The inferior performance of [68Ga]Ga-FAPI-04 PET/CT as a diagnostic and theranostic biomarker in [177Lu]Lu-DOTATATE refractory well-differentiated neuroendocrine tumors

Abstract

Purpose: We aimed to investigate the potential of [⁶⁸Ga]Ga-FAPI-04 PET/CT as an alternative diagnostic and theranostic tool in well-differentiated NETs refractory to [¹⁷⁷Lu]Lu-DOTATATE therapy.

Methods: Patients who received at least two cycles of [¹⁷⁷Lu]Lu-DOTATATE therapy for metastatic NETs and progressed under treatment were included. All patients had performed [⁶⁸Ga]Ga-DOTATATE and [⁶⁸Ga]Ga-FAPI-04 PET/CT within 3 weeks. The number of PET-positive lesions related to NETs and tumor sites was documented. Mann-Whitney U and chi-square tests were used to compare SUVmax levels of tracers and the number of detected metastases.

Results: Twelve patients (7 male, 5 female) who met the eligibility criteria were included in the study. Ten patients had grade 1-2 NET of various origins, and two had paraganglioma and pheochromocytoma. One hundred ninety-eight of 230 lesions (86%) were SSTR positive with a median SUVmax of 16.6 (2.2-76.5), and 88 of 230 lesions (38.2%) were [⁶⁸Ga]Ga-FAPI-04 positive with a median SUVmax of 5.1 (2.3-21). Median SUVmax level and detected number of tumors were significantly higher in [⁶⁸Ga]Ga-DOTATATE PET/CT (p=<0.001). [⁶⁸Ga]Ga-FAPI-04 PET/CT was completely (n:2) or almost completely (n:3) negative in 5 (42%) patients. Two (17%) patients had flip-flop SSTR/FAPI uptake in tumors. In four patients (33%), tumor uptake or the number of PET-positive lesions was inferior in [⁶⁸Ga]Ga-FAPI-04 PET/CT. In only one patient (8%), tumor uptakes were higher in [⁶⁸Ga]Ga-FAPI-04 PET/CT. Low-dose [¹⁷⁷Lu]Lu-FAPI-46 dosimetry was performed on the FAPI-dominant patient; absorbed radiation doses per GBq were 1.26 Gy, 0.36 Gy, 0.32 Gy, and 0.2 Gy for kidneys, liver, spleen, and total body, respectively. The mean absorbed dose per GBq was 0.33 Gy for liver mass and 0.41 Gy for metastatic lymph nodes.

Conclusion: Our preliminary results demonstrated that [⁶⁸Ga]Ga-FAPI-04 PET/CT mainly failed in well-differentiated NETs refractory to [¹⁷⁷Lu]Lu-DOTATATE therapy and had a limited role as an alternative diagnostic or theranostic agent. Further investigations with a larger patient population are required to determine the impact of [⁶⁸Ga]Ga-FAPI-04 PET/CT on NETs.

Keywords: 68Ga-DOTATATE PET/CT; 68Ga-FAPI PET/CT; Cancer-associated fibroblast; Neuroendocrine tumor; Theranostic.