Pharmacokinetic Evaluation of Fibroblast Activation Protein-Targeted Radiopharmaceutical Uptake in Low-Stage Rectal Cancer Tumor Microenvironment

Abstract

Purpose: Radionuclide therapy targeting fibroblast activation protein (FAP) offers an effective treatment for tumors with high FAP expression, such as those imaged with 68 Ga-fibroblast activation protein inhibitor (FAPI) and treated with 177 Lu-FAPI. Personalized therapy planning, based on imaging-derived standardized uptake values, pharmacokinetic parameters, and dosimetric modeling, is essential to optimize therapeutic outcomes while minimizing toxicity to healthy tissues. Methods and Results: The study develops a comprehensive personalized therapy planning framework integrating 68 Ga-FAPI positron emission tomography (PET), pharmacokinetic modeling, and voxel-based dosimetry for optimized tumor doses and safety in 177 Lu-FAPI radionuclide therapy. A cohort of 26 patients (mean age: 56.3 ± 9.2 years) with stage I–II rectal cancer underwent 68 Ga-FAPI PET/computed tomography imaging after intravenous injection of 68 Ga-FAPI (150–250 MBq). SUV max ranged from 8.5 to 12.5, with imaging performed at multiple time points (10, 30, 60, and 120 min) to capture tracer kinetics. Pharmacokinetic modeling was used to estimate uptake rate (K 1 = 0.182 ± 0.036 min −1 ), washout rate (k 2 = 0.094 ± 0.021 min −1 ), and retention coefficient (k 3 = 0.138 ± 0.028 min −1 ). Results: Voxel-based dosimetry derived absorbed doses using time–activity curves and radionuclide-specific S-values. Activity scaling was applied to estimate tumor doses with 3–7 GBq of 177 Lu-FAPI. With 5–7 GBq of 177 Lu-FAPI, 92.3% of patients received tumor doses of at least 20 Gy, ranging from 18.2 to 26.4 Gy. Kidney dosages ranged from 2.2 to 5.0 Gy, whereas liver doses varied from 1.7 to 4.1 Gy. SUV max showed a high correlation with absorbed dose ( r = 0.88, p < 0.001). Conclusions: The methodology successfully enhanced tumor dose coverage while ensuring organ safety through activity optimization. This system offers a clinically applicable approach to targeted radionuclide therapy by combining PET imaging, pharmacokinetics, and dosimetry to deliver optimal tumor doses while meeting organ-at-risk constraints.