Optimizing the Therapeutic Index: Sequential Intraarterial-Intravenous PRRT with Personalized Volumetric-Adjusted Dosing.

Abstract

Patients with well-differentiated neuroendocrine tumors (NETs) frequently present with liver-dominant metastases, which significantly impact prognosis and limit curative options. Although standard intravenous peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTATATE is effective, strategies to intensify the radiation dose to hepatic lesions are needed to improve outcomes. This prospective clinical trial investigated the feasibility, tolerability, and preliminary efficacy of a personalized treatment schedule combining intraarterial and intravenous administrations of ¹⁷⁷Lu-DOTATATE. Methods: Ten consecutive adults with progressive, nonresectable, liver-dominant metastatic gastroenteropancreatic NETs expressing somatostatin receptors were enrolled. The treatment protocol comprised 4 cycles of ¹⁷⁷Lu-DOTATATE administered every 2 mo (2 initial intraarterial cycles followed by 2 intravenous cycles). Intraarterial administration involved angiographically guided, selective catheterization of the hepatic arteries with volumetrically adjusted activity to maximize targeted delivery. Safety monitoring, radiation protection, and dosimetry comparisons between intraarterial and intravenous routes were performed. Results: The intraarterial administration procedure was feasible in 100% of patients. Radiation exposure to staff and patients remained within regulatory limits, with no contamination events. Dosimetry analysis indicated that intraarterial administration (cycle 1) delivered a greater than 3-fold higher radiation dose to liver metastases compared with the intravenous route (cycle 3), although interim response may have played a role. Furthermore, ⁶⁸Ga-DOTATATE PET imaging revealed an 86% increase in median liver lesion uptake with intraarterial administration. The regimen was generally well-tolerated, with only 1 severe adverse event reported (low esophageal tear), which was not attributed to the administration route. Efficacy analysis showed partial response rates in 67% of patients at the first follow-up 3 mo after treatment completion, improving to 87% at the second follow-up (6 mo) in accordance with RECIST and volumetric criteria. Conclusion: The sequential administration of intraarterial followed by intravenous ¹⁷⁷Lu-DOTATATE is a feasible and safe therapeutic strategy for liver-dominant metastatic NETs. The use of a personalized, volumetric-based approach provided higher uptake and absorbed doses in hepatic metastases, with high objective response rates and effectively maintained systemic coverage.