Impact of FAPI-46/dual-tracer PET/CT imaging on radiotherapeutic management in esophageal cancer

Wegen et al. Radiation Oncology (2024) 19:44 https://doi.org/10.1186/s13014-024-02430-9 Radiation Oncology Open Access RESEARCH Impact of FAPI-46/dual-tracer PET/CT imaging on radiotherapeutic management in esophageal cancer Simone Wegen1,2* , Karina Claus1,2, Philipp Linde1,2, Johannes Rosenbrock1,2, Maike Trommer1,2,8, Thomas Zander2,3, Armin Tuchscherer2,3, Christiane Bruns4, Hans Anton Schlößer4,9, Wolfgang Schröder4, Marie-Lisa Eich5, Thomas Fischer6, Klaus Schomäcker6, Alexander Drzezga6,7, Carsten Kobe6, Katrin Sabine Roth6 and Jasmin Josefine Weindler6 Abstract Background Fibroblast activation protein (FAP) is expressed in the tumor microenvironment (TME) of various cancers. In our analysis, we describe the impact of dual-tracer imaging with Gallium-68-radiolabeled inhibitors of FAP (FAPI-46-PET/CT) and fluorodeoxy-D-glucose (FDG-PET/CT) on the radiotherapeutic management of primary esophageal cancer (EC). Methods 32 patients with EC, who are scheduled for chemoradiation, received FDG and FAPI-46 PET/CT on the same day (dual-tracer protocol, 71%) or on two separate days (29%) We compared functional tumor volumes (FTVs), gross tumor volumes (GTVs) and tumor stages before and after PET-imaging. Changes in treatment were categorized as “minor” (adaption of radiation field) or “major” (change of treatment regimen). Immunohistochemistry (IHC) staining for FAP was performed in all patients with available tissue. Results Primary tumor was detected in all FAPI-46/dual-tracer scans and in 30/32 (93%) of FDG scans. Compared to the initial staging CT scan, 12/32 patients (38%) were upstaged in nodal status after the combination of FDG and FAPI-46 PET scans. Two lymph node metastases were only visible in FAPI-46/dual-tracer. New distant metastasis was observed in 2/32 (6%) patients following FAPI-4 -PET/CT. Our findings led to larger RT fields (“minor change”) in 5/32 patients (16%) and changed treatment regimen (“major change”) in 3/32 patients after FAPI-46/dual-tracer PET/CT. GTVs were larger in FAPI-46/dual-tracer scans compared to FDG-PET/CT (mean 99.0 vs. 80.3 ml, respectively (p < 0.001)) with similar results for nuclear medical FTVs. IHC revealed heterogenous FAP-expression in all specimens (mean H-score: 36.3 (SD 24.6)) without correlation between FAP expression in IHC and FAPI tracer uptake in PET/CT. Conclusion We report first data on the use of PET with FAPI-46 for patients with EC, who are scheduled to receive RT. Tumor uptake was high and not depending on FAP expression in TME. Further, FAPI-46/dual-tracer PET had relevant impact on management in this setting. Our data calls for prospective evaluation of FAPI-46/dual-tracer PET to improve clinical outcomes of EC. *Correspondence: Simone Wegen Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Wegen et al. Radiation Oncology (2024) 19:44 Page 2 of 11 Keywords FDG, Esophageal cancer, FAPI-46, Radiotherapy planning, PET-based Introduction Esophageal carcinomas (EC) account for approximately 1% of all malignant diseases and 2% of all cancer-related deaths in Germany [1] and the incidence of adenocarcinoma is growing. Exact tumor staging is crucial to select the right treatment option for each patient. 30–40% of patients are in a resectable tumor stage when first diagnosed. Both, undertreatment of patients with undetected metastatic lesions (cM1) as well as overtreatment (intense chemotherapy regimens) in patients with early-stage EC and wrong positive findings in conventional staging can impact patients’ prognosis and outcomes. FDG PET/CT is a helpful tool for tumor delineation in radiation oncology (RO) and has become, if available, a recommended diagnostic tool in many countries Table 1 Patient characteristics Overall (N = 32) Age Mean (SD) Sex female male BMI Mean (SD) Smoker current former never Tumor grade 1 2 3 missing Histology adenocarcinoma SCC Intended Treatment (pre-PET) definitive CRT neoadjuvant CRT other N-stage (pre-PET) 0 1 2 3 M-stage (pre-PET) 0 1* 64.6 (12.3) 6 (18.8%) 26 (81.3%) 24.2 (5.38) 14 (43.8%) 11 (34.4%) 7 (21.9%) 3 (9.4%) 19 (59.4%) 9 (28.1%) 1 (3.1%) 15 (46.9%) 17 (53.1%) 15 (46.9%) 16 (50.0%) 1 (3.1%) 9 (28.1%) 10 (31.3%) 6 (18.8%) 7 (21.9%) 30 (93.8%) 2 (6.3%) SD = standard deviation, BMI = body mass index, SCC = squamous cell carcinoma, CRT = chemoradiotherapy, PET = Positron Emission Tomography *= distal EC with suspicion of a cervical (supraclavicular) metastasis [2], yet there is no consensus on radiotherapeutic management of FDG-positive lesions. Sensitivity for detection of lymph node (LN) metastasis in FDG PET/CT is described as 49%, specificity 87%% and accuracy 68% [3]. In comparison, endobronchial ultrasound (EUS) and fine-needle aspiration of LN show higher rates of pooled specificity and accuracy (81% and 77%, respectively). Given poor prognosis of EC, there is great interest in identifying novel diagnostic targets. In several tumor entities, FAPI-labelled PET tracers showed to be superior to conventional FGD PET/CT [4]. There is first evidence, that initial tumor staging with FAPI PET/CT shows good diagnostic performance in detecting primary tumor and lymph node metastases in patients with EC [5]. In a newly developed dual-tracer protocol, we showed greater Gross Tumor Volumes (GTVs) derived from FAPI-46/dual-tracer PET/CT in a case series of cervical, head and neck and esophageal cancer patients [6, 7] leading to larger irradiation fields. Our aim in this analysis is to describe the impact of imaging with radiolabeled inhibitors of FAPI ([68Ga]Ga-FAPI-46-PET/CT) and fluorodeoxy-D-glucose ([18F]F-FDG-PET/CT) on radiotherapeutic management of esophageal cancer (EC). Patients and methods Patient cohort, dual-tracer protocol and PET/CT imaging Our retrospective analysis included 32 patients with primary esophageal cancer who received PET/CT scans between May 2020 and May (...truncated)