Incidence and Clinical Impact of Inflammatory Fluorodeoxyglucose Positron Emission Tomography Uptake After Neoadjuvant Pembrolizumab in Patients with Organ-confined Bladder Cancer Undergoing Radical Cystectomy - Beyond the Abstract

The introduction of immunotherapy strategies in the therapeutic armamentarium for almost all types of tumors could redesign the role of fluorodeoxyglucose positron emission tomography (FDG-PET/CT). Immune stimulation related to immunotherapy can lead to inflammatory reactions in many organs and the differential diagnosis between immune-related changes and progression of disease needs caution. Some data suggest that the development of immune-related adverse events (irAEs) could be associated with improved clinical outcomes in patients treated with immunotherapy, and this hypothesis has also been proposed by considering irAEs detected on PET/CT in advanced solid tumors.1,2 However, the role of Fluorodeoxyglucose Positron Emission Tomography (PET/CT) in the context of non-metastatic, localized solid tumors receiving immune-checkpoint inhibitors is still an under-investigated field.

The PURE-01 study (NCT02736266) was a trial evaluating single-agent neoadjuvant immunotherapy with pembrolizumab in patients with clinical stage T2-4aN0M0 muscle-invasive bladder cancer. Updated results of this trial showed a pathologic complete response rate of 37%.3 An imaging biomarker program focused on staging and response evaluation was included in the PURE-01 trial. One of the objectives of this project included the evaluation of the role of PET/CT to visualize the development of irAEs and the assessment of the association of irAES detected on PET/CT with clinical outcomes.4

Patients enrolled in PURE-01 were staged with PET/CT scan, contrast-enhanced thorax-abdomen CT scan, and bladder multiparametric MRI during screening and after three cycles of pembrolizumab, before radical cystectomy (RC). PET/CT was considered to be suggestive of irAEs whenever a new onset of abnormal uptake in any organ, outside of the physiological uptake areas, was found after treatment compared with baseline pre-pembrolizumab PET/CT. A total of 103 patients with paired pre- and post-therapy PET/CT were included in this analysis. Post pembrolizumab PET/CT showed inflammatory changes (irAEs + PET/CT) in several target organs/regions in 40 patients (39%). The most frequent affected organs were the thyroid (N = 18), stomach (N = 14), mediastinal lymph nodes (N = 9), and lung (N = 5). Among these patients, only 18 (45%) showed corresponding clinical adverse events (signs/symptoms or laboratory changes), all of grade 1 or 2, most frequently thyroiditis (N = 15/18). We next explored the association between the development of irAEs + PET/CT and clinical outcomes. The rate of complete pathological responses (ypT0N0) was 47.5% (19/40) in patients with irAEs + PET/CT versus (vs.) 32% (20/63) in patients without irAEs at PET/CT (irAEs–PET/CT), and downstaging to non–muscle-invasive disease (ypT £1N0) was 70% (28/40) in irAEs + PET/CT vs. 55.5% (35/63) in irAEs - PET/CT. However, at univariate analyses, irAEs + PET/CT did not predict ypT0N0 nor ypT£1N0. PFS rate at 24 months was higher in irAE + PET/CT patients (88.3% [95% confidence interval [CI]: 77.8–100] in irAE + PET/CT vs. 76.5% [95% CI: 64.4–90.8] in irAE- PET/CT), however the difference was not statistically significant. The low number of events should be considered when interpreting this result and a longer follow up is needed for a proper evaluation.

Whether the detection on PET/CT of sub-clinical irAEs could have a clinical impact on patients is yet to be established. However, this study, which considered patients with localized disease, could represent a model to assess the immune-related inflammatory changes detected on PET/CT without the confounding related to the metastatic disease sites. The results of this study could be informative when judging the increased FDG uptake on PET/CT of metastatic patients, and the high proportion of patients who developed irAE+ PET/CT highlights that a careful evaluation is needed when interpreting PET/CT images to avoid misinterpretation of the results.

Written by: Laura Marandino, MD, and Andrea Necchi, MD, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy


  1. Nobashi, Tomomi, Lucia Baratto, Sunil A. Reddy, Sandhya Srinivas, Akira Toriihara, Negin Hatami, Thomas K. Yohannan, and Erik Mittra. "Predicting response to immunotherapy by evaluating tumors, lymphoid cell-rich organs, and immune-related adverse events using FDG-PET/CT." Clinical nuclear medicine 44, no. 4 (2019): e272-e279.
  2. Sachpekidis, Christos, Lionel Larribère, Annette Kopp-Schneider, Jessica C. Hassel, and Antonia Dimitrakopoulou-Strauss. "Can benign lymphoid tissue changes in 18 F-FDG PET/CT predict response to immunotherapy in metastatic melanoma?." Cancer Immunology, Immunotherapy 68, no. 2 (2019): 297-303.
  3. Necchi, Andrea, Daniele Raggi, Andrea Gallina, Russell Madison, Maurizio Colecchia, Roberta Lucianò, Rodolfo Montironi et al. "Updated results of PURE-01 with preliminary activity of neoadjuvant pembrolizumab in patients with muscle-invasive bladder carcinoma with variant histologies." European urology 77, no. 4 (2020): 439-446.
  4. Marandino, Laura, Antonella Capozza, Marco Bandini, Daniele Raggi, Elena Farè, Filippo Pederzoli, Andrea Gallina et al. "Incidence and Clinical Impact of Inflammatory Fluorodeoxyglucose Positron Emission Tomography Uptake After Neoadjuvant Pembrolizumab in Patients with Organ-confined Bladder Cancer Undergoing Radical Cystectomy." European Urology Focus (2020).
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