Triple-tracer PET (¹⁸F-FDG, ⁶⁸Ga-DOTANOC, ⁶⁸Ga-FAPI) maps inter- and intra-lesional heterogeneity in metastatic high-grade neuroendocrine neoplasms

Abstract

This pilot study evaluated the diagnostic performance of a triple-tracer PET/CT protocol in 13 patients with advanced, high-grade neuroendocrine neoplasms (NENs; Ki-67 > 40%). NENs are characterized by biological heterogeneity and variable tracer avidity, complicating accurate staging and therapy selection. Each patient underwent imaging with [18F] FDG (metabolic activity), [68Ga] Ga-DOTANOC (somatostatin receptor expression), and [68Ga] Ga-FAPI-04 (fibroblast activation) within one week, enabling complementary biological assessment. A total of 92 metastatic lesions were analyzed (29 hepatic, 36 osseous, 27 nodal). In the liver, [18F] FDG demonstrated the highest uptake (SUV_max 18.6 ± 5.3) compared with [68Ga] Ga- FAPI (12.3 ± 3.5) and [68Ga] Ga-DOTANOC (7.8 ± 2.6). Bone metastases were predominantly [68Ga] Ga-FAPI-avid (SUV_max 9.1 ± 3.0), with 23% detected by [68Ga] Ga-FAPI. Lymph nodes exhibited mixed avidity ([18F] FDG 10.2 ± 4.3; [68Ga] Ga- FAPI 7.0 ± 2.7; [68Ga] Ga-DOTANOC 5.2 ± 3.0). Marked inter- and intra-patient heterogeneity was observed across tracers. The combined protocol improved lesion characterization, reduced false negatives, and revealed heterogeneity that would have been underestimated by single-tracer imaging. These findings demonstrate the feasibility and potential clinical utility of integrating [18F] FDG, [68Ga] Ga-DOTANOC and [68Ga] Ga-FAPI PET in high-grade NENs, providing a more comprehensive theranostics roadmap. Given the limited sample size and statistical power, larger prospective studies are warranted to validate these preliminary observations and refine patient selection for multitracer imaging or future “cocktail” therapy strategies.