Abstract
Immune checkpoint inhibitors (ICI) have revolutionized therapy of metastatic melanoma. The first ICI was ipilimumab, a cytotoxic T lymphocyte-associated Ag 4 (CLTA-4) inhibitor with response rates of approximately 11% and disease control of 22%. The programmed cell death 1 (PD-1) inhibitors, such as pembrolizumab and nivolumab, led to longer progression-free survival and overall survival rates with fewer side effects. Molecular imaging techniques, such as positron emission tomography–computed tomography (PET–CT) with 2-deoxy-2-(18F)fluoro-d-glucose (18F-FDG) are in use for staging and therapy monitoring of metastatic melanoma. However, classical radiological imaging criteria such as RECIST and WHO are not appropriate for the assessment of ICI response. New immune-related criteria have been defined such as iRECIST or irRC, which refer to radiological imaging modalities. Until now only a few studies report on immunotherapy response assessment based on 18F-FDG PET–CT. The classical criteria used for therapy monitoring with 18F-FDG PET, such as the EORTC criteria, are not suitable for ICI monitoring. In this focussed review, we present different criteria proposed for ICI monitoring with 18F-FDG and their limitations. One goal is to early identify non-responders to tailor immunotherapy. Another question is pseudoprogression and how to interpret the 18F-FDG images for response assessment. Finally, the definition of 18F-FDG criteria which can be used to identify progress is crucial and discussed in the review. The recent presented PET-based immune-related criteria, the so-called PERCIMT (PET Response Evaluation Criteria for IMmunoTherapy) are presented. Furthermore, new tracers are discussed.
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Abbreviations
- CB:
-
Clinical benefit
- CR:
-
Complete remission
- CT:
-
Computed tomography
- CTLA-4:
-
Cytotoxic T lymphocyte-associated Ag 4
- EORTC:
-
European Organisation for Research and Treatment of Cancer
- FD:
-
Fractal dimension
- FDA:
-
Food and Drug Administration
- 18F-FDG:
-
2-Deoxy-2-(18F)fluoro-d-glucose
- 18F-FLT:
-
18F-3′-Fluoro-3′-deoxythymidine
- Ga-68:
-
Gallium-68
- GIST:
-
Gastrointestinal stromal tumor
- ICI:
-
Immune checkpoint inhibitors
- iCPD:
-
Immune-related confirmed progressive disease
- irAE:
-
Immune-related adverse events
- iRECIST:
-
Immune-related Response Evaluation Criteria in Solid Tumors
- irRC:
-
Immune-related response criteria
- iUPD:
-
Immune-related unconfirmed progressive disease
- LDH:
-
Lactate dehydrogenase
- Lu-177:
-
Lutetium-177
- MAPK:
-
Mitogen-activated protein kinase
- MDSC:
-
Myeloid-derived suppressor cells
- MIP:
-
Maximum intensity projection
- MRI:
-
Magnetic resonance imaging
- mWHO:
-
Modified World Health Organisation
- NK cells:
-
Natural killer cells
- No-CB:
-
No clinical benefit
- OS:
-
Overall survival
- PD:
-
Progressive disease
- PD-1:
-
Programmed death 1 receptor
- PERCIMT:
-
PET Response Evaluation Criteria for Immunotherapy
- PERCIST:
-
PET Response Criteria in Solid Tumors
- PET:
-
Positron emission tomography
- PFS:
-
Progression-free survival
- PMD:
-
Progressive metabolic disease
- PMR:
-
Partial metabolic response
- PR:
-
Partial remission
- RECIST:
-
Response Evaluation Criteria in Solid Tumors
- ROI:
-
Region of interest
- SD:
-
Stable disease
- SMD:
-
Stable metabolic disease
- SSTR:
-
Somatostatin receptor
- SUL:
-
Standardized uptake value normalized for lean body mass
- SUV:
-
Standardized uptake value
- TCR:
-
T-cell receptor for Ag
- TIL:
-
Tumor-infiltrating lymphocyte
- VEGF:
-
Vascular endothelial growth factor
- WHO:
-
World Health Organisation
- Y-90:
-
Yttrium-90
References
Luke JJ, Flaherty KT, Ribas A, Long GV (2017) Targeted agents and immunotherapies: optimizing outcomes in melanoma. Nat Rev Clin Oncol 14:463–482
Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Nevns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, Keynote-006 Investigators (2015) Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med 372:2521–2532
Wolchok JD, Hoos A, O’Dav S, Weber JS, Hamid O, Lebbe C, Maio M, Binder M, Bohnsack O, Nichol G, Humphrey R, Hodi FS (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420
Eisenhauer EA, Therasse P, Bogaerts et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS (2013) Developing a common language for tumor response to immunotherapy: immune-related response criteria using unidimensional measurements. Clin Cancer Res 19:3936–3943
Hodi FS, Hwu W-J, Kefford R, Weber JS, Daud A, Hamid O, Patnaik A, Ribas A, Robert C, Gangadhar TC, Joshua AM, Hersey P, Dronca R, Joseph R, Hille D, Xue D, Li XN, Kang P, Ebbinghaus S, Perrone A, Wolchok JD (2016) Evaluation of immune-related response criteria and RECIST v1.1 in patients with advanced melanoma treated with pembrolizumab. J Clin Oncol 34:1510–1517
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litière S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EG (2017) iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 18:143–152
Strauss LG, Conti PS (1991) The applications of PET in clinical oncology. J Nucl Med 32:623–648
Young H, Baum R, Cremerius U et al (1999) Measurement of clinical and subclinical tumour response using (18F)-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 35:1773–1782
Wahl RL, Jacene H, Kasamon Y, Lodge MA (2009) From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 50(Suppl 1):122S–150S
Kraeber-Bodere F, Carlier T, Naegelen VM, Shochat E, Lumbroso J, Trampal C, Nagarajah J, Chua S, Hugonnet F, Stokkel M, Gleeson F, Tessier J (2012) Differences in the biologic activity of 2 novel MEK inhibitors revealed by 18F-FDG PET: analysis of imaging data from 2 phase I trials. J Nucl Med 53:1836–1846
McArthur GA, Puzanov I, Amaravadi R, Ribas A, Chapman P, Kim KB, Sosman JA, Lee RJ, Nolop K, Flaherty KT, Callahan J, Hicks RJ (2012) Marked, homogeneous, and early [18F]fluorodeoxyglucose-positron emission tomography responses to vemurafenib in BRAF-mutant advanced melanoma. J Clin Oncol 30:1628–1634
Wong ANM, McArthur GA, Hofman MS, Hicks RJ (2017) 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 44(Suppl 1):67–77
Sachpekidis C, Larribere L, Pan L, Haberkorn U, Dimitrakopoulou-Strauss A, Hassel JC (2015) 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 42:386–396
Anwar H, Sachpekidis C, Winkler J, Kopp-Schneider A, Haberkorn U, Hassel JC, Dimitrakopoulou-Strauss A (2018) Absolute number of new lesions on 18F-FDG PET/CT is more predictive of clinical response than SUV changes in metastatic melanoma patients receiving ipilimumab. Eur J Nucl Med Mol Imaging 45:376–383
Ribas A, Benz MR, Allen-Auerbach MS, Radu C, Chmielowski B, Seja E, Williams JL, Gomez-Navarro J, McCarthy T, Czernin J (2010) Imaging of CTLA4 blockade-induced cell replication with 18F-FLT PET in patients with advanced melanoma treated with tremelimumab. J Nucl Med 51:340–346
Cho SY, Lipson EJ, Im HJ, Rowe SP, Gonzalez EM, Blackford A, Chirindel A, Pardoll DM, Topalian SL, Wahl RL (2017) Prediction of response to immune checkpoint inhibitor therapy using early-time-point 18F-FDG PET/CT imaging in patients with advanced melanoma. J Nucl Med 58:1421–1428
Breki CM, Dimitrakopoulou-Strauss A, Hassel J, Theoharis T, Sachpekidis C, Pan L, Provata A (2016) Fractal and multifractal analysis of PET/CT images of metastatic melanoma before and after treatment with ipilimumab. EJNMMI Res 6(1):61
Couzin-Frankel J (2013) Breakthrough of the year 2013—cancer immunotherapy. Science 342(6165):1432–1433
Yoest JM (2017) Clinical features, predictive correlates, and pathophysiology of immune-related adverse events in immune checkpoint inhibitor treatments in cancer: a short review. Immunotargets 6:73–82
Mekki A, Dercle L, Lichtenstein P, Marabelle A, Michot JM, Lambotte O, Le Pavec J, De Martin E, Balleyguier C, Champiat S, Ammari S (2018) Detection of immune-related adverse events by medical imaging in patients treated with anti-programmed cell death 1. Eur J Cancer 96:91–104
Jessurun CAC, Vos JAM, Limpens J, Luiten RM (2017) Biomarkers for response of melanoma patients to immune checkpoint inhibitors: a systematic review. Front Oncol 7:233
Sacher AG, Gandhi L (2016) Biomarkers for the clinical use of PD-1/PD-L1 inhibitors in non-small-cell lung cancer: a review. JAMA Oncol 2:1217–1222
Mayer AT, Natarajan A, Gordon SR, Maute RL, Mc Cracken MN, Ring AM, Weissman IL, Gambhir SS (2107) Practical immuno-PET radiotracer design considerations for human immune checkpoint imaging. J Nucl Med 58:538–546
Natarajan A, Mayer AT, Reeves RE, Nagamine CM, Gambhir SS (2017) Development of novel ImmunoPET tracers to image PD-1 checkpoint expression on tumor-infiltrating lymphocytes in a humanized mouse model. Mol Imaging Biol 19:903–914
Tavare R, McCracken MN, Zettlitz KA, Salazar FB, Olafsen T, Witte ON, Wu AM (2015) Immuno PET of Murine T cell reconstitution postadoptive stem cell transplantation using anti-CD4 and anti-CD8 cys-diabodies. J Nucl Med 56:1258–1264
Mall S, Yusufu N, Wagner R, Klar R, Bianchi H, Steiger K, Straub M, Audehm S, Laitinen I, Aichler M, Peschel C, Ziegler S, Mustafa M, Schwaiger M, Dállesandria C, Krackhardt AM (2016) Immuno–PET imaging of engineered human T cells in tumor. Cancer Res 76:4113–4123
Acknowledgements
The author would like to thank Jessica Hassel, MD, for her contribution to all PET–CT studies in melanoma patients.
Funding
Some of the studies mentioned in this review are based on funding upon the German Cancer Aid under the project with the title “Therapy monitoring of ipilimumab based on the quantification of 18F-FDG kinetics with 4D PET/CT (dPET–CT) in patients with melanoma (stage 4)”. The funders had no role in the preparation of this review. No additional external funding was received for this review.
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Not applicable. This is a review and not an original paper.
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Not applicable. This is a review and not an original paper. All patients agreed on the publication of their images.
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This paper is a Focussed Research Review based on a presentation given at the Seventeenth International Conference on Progress in Vaccination against Cancer (PIVAC 17), held in Loutraki, Corinthia, Greece, 27th–30th September, 2017. It is part of a Cancer Immunology, Immunotherapy series of PIVAC 17 papers.
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Dimitrakopoulou-Strauss, A. Monitoring of patients with metastatic melanoma treated with immune checkpoint inhibitors using PET–CT. Cancer Immunol Immunother 68, 813–822 (2019). https://doi.org/10.1007/s00262-018-2229-6
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DOI: https://doi.org/10.1007/s00262-018-2229-6