Theranostic Radiopharmaceutical-Guided Robotic Surgery for Precision Tumor Resection and Targeted Elimination of Residual Disease in Digestive System Malignancies

Background: Digestive system malignancies frequently recur because occult lesions and microscopic residual disease may persist despite apparently complete resection. The authors evaluated an integrated fibroblast activation protein (FAP)-targeted theranostic workflow combining preoperative [ 68 Ga]Ga-FAPI-46 positron emission tomography/computed tomography (PET/CT), intraoperative radiopharmaceutical-guided robotic surgery, and postoperative [ 177 Lu]Lu-FAPI-46 therapy. Methods: In this prospective translational feasibility study, 36 patients with colorectal ( n = 24), gastric ( n = 8), or pancreatic ( n = 4) adenocarcinoma underwent preoperative [ 68 Ga]Ga-FAPI-46 PET/CT and radiopharmaceutical-guided robotic resection. Patients with postoperative residual disease were considered for [ 177 Lu]Lu-FAPI-46 therapy. Imaging, surgical, pathological, therapeutic, dosimetric, and safety outcomes were assessed. Results: [ 68 Ga]Ga-FAPI-46 PET/CT increased lesion detection from 42.6% ± 10.7% to 75.8% ± 11.9% ( p = 0.004) and correlated with operative/pathological lesion burden ( R 2 = 0.7736, p < 0.0001). Radioguided surgery significantly reduced target lesion counts after excision (536 ± 219 vs. 92 ± 46 counts/s, p < 0.001) and improved lesion localization, additional lesion retrieval, and margin-negative resection. Residual disease was identified in 14 of 36 patients; 10 received [ 177 Lu]Lu-FAPI-46. In the treated residual disease subset, residual lesion maximum standardized uptake value and circulating tumor DNA decreased after therapy, with preliminary short-term residual disease control observed in 71% of evaluable cases. Organ-absorbed doses were modest, 9 of 10 treated patients had no grade ≥3 toxicity, and no treatment-limiting safety signal was observed. Conclusions: This FAP-targeted perioperative theranostic strategy was feasible and showed promising imaging, surgical, therapeutic, and safety performance in digestive system malignancies.