Abstract
BackgroundThe usage of immune checkpoint inhibitors (ICIs) is the standard practice for the treatment of metastatic melanoma. However, a significant amount of patients show no response to immunotherapy, while issues on its reliable response interpretation exist. Aim of this study was to investigate the phenomenon of early disease progression in 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in melanoma patients treated with ICIs.MethodsThirty-one patients under ICIs serially monitored with 18F-FDG PET/CT were enrolled. All patients exhibited progressive metabolic disease (PMD) after two ICIs’ cycles according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, and were characterized as unconfirmed PMD (uPMD). They were further followed with at least one PET/CT for either confirmation of PMD (cPMD) or demonstration of pseudoprogression remission. Patients were also evaluated with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT). Moreover, in an attempt to investigate immune activation, the spleen to liver ratios (SLRmean, SLRmax) of 18F-FDG uptake were measured.ResultsMedian follow up was 69.7 months [64.6–NA]. According to EORTC, 26/31 patients with uPMD eventually showed cPMD (83.9%) and 5/31 patients showed pseudoprogression (16.1%). Patients with cPMD (n = 26) had a median OS of 10.9 months [8.5–NA], while those with pseudoprogression (n = 5) did not reach a median OS [40.9–NA]. Respectively, after application of PERCIMT, 2/5 patients of the pseudoprogression group were correctly classified as non-PMD, reducing the uPMD cohort to 29 patients; eventually, 26/29 patients demonstrated cPMD (89.7%) and 3/29 pseudoprogression (10.3%). One further patient with pseudoprogression exhibited transient, sarcoid-like, mediastinal/hilar lymphadenopathy, a known immune-related adverse event (irAE). Finally, patients eventually showing cPMD exhibited a significantly higher SLRmean than those showing pseudoprogression after two ICIs’ cycles (p = 0.038).ConclusionPET/CT, performed already after administration of two ICIs’ cycles, can identify the majority of non-responders in melanoma immunotherapy. In order to tackle however, the non-negligible phenomenon of pseudoprogression, another follow-up PET/CT, the usage of novel response criteria and vigilance over emergence of radiological irAEs are recommended. Moreover, the investigation of spleen glucose metabolism may offer further prognostic information in melanoma patients under ICIs.
Highlights
The usage of immune checkpoint inhibitors (ICIs) is the standard practice for the treatment of meta‐ static melanoma
Concerning the pseudoprogression group, 4/5 patients were under ipilimumab, while 1/5 patient was under combination treatment of ipilimumab/nivolumab
Compared to EORTC, the application of PET Response Evaluation Criteria for Immunotherapy (PERCIMT) classified 2/5 patients of the above-mentioned pseudoprogression group as stable metabolic disease (SMD), since they did not fulfill the requirements for progression according to these criteria
Summary
The usage of immune checkpoint inhibitors (ICIs) is the standard practice for the treatment of meta‐ static melanoma. All patients exhibited progressive metabolic disease (PMD) after two ICIs’ cycles according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, and were characterized as unconfirmed PMD (uPMD) They were further fol‐ lowed with at least one PET/CT for either confirmation of PMD (cPMD) or demonstration of pseudoprogression remis‐ sion. The usage of ICIs is considered nowadays the standard practice for the treatment of metastatic melanoma [5] Despite these improvements, a significant amount of patients—approximately 40–45%—show no response to immunotherapy [6]. Immunotherapeutic agents act markedly different than usual cytotoxic approaches, notably by generating inflammations rather than direct lysis This unique mechanism of action can lead to novel response patterns, which pose relevant challenges in the interpretation of treatment response by conventional imaging approaches [7]. Regardless of etiology, since pseudoprogression may be misclassified as progressive disease, its reliable and early identification would offer significant therapeutic implications in patient management
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