Repetitive Early 68Ga-FAPI PET Acquisition Comparing 68Ga-FAPI-02, 68Ga-FAPI-46, and 68Ga-FAPI-74: Methodologic and Diagnostic Implications for Malignant, Inflammatory/Reactive, and Degenerative Lesions

Abstract

⁶⁸Ga-labeled fibroblast activation protein (FAP) inhibitor (⁶⁸Ga-FAPI) PET targets ⁶⁸Ga-FAPI-positive activated fibroblasts and is a promising imaging technique for various types of cancer and nonmalignant pathologies. However, discrimination between malignant and nonmalignant ⁶⁸Ga-FAPI-positive lesions based on static PET with a single acquisition time point can be challenging. Additionally, the optimal imaging time point for ⁶⁸Ga-FAPI PET has not been identified yet, and different ⁶⁸Ga-FAPI tracer variants are currently used. In this retrospective analysis, we evaluate the diagnostic value of repetitive early ⁶⁸Ga-FAPI PET with ⁶⁸Ga-FAPI-02, ⁶⁸Ga-FAPI-46, and ⁶⁸Ga-FAPI-74 for malignant, inflammatory/reactive, and degenerative lesions and describe the implications for future ⁶⁸Ga-FAPI imaging protocols. Methods: Whole-body PET scans of 24 cancer patients were acquired at 10, 22, 34, 46, and 58 min after the administration of 150-250 MBq of ⁶⁸Ga-FAPI tracer molecules (8 patients each for ⁶⁸Ga-FAPI-02, ⁶⁸Ga-FAPI-46, and ⁶⁸Ga-FAPI-74). Detection rates and SUVs (SUV_max and SUV_mean) for healthy tissues, cancer manifestations, and nonmalignant lesions were measured, and target-to-background ratios (TBR) versus blood and fat were calculated for all acquisition time points. Results: For most healthy tissues except fat and spinal canal, biodistribution analysis showed decreasing uptake over time. We analyzed 134 malignant, inflammatory/reactive, and degenerative lesions. Detection rates were minimally reduced for the first 2 acquisition time points and remained at a constant high level from 34 to 58 min after injection. The uptake of all 3 variants was higher in malignant and inflammatory/reactive lesions than in degenerative lesions. ⁶⁸Ga-FAPI-46 showed the highest uptake and TBRs in all pathologies. For all variants, TBRs versus blood constantly increased over time for all pathologies, and TBRs versus fat were constant or decreased slightly. Conclusion: ⁶⁸Ga-FAPI PET/CT is a promising imaging modality for malignancies and benign lesions. Repetitive early PET acquisition added diagnostic value for the discrimination of malignant from nonmalignant ⁶⁸Ga-FAPI-positive lesions. High detection rates and TBRs over time confirmed that PET acquisition earlier than 60 min after injection delivers high-contrast images. Additionally, considering clinical feasibility, acquisition at 30-40 min after injection might be a reasonable compromise. Different ⁶⁸Ga-FAPI variants show significant differences in time-dependent biodistributional behavior and should be selected carefully depending on the clinical setting.

Keywords: FAPI; PET; biodistribution; cancer; fibroblast activation protein.

Graphical abstract

FIGURE 1.

Biodistribution analysis (SUV_mean [red] and SUV_max [blue] ± SD) of 24 patients, 8 patients per ⁶⁸Ga-FAPI variant, with high-uptake (A) and low-uptake (B) tissues over time at acquisition time points of 10 min (1), 22 min (2), 34 min (3), 46 min (4), and 58 min (5) after application of ⁶⁸Ga-FAPI variants of ⁶⁸Ga-FAPI-02, ⁶⁸Ga-FAPI-46, or ⁶⁸Ga-FAPI-74.

FIGURE 2.

Dominating ⁶⁸Ga-FAPI variant for each considered tissue, with red indicating highest uptake; yellow, medium uptake; green, lowest uptake; and orange, approximately equal uptake.

FIGURE 3.

(A) Representative maximum-injection projections of ⁶⁸Ga-FAPI PET/CT for ⁶⁸Ga-FAPI-02 (top row, 56-y-old man with resected pancreatic carcinoma, staging for metastases, no local recurrence, single hepatic metastasis), ⁶⁸Ga-FAPI-46 (middle row, 64-y-old man with pancreatic cancer, staging for suspected local recurrence, no metastases), and ⁶⁸Ga-FAPI-74 (bottom row, 60-y-old man with pancreatic carcinoma, staging in advance of radiation therapy, primary, single hepatic metastasis) over time with acquisition time points of 10 min (1), 22 min (2), 34 min (3), 46 min (4), and 58 min (5) after application. (B) Representative axial ⁶⁸Ga-FAPI PET/CT images of upper thorax showing uptake for blood, muscle, and lungs over time with acquisition time points of 10 min (1), 22 min (2), 34 min (3), 46 min (4), and 58 min (5) after application of ⁶⁸Ga-FAPI-02 (left column, 56-y-old man with resected pancreatic carcinoma, staging for metastases, no local recurrence, single hepatic metastasis), ⁶⁸Ga-FAPI-46 (middle column, 58-y-old man with retroperitoneal liposarcoma, staging in advance of neoadjuvant radiation therapy, primary, 3 metastases), and ⁶⁸Ga-FAPI-74 (60-y-old man with pancreatic carcinoma, staging in advance of radiation therapy, primary, single hepatic metastasis). p.i. = after injection.

FIGURE 4.

SUV_max and SUV_mean for malignant (M), inflammatory/reactive (IR), or degenerative (D) pathologies over time at 10 min (1), 22 min (2), 34 min (3), 46 min (4), and 58 min (5) after injection of 3 ⁶⁸Ga-FAPI variants (⁶⁸Ga-FAPI-02, ⁶⁸Ga-FAPI-46, and ⁶⁸Ga-FAPI-74). Boxes represent interquartile range, whiskers represent interquartile range of 1.5, horizontal line within box indicates median, and small box indicates mean. Data outliers are shown separately within graph. Trending lines regarding mean are shown.

FIGURE 5.

Example maximum-intensity projection (top) and axial PET/CT images of ⁶⁸Ga-FAPI-74 PET/CT scans (bottom) of 56-y-old man with pancreatic carcinoma after resection (no local recurrence, 4 metastases) over time with acquisition time points of 10 min (1), 22 min (2), 34 min (3), 46 min (4), and 58 min (5) after application. Clinically, patient showed hepatic metastasis (green arrows, second row, malignant manifestation), pancreatitis-related uptake (red arrows, third row, inflammatory lesion), and insertion-related tendinopathy in right trochanter region (yellow arrows, fourth row, degenerative lesion). p.i. = after injection.

FIGURE 6.

TBRs for SUV_max (A) and SUV_mean (B) regarding malignant (M), inflammatory/reactive (IR), and degenerative (D) pathologies vs. blood and vs. fat tissue for 3 ⁶⁸Ga-FAPI variants (⁶⁸Ga-FAPI-02, ⁶⁸Ga-FAPI-46, and ⁶⁸Ga-FAPI-74) over time, with acquisition time points of 10 min (1), 22 min (2), 34 min (3), 46 min (4), and 58 min (5) after injection. Boxes represent interquartile range, whiskers represent interquartile range of 1.5, horizontal line within box indicates median, and small box indicates mean. Data outliers are shown separately within graph. Trending lines regarding mean are shown. a.u. = arbitrary units.