Impact of [68Ga]-FAPI /[18F]FDG- dual tracer PET/CT imaging on radiotherapeutic management and target volume definition in esophageal cancer

Introduction: Lately, the development of PET/CT-tracer acting as an Inhibitor of Fibroblast Activation Protein (FAP) like [⁶⁸Ga]-FAP-Inhibitor (FAPI)-46 has become an interesting diagnostic tool in oncological imaging. Since overexpression of FAP has been seen in several tumor microenvironments, further focus has been shifted to [⁶⁸Ga]-FAPI-PET/CT to evaluate its feasibility compared to [¹⁸F]-Fluordesoxyglucose (FDG)-PET/CT. Here, we aimed to compare the impact of [⁶⁸Ga]-FAPI-46-PET/CT and [¹⁸F]- FDG-PET/CT on the initial staging of esophageal cancer (EC) prior to radiotherapy.

Methods: We retrospectively analyzed [¹⁸F]FDG-PET/CT and [⁶⁸Ga]-FAPI-46-PET/CT for initial staging of 32 patients with histological identified EC. [⁶⁸Ga]-FAPI-46-PET/CT was performed either on the same day as [¹⁸F]FDG-PET/CT according to a recently published dual-tracer PET/CT-protocol (n=23) or on a day other than the [¹⁸F]FDG-PET/CT scan (n=9). Functional tumor volume (FTV) of the primary tumor, metastases, and total tumor burden were calculated for [¹⁸F]FDG-PET/CT as well as for [⁶⁸Ga]-FAPI-46-PET/CT (including dual-tracer-PET/CT-protocol). In case of dual-tracer-PET/CT-protocol a bloodpool-adapted FTV measurement was used for correction of increased background uptake meaning that instead of a fixed threshold of Standardized Uptake Value (SUV) 4.0 a 2.5-fold increase of SUV of the bloodpool was used for FTV measurements. Furthermore, gross tumor volume (GTV) was measured prior to radiotherapy for [¹⁸F]FDG-PET/CT and separately for [⁶⁸Ga]-FAPI-46-PET/CT (including dual-tracer-PET/CT-protocol). Status of nodal and distant metastases was evaluated for [¹⁸F]FDG-PET/CT as well as for [⁶⁸Ga]-FAPI-46-PET/CT.

Results: Primary tumors were detected in all 32 patients (25 male and 7 female) using [⁶⁸Ga]-FAPI-46-PET/CT, whereas [¹⁸F]FDG-PET/CT lead to a detection rate of 93% for primary tumors (30/32). In 38% (12/32) of the patients [⁶⁸Ga]-FAPI-PET/CT lead to an upstaging in nodal status and in 6% (2/32) additional distant metastases (1 liver metastasis, 1 soft tissue metastasis) were detected using [⁶⁸Ga]-FAPI-46-PET/CT compared to [¹⁸F]FDG-PET/CT. Three lymph nodes were only visible in [⁶⁸Ga]-FAPI-46-PET/CT with no tracer accumulation in [¹⁸F]FDG-PET/CT. Radiation field was adapted in 16% (5/32) and a change of therapy regime was made in 9% due to results of [⁶⁸Ga]-FAPI-46-PET/CT (3/32).

FTV of the primary tumors (p=0.002; FAPI: 49.2±63.7ml; FDG: 32.8±49.7ml) and FTV of total tumor burden (p<0.001; FAPI: 77.0±84.0ml; FDG: 58.1±76.2ml) were significantly larger in [⁶⁸Ga]-FAPI-46-PET/CT compared to [¹⁸F]FDG-PET/CT. In contrast, FTV of metastases was significantly smaller in [⁶⁸Ga]-FAPI-46-PET/CT than in [¹⁸F]FDG-PET/CT (n=24; p=0.008; FAPI: 33.7±74.6ml; FDG: 40.0±82.0ml). Additionally, GTVs were significantly larger in [⁶⁸Ga]-FAPI-46 -PET/CT compared to [¹⁸F]FDG-PET/CT (p<0.001; FAPI: 99.0±98ml; FDG: 80.3±84.4ml).

Conclusions: [⁶⁸Ga]-FAPI-46 -PET/CT not only as single tracer but also in combination with [¹⁸F]FDG-PET/CT as acquired within a dual-tracer-protocol seems to be a promising tool in primary staging of EC by leading to potential changes in treatment concepts and the radiotherapy field through detecting more suspect lesions as well as higher total FTVs as compared to [¹⁸F]FDG-PET/CT only. Further studies are needed to assess the clinical benefit for e.g. survival and progression free survival deriving from the use of [⁶⁸Ga]-FAPI-46-PET/CT in EC prior to radiotherapy.