[18F]FDG and [68Ga]Ga-FAPI-04-Directed Imaging for Outcome Prediction in Patients with High-Grade Neuroendocrine Neoplasms.

We aimed to quantitatively investigate the prognostic value of PET-based biomarkers on [¹⁸F]FDG and [⁶⁸Ga]Ga-fibroblast activation protein inhibitor (FAPI)-04 PET/CT in patients with highly aggressive neuroendocrine neoplasms (NENs) and to compare the visually assessed differences in uptake on both examinations with progression-free survival (PFS). Methods: In this single-center retrospective analysis, 20 patients with high-grade NENs had undergone [¹⁸F]FDG and [⁶⁸Ga]Ga-FAPI-04 PET. Both PET scans were visually compared, and the presence of [¹⁸F]FDG-positive, [⁶⁸Ga]Ga-FAPI-04-negative (FDG+/FAPI-) lesions was noted. In addition, we assessed maximum, peak, and mean SUV; tumor volume (TV); and total lesion uptake (TLU = TV × SUV_mean) for both radiotracers using a 40% lesion-based threshold. The results of quantitative and visual analysis were correlated with PFS using log-rank analysis or univariate Cox regression. PFS was defined radiographically using RECIST 1.1., clinically using signs of disease progression, or as death. Results: Most primary tumors were located in the gastrointestinal tract (13/20 patients, 65%) or were cancer of unknown primary (5/20 patients, 25%). FDG+/FAPI- lesions were found in 9 of 20 patients (45%). Patients with FDG+/FAPI- lesions had a significantly decreased PFS of 4 mo, compared with 9 mo for patients without FDG+/FAPI- metastases (P = 0.0063 [log-rank test]; hazard ratio [HR], 5.637; 95% CI 1.619-26.16; P = 0.0110 [univariate Cox regression]). On univariate analysis, a significant correlation was also found between PFS and TV for both radiotracers ([¹⁸F]FDG: mean TV, 258 ± 588 cm³; HR, 1.024 [per 10 cm³]; 95% CI, 1.007-1.046; P = 0.0204) ([⁶⁸Ga]Ga-FAPI-04: mean TV, 130 ± 192 cm³; HR, 1.032 [per 10 cm³]; 95% CI, 1.001-1.062; P = 0.0277) and TLU on [¹⁸F]FDG PET (mean TLU, 1,931 ± 4,248 cm³; HR, 1.004 [per 10 cm³]; 95% CI, 1.001-1.007; P = 0.0135). Conclusion: The presence of discordant FDG+/FAPI- lesions is associated with a significantly shorter PFS, which might indicate more aggressive disease prone to early progression. Dual-tracer PET/CT of patients with highly aggressive NENs could help guide treatment decisions or identify high-risk lesions for additional local therapeutic approaches.