Regional 213Bi-DOTATOC peptide receptor alpha-therapy in patients with neuroendocrine liver metastases refractory to beta-radiation

Objectives Radiopeptide therapy using beta-emitter labeled somatostatin analogs as 90Y/177Lu-DOTATOC is a therapeutic option in neuroendocrine cancer. However, some patients become refractory to that treatment. The alpha-emitter 213Bi was able to break radioresistance to beta-emitters in vitro. Its relatively short half-life of 46 min requires rapid tumor targeting. Recently, we demonstrated an accelerated tumor uptake of DOTATOC by regional arterial administration. The present work evaluates the efficiency of regional 213Bi-DOTATOC alphapeptide therapy in patients refractory to beta therapy.

Methods Ten patients with neuroendocrine liver metastases, refractory to a previous treatment with 90Y-/177Lu-DOTATOC, were enrolled. The cumulative activity administered was up to 4 GBq 213Bi per patient. The activity of a single treatment was escalated from 1 to 4 GBq per cycle and was injected in fractions of 0.5 to 1 GBq into a catheter placed in the hepatic artery. Response was assessed with contrast enhanced sonography, MRI, DSA, 68Ga-DOTATOC-PET/CT and tumor markers. Hematologic, kidney and endocrine toxicity was assessed according to CTCAE criteria initial and after the final treatment.

Results The minimal effective activity inducing partial remission (>30% of the diameter) was 1 GBq 213Bi-DOTATOC. No acute kidney, endocrine or hematologic toxicity higher than grade 0/I were observed in the first escalation steps (≤2.5 GBq cumulative activity, ≤1.5 GBq per cycle). Short term follow up demonstrated reduced tumor-perfusion (increase of TTP >25%) in 7/9 patients (morphologic long term response pending).

Conclusions 213Bi-DOTATOC demonstrated to be effective by inducing tumor remission for metastases refractory to 90Y- and 177Lu-DOTATOC while no severe toxicity was observed with the activities administered. Moreover, the maximum tolerable dose was not reached so far and dose escalation continues