-17-1434
  38. Nishino M, Giobbie-Hurder A, Manos MP, Bailey N, Buchbinder EI, Ott PA, et al. Immune-related tumor response dynamics in melanoma patients treated with pembrolizumab: identifying markers for clinical outcome and treatment decisions. Clin Cancer Res 2017;23:4671-4679  https://doi.org/10.1158/1078-0432.CCR-17-0114
  39. Thust SC, van den Bent MJ, Smits M. Pseudoprogression of brain tumors. J Magn Reson Imaging 2018;48:571-589  https://doi.org/10.1002/jmri.26171
  40. Kataoka Y, Hirano K. Which criteria should we use to evaluate the efficacy of immune-checkpoint inhibitors? Ann Transl Med 2018;6:222 
  41. 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 
  42. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018;378:158-168  https://doi.org/10.1056/NEJMra1703481
  43. Nishino M, Hatabu H, Hodi FS. Imaging of cancer immunotherapy: current approaches and future directions. Radiology 2019;290:9-22  https://doi.org/10.1148/radiol.2018181349
  44. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16:563-580  https://doi.org/10.1038/s41571-019-0218-0
  45. 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;35:709-717  https://doi.org/10.1200/JCO.2016.68.2005
  46. Kalisz KR, Ramaiya NH, Laukamp KR, Gupta A. Immune checkpoint inhibitor therapy-related pneumonitis: patterns and management. Radiographics 2019;39:1923-1937  https://doi.org/10.1148/rg.2019190036
  47. Nishino M, Ramaiya NH, Awad MM, Sholl LM, Maattala JA, Taibi M, et al. PD-1 inhibitor-related pneumonitis in advanced cancer patients: radiographic patterns and clinical course. Clin Cancer Res 2016;22:6051-6060  https://doi.org/10.1158/1078-0432.CCR-16-1320
  48. Fragkou P, Souli M, Theochari M, Kontopoulou C, Loukides S, Koumarianou A. A case of organizing pneumonia (OP) associated with pembrolizumab. Drug Target Insights 2016;10:9-12  https://doi.org/10.33393/dti.2016.1420
  49. Ferguson EC, Berkowitz EA. Lung CT: part 2, the interstitial pneumonias--clinical, histologic, and CT manifestations. AJR Am J Roentgenol 2012;199:W464-W476  https://doi.org/10.2214/AJR.10.7309
  50. Larici AR, Cicchetti G, Marano R, Merlino B, Elia L, Calandriello L, et al. Multimodality imaging of COVID-19 pneumonia: from diagnosis to follow-up. A comprehensive review. Eur J Radiol 2020;131:109217 
  51. Delaunay M, Cadranel J, Lusque A, Meyer N, Gounant V, Moro-Sibilot D, et al. Immune-checkpoint inhibitors associated with interstitial lung disease in cancer patients. Eur Respir J 2017;50:1700050 
  52. Montaudie H, Pradelli J, Passeron T, Lacour JP, Leroy S. Pulmonary sarcoid-like granulomatosis induced by nivolumab. Br J Dermatol 2017;176:1060-1063  https://doi.org/10.1111/bjd.14808
  53. Hiraki T, Hatanaka M, Arimura A, Kawahira H, Kirishima M, Kitazono I, et al. Granulomatous/sarcoid-like reactions in the setting of programmed cell death-1 inhibition: a potential mimic of disease recurrence. J Cutan Pathol 2020;47:154-160  https://doi.org/10.1111/cup.13569
  54. Nishino M, Sholl LM, Awad MM, Hatabu H, Armand P, Hodi FS. Sarcoid-like granulomatosis of the lung related to immune-checkpoint inhibitors: distinct clinical and imaging features of a unique immune-related adverse event. Cancer Immunol Res 2018;6:630-635  https://doi.org/10.1158/2326-6066.CIR-17-0715
  55. Baxi S, Yang A, Gennarelli RL, Khan N, Wang Z, Boyce L, et al. Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis. BMJ 2018;360:k793 
  56. Eigentler TK, Hassel JC, Berking C, Aberle J, Bachmann O, Grunwald V, et al. Diagnosis, monitoring and management of immune-related adverse drug reactions of anti-PD-1 antibody therapy. Cancer Treat Rev 2016;45:7-18  https://doi.org/10.1016/j.ctrv.2016.02.003
  57. Hofmann L, Forschner A, Loquai C, Goldinger SM, Zimmer L, Ugurel S, et al. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy. Eur J Cancer 2016;60:190-209  https://doi.org/10.1016/j.ejca.2016.02.025
  58. Abu-Sbeih H, Tang T, Lu Y, Thirumurthi S, Altan M, Jazaeri AA, et al. Clinical characteristics and outcomes of immune checkpoint inhibitor-induced pancreatic injury. J Immunother Cancer 2019;7:31 
  59. Porcu M, Solinas C, Migali C, Battaglia A, Schena M, Mannelli L, et al. Immune checkpoint inhibitor-induced pancreatic injury: imaging findings and literature review. Target Oncol 2020;15:25-35  https://doi.org/10.1007/s11523-019-00694-w
  60. Manikkavasakar S, AlObaidy M, Busireddy KK, Ramalho M, Nilmini V, Alagiyawanna M, et al. Magnetic resonance imaging of pancreatitis: an update. World J Gastroenterol 2014;20:14760-14777  https://doi.org/10.3748/wjg.v20.i40.14760
  61. Barral M, Taouli B, Guiu B, Koh DM, Luciani A, Manfredi R, et al. Diffusion-weighted MR imaging of the pancreas: current status and recommendations. Radiology 2015;274:45-63  https://doi.org/10.1148/radiol.14130778
  62. Alabed YZ, Aghayev A, Sakellis C, Van den Abbeele AD. Pancreatitis secondary to anti-programmed death receptor 1 immunotherapy diagnosed by FDG PET/CT. Clin Nucl Med 2015;40:e528-e529  https://doi.org/10.1097/RLU.0000000000000940
  63. Manfredi R, Frulloni L, Mantovani W, Bonatti M, Graziani R, Pozzi Mucelli R. Autoimmune pancreatitis: pancreatic and extrapancreatic MR imaging-MR cholangiopancreatography findings at diagnosis, after steroid therapy, and at recurrence. Radiology 2011;260:428-436  https://doi.org/10.1148/radiol.11101729
  64. Furtado VF, Melamud K, Hassan K, Rohatgi S, Buch K. Imaging manifestations of immune-related adverse effects in checkpoint inhibitor therapies: a primer for the radiologist. Clin Imaging 2020;63:35-49  https://doi.org/10.1016/j.clinimag.2020.02.006
  65. Mizuno K, Ito T, Ishigami M, Ishizu Y, Kuzuya T, Honda T, et al. Real world data of liver injury induced by immune checkpoint inhibitors in Japanese patients with advanced malignancies. J Gastroenterol 2020;55:653-661  https://doi.org/10.1007/s00535-020-01677-9
  66. Alessandrino F, Sahu S, Nishino M, Adeni AE, Tirumani SH, Shinagare AB, et al. Frequency and imaging features of abdominal immune-related adverse events in metastatic lung cancer patients treated with PD-1 inhibitor. Abdom Radiol (NY) 2019;44:1917-1927  https://doi.org/10.1007/s00261-019-01935-2
  67. Izumi H, Kodani M, Kurai J, Takeda K, Okazaki R, Yamane K, et al. Nivolumab-induced cholangitis in patients with non-small cell lung cancer: case series and a review of literature. Mol Clin Oncol 2019;11:439-446  https://doi.org/10.3892/mco.2019.1923
  68. Psimaras D. Neuromuscular complications of immune checkpoint inhibitors. Presse Med 2018;47:e253-e259  https://doi.org/10.1016/j.lpm.2018.10.009
  69. Liewluck T, Kao JC, Mauermann ML. PD-1 inhibitor-associated myopathies: emerging immune-mediated myopathies. J Immunother 2018;41:208-211  https://doi.org/10.1097/CJI.0000000000000196
  70. Kao JC, Brickshawana A, Liewluck T. Neuromuscular complications of programmed cell death-1 (PD-1) inhibitors. Curr Neurol Neurosci Rep 2018;18:63 
  71. Mekki A, Dercle L, Lichtenstein P, Marabelle A, Michot JM, Lambotte O, et al. Detection of immune-related adverse events by medical imaging in patients treated with anti-programmed cell death 1. Eur J Cancer 2018;96:91-104  https://doi.org/10.1016/j.ejca.2018.03.006
  72. Yamauchi I, Yasoda A, Matsumoto S, Sakamori Y, Kim YH, Nomura M, et al. Incidence, features, and prognosis of immune-related adverse events involving the thyroid gland induced by nivolumab. PLoS One 2019;14:e0216954 
  73. Byun DJ, Wolchok JD, Rosenberg LM, Girotra M. Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol 2017;13:195-207 https://doi.org/10.1038/nrendo.2016.205