A prospective comparison of [⁶⁸Ga]Ga-FAPI-2286 and [¹⁸F]FDG PET/CT for evaluating viable brain metastases in lung cancer

Standard [¹⁸F]FDG PET/CT has suboptimal sensitivity for assessing viable brain metastases due to high physiological brain background. Fibroblast activation protein (FAP)-targeted PET, with minimal brain expression, may overcome this limitation. This study aimed to compare the diagnostic performance of [⁶⁸Ga]Ga-FAPI-2286 versus [¹⁸F]FDG PET/CT for detecting viable brain metastases in lung cancer and evaluate their complementary value. In this prospective intra-individual study, 24 lung cancer patients with brain metastases underwent both [⁶⁸Ga]Ga-FAPI-2286 and [¹⁸F]FDG PET/CT within 3 days. Images were independently and blindly reviewed by two senior nuclear medicine physicians. Diagnostic performance (sensitivity, specificity, accuracy) was evaluated per-lesion and per-patient against a composite reference standard (characteristic imaging features, ≥ 3-month follow-up, comprehensive clinical evaluation). Quantitative parameters (SUVmax, target-to-background ratio [TBR], background uptake [SUVbgd]) and complementary detection patterns were analyzed. Among 43 lesions (36 viable, 7 non-viable), [⁶⁸Ga]Ga-FAPI-2286 demonstrated significantly higher per-lesion sensitivity (83.3% vs. 75.0%, P = 0.032) and accuracy (86.0% vs. 79.1%, P = 0.002) than [¹⁸F]FDG. Per-patient sensitivity (89.5% vs. 73.7%, P = 0.004) and accuracy (91.7% vs. 79.2%, P = 0.003) were also superior. The AUC for [⁶⁸Ga]Ga-FAPI-2286 was 0.917 (95% CI: 0.834–0.999) versus 0.875 (95% CI: 0.772–0.978) for [¹⁸F]FDG ( P = 0.031). [⁶⁸Ga]Ga-FAPI-2286 provided dramatically higher TBR in viable lesions (85.39 ± 57.99 vs. 5.19 ± 2.56, P < 0.001) due to minimal physiological brain background (SUVbgd 0.09 ± 0.11). Dual-tracer imaging supplemented the detection of 15 viable tumor lesions in 9 patients that were missed by either single tracer alone, increasing per-lesion sensitivity to 100% and preventing potential underdiagnosis in 47.4% (9/19) of patients with viable disease. [⁶⁸Ga]Ga-FAPI-2286 PET/CT outperforms [¹⁸F]FDG in identifying viable brain metastases from lung cancer, primarily due to its exceptional tumor-to-background contrast. The complementary detection patterns of the two tracers suggest that combined use can minimize diagnostic omissions, supporting an integrative imaging paradigm for more accurate intracranial staging/restaging. Registered 10 October 2022, https://www.chictr.org.cn , ChiCTR2100044131.