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 [68Ga]Ga-FAPI-46 positron emission tomography/computed tomography (PET/CT), intraoperative radiopharmaceutical-guided robotic surgery, and postoperative [177Lu]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 [68Ga]Ga-FAPI-46 PET/CT and radiopharmaceutical-guided robotic resection. Patients with postoperative residual disease were considered for [177Lu]Lu-FAPI-46 therapy. Imaging, surgical, pathological, therapeutic, dosimetric, and safety outcomes were assessed.

RESULTS

[68Ga]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 (R2 = 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 [177Lu]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.