Synthesis of 213Bi-DOTATOC for peptide receptor alpha-therapy of GEP-NET patients refractory to beta therapy

Abstract

Aim: Therapy with beta-emitter labelled 90Y- or 177Lu-DOTATOC is a promising option for treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NET). However, some patients become refractory to treatment with beta emitters. The alpha emitter 213Bi has demonstrated the capability to break radioresistance to beta-radiation in vitro; we report a method for the synthesis of 213Bi-DOTATOC in clinical levels and give an interim analysis of an ongoing dose escalation study assessing the toxicity and efficacy of intraarterially administered 213Bi-DOTATOC. Methods: 213Bi-DOTATOC was synthesized using a microwave assisted labeling protocol; quality control was performed using ITLC and Radio-HPLC. 17 GEP-NET patients, refractory to previous treatment with 90Y-/177Lu-DOTATOC, were enrolled. The activity administered during a single treatment cycle was escalated from 1-10 GBq and the cumulative activity administered was up to 20 GBq 213Bi per patient. Response was assessed with contrast enhanced sonography, MRI, DSA, 68Ga-DOTATOC-PET/CT and tumor markers. Markers for hematologic, kidney and endocrine toxicity were monitored initially, interim and following the final treatment. Results: The labeling protocol allowed reliable synthesis of 213Bi-DOTATOC at doses up to 1.5 GBq with specific activities up to 240 MBq/nmol and radiochemical purity of 99.7±0.3%. No acute kidney, endocrine or hematologic toxicity higher than grade 0/I were observed after administration of ≤6 GBq per cycle. Moderate hair loss occurred in 3 out of 6 patients receiving single doses of 6 to 10 GBq; 1 case of radiation pneumonitis was observed in the patient receiving 10 GBq. While morphologic long term response is still pending, shrinkage of primary tumors as well as liver and bone metastases has already been observed. Conclusion: This study demonstrates that 213Bi-DOTATOC can be reliably synthesized in clinical settings. The maximum tolerable dose of a single administration of 213Bi-DOTATOC has been determined as 6 GBq. Therapeutic effects have been observed in several patients refractory to treatment with beta emitters. Peptide receptor alpha therapy with 213Bi-DOTATOC is a new treatment option for GEP-NET patients refractory to standard therapies.