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

  • Hoda AnwarEmail author
  • Christos Sachpekidis
  • Julia Winkler
  • Annette Kopp-Schneider
  • Uwe Haberkorn
  • Jessica C. Hassel
  • Antonia Dimitrakopoulou-Strauss
Original Article



Evaluation of response to immunotherapy is a matter of debate. The aim of the present study was to evaluate the response of metastatic melanoma to treatment with ipilimumab by means of 18F-FDG PET/CT, using the patients’ clinical response as reference.


The final cohort included in the analyses consisted of 41 patients with metastatic melanoma who underwent 18F-FDG PET/CT before and after administration of ipilimumab. After determination of the best clinical response, the PET/CT scans were reviewed and a separate independent analysis was performed, based on the number and functional size of newly emerged 18F-FDG-avid lesions, as well as on the SUV changes after therapy.


The median observation time of the patients after therapy was 21.4 months (range 6.3–41.9 months). Based on their clinical response, patients were dichotomized into those with clinical benefit (CB) and those without CB (No-CB). The CB group (31 patients) included those with stable disease, partial remission and complete remission, and the No-CB group (10 patients) included those with progressive disease. The application of a threshold of four newly emerged 18F-FDG-avid lesions on the posttherapy PET/CT scan led to a sensitivity (correctly predicting CB) of 84% and a specificity (correctly predicting No-CB) of 100%. This cut-off was lower for lesions with larger functional diameters (three new lesions larger than 1.0 cm and two new lesions larger than 1.5 cm). SUV changes after therapy did not correlate with clinical response. Based on these findings, we developed criteria for predicting clinical response to immunotherapy by means of 18F-FDG PET/CT (PET Response Evaluation Criteria for Immunotherapy, PERCIMT).


Our results show that a cut-off of four newly emerged 18F-FDG-avid lesions on posttherapy PET/CT gives a reliable indication of treatment failure in patients under ipilimumab treatment. Moreover, the functional size of the new lesions plays an important role in predicting the clinical response. Validation of these results in larger cohorts of patients is warranted.


18F-FDG PET/CT Metastatic melanoma Ipilimumab Treatment response evaluation Immunotherapy 



This study was supported in part by the German Cancer Aid under the project “Therapy monitoring of ipilimumab based on the quantification of F-18-FDG kinetics with 4D PET/CT (dPET-CT) in patients with melanoma (stage 4)”. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.

Compliance with ethical standards

Conflicts of interest

Julia Winkler received speakers honoraria from MSD, and travel support from AMGEN, BMS, MSD, Philochem and Roche. Jessica C. Hassel received honoraria for talks and travel expenses from BMS. The other authors declare no conflicts of interest.

Ethical approval

The study was approved by the Ethics Committee of the University of Heidelberg (S-107/2012) and the Federal Agency for Radiation Protection (Bundesamt für Strahlenschutz).

Informed consent

Informed consent was obtained from all individual participants included in the study. This study did not include any studies with animals performed by any of the authors.


  1. 1.
    Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981;47:207–14.CrossRefPubMedGoogle Scholar
  2. 2.
    Young H, Baum R, Cremerius U, Herholz K, Hoekstra O, Lammertsma AA, et al. 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. 1999;35:1773–82.CrossRefPubMedGoogle Scholar
  3. 3.
    Missailidis S. Anticancer therapeutics. Chichester: Wiley-Blackwell; 2008.CrossRefGoogle Scholar
  4. 4.
    Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, et al. Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci U S A. 2008;105:3005–10.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbé C, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–20.CrossRefPubMedGoogle Scholar
  6. 6.
    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;42:386–96.CrossRefPubMedGoogle Scholar
  7. 7.
    Balch CM, Gershenwald JE, Soong S-J, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–206.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Lin E, Alavi A. PET and PET/CT: a clinical guide. New York: Thieme; 2009.Google Scholar
  9. 9.
    PMOD Technologies. Iso-contour mode (Pseudo-Snake). Zürich: PMOD Technologies LLC. Accessed 5 November 2017.
  10. 10.
    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:e143–52.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, et al. A new member of the immunoglobulin superfamily – CTLA-4. Nature. 1987;328:267–70.CrossRefPubMedGoogle Scholar
  12. 12.
    Food and Drug Administration. Yervoy® (ipilimumab) injection, for intravenous use. Silver Spring, MD: Food and Drug Administration; 2015. Accessed 5 November 2017.
  13. 13.
    Goode EF, Smyth EC. Immunotherapy for gastroesophageal cancer. J Clin Med. 2016;5, 84.CrossRefPubMedCentralGoogle Scholar
  14. 14.
    Dimitrakopoulou-Strauss A. PET-based molecular imaging in personalized oncology: potential of the assessment of therapeutic outcome. Future Oncol. 2015;11:1083–91.CrossRefPubMedGoogle Scholar
  15. 15.
    Wahl RL. 2013 SNMMI highlights lecture: oncology. J Nucl Med. 2013;54:11N–22N.PubMedGoogle Scholar
  16. 16.
    Ribas A, Benz MR, Allen-Auerbach MS, Radu C, Chmielowski B, Seja E, et al. Imaging of CTLA4 blockade-induced cell replication with (18)F-FLT PET in patients with advanced melanoma treated with tremelimumab. J Nucl Med. 2010;51:340–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Breki C-M, 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;6:61.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kong BY, Menzies AM, Saunders CAB, 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;29:572–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Cho SY, Lipson EJ, Im H-J, Rowe SP, Gonzalez EM, Blackford A, et al. 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. 2017;58:1421–8.CrossRefPubMedGoogle Scholar
  20. 20.
    Wong AN, 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.CrossRefPubMedGoogle Scholar
  21. 21.
    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;3:1185–92.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kähler KC, Hassel JC, Heinzerling L, Loquai C, Mössner R, Ugurel S, et al. Management of side effects of immune checkpoint blockade by anti-CTLA-4 and anti-PD-1 antibodies in metastatic melanoma. J Dtsch Dermatol Ges. 2016;14:662–81.Google Scholar
  23. 23.
    Wachsmann JW, Ganti R, Peng F. Immune-mediated disease in Ipilimumab immunotherapy of melanoma with FDG PET-CT. Acad Radiol. 2017;24:111–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  1. 1.Medical PET Group-Biological Imaging, Clinical Cooperation Unit Nuclear MedicineGerman Cancer Research CenterHeidelbergGermany
  2. 2.Department of Dermatology and National Center for Tumor DiseasesUniversity Hospital HeidelbergHeidelbergGermany
  3. 3.Department of BiostatisticsGerman Cancer Research CenterHeidelbergGermany
  4. 4.Division of Nuclear MedicineUniversity of HeidelbergHeidelbergGermany

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