Comparison of Somatostatin Receptor Agonist and Antagonist for Peptide Receptor Radionuclide Therapy: A Pilot Study

Abstract

Preclinical and clinical studies have indicated that somatostatin receptor (sst)-expressing tumors demonstrate higher uptake of radiolabeled sst antagonists than of sst agonists. In 4 consecutive patients with advanced neuroendocrine tumors, we evaluated whether treatment with 177 Lu-labeled sst antagonists is feasible. Methods: After injection of approximately 1 GBq of 177 Lu-DOTA-[Cpa-c(DCys-Aph(Hor)-DAph(Cbm)-Lys-Thr-Cys)-DTyr-NH 2 ] ( 177 Lu-DOTA-JR11) and 177 Lu-DOTATATE, 3-dimensional voxel dosimetry analysis based on SPECT/CT was performed. A higher tumor-to-organ dose ratio for 177 Lu-DOTA-JR11 than for 177 Lu-DOTATATE was the prerequisite for treatment with 177 Lu-DOTA-JR11. Results: Reversible minor adverse effects of 177 Lu-DOTA-JR11 were observed. 177 Lu-DOTA-JR11 showed a 1.7-10.6 times higher tumor dose than 177 Lu-DOTATATE. At the same time, the tumor-to-kidney and tumor-to-bone marrow dose ratio was 1.1-7.2 times higher. All 4 patients were treated with 177 Lu-DOTA-JR11, resulting in partial remission in 2 patients, stable disease in 1 patient, and mixed response in the other patient. Conclusion: Treatment of neuroendocrine tumors with radiolabeled sst antagonists is clinically feasible and may have a significant impact on peptide receptor radionuclide therapy. The purpose of this pilot study was to evaluate the feasibility of peptide receptor radionuclide therapy with the novel sst antagonist 177 Lu-DOTA-JR11. Before treatment, tumor and organ doses of 177 Lu-DOTATATE and 177 Lu-DOTA-JR11 were compared in the same patient after injection of a nontherapeutic test dose. A higher tumor-toorgan dose ratio for 177 Lu-DOTA-JR11 than for 177 Lu-DOTATATE was the prerequisite for treatment with 177 Lu-DOTA-JR11. MATERIALS AND METHODS PatientsFour consecutive patients with progressive neuroendocrine tumors and limited treatment options due to chronic grade 2 or 3 kidney disease were prospectively recruited. Patient characteristics are summarized in Table 1. Exclusion criteria were concurrent antitumor treatment (octreotide [Sandostatin; Novartis Pharmaceuticals] depot less than 4 wk before test injection and treatment), preexisting grade 3 and 4 hematologic toxicity, and pregnancy or breastfeeding. The institutional review board approved this study, and all subjects gave written informed consent in accordance with the Declaration of Helsinki.Radiochemistry DOTA-JR11 was synthesized as previously described (5). DOTA-TATE was received from piChem (Austria). For the preparation of 177 Lu-DOTA-JR11 and 177 Lu-DOTATATE, the corresponding peptide conjugate was dissolved in 500 mL of ascorbate buffer, pH 5.0, and 177 LuCl 3 was added. The solution was incubated at 95°C for 30 min. Quality control was performed by analytic reverse-phase high-performance liquid chromatography on a Phenomenex Jupiter C18 4-mm, 250 · 4.6 mm column (eluents, A 5 0.1% trifluoroacetic acid in water and B 5 acetonitrile; gradient, 0-25 min, 95%-50% A; flow, 0.75 mL/min). The labeling yield of 177 Lu-DOTATATE and 177 Lu-DOTA-JR11 was mor...

Radiopeptides for Imaging and Therapy: A Radiant Future

“…The use of SSTR antagonists has enhanced tumor targeting and prolonged tumor retention compared with SSTR agonists, resulting in an enhanced tumor radiation dose during PRRT. In a clinical study, the SSTR antagonist 177 Lu-DOTA-JR11 exhibited higher tumor uptake and a longer intratumoral residence time than the SSTR agonist 177 Lu-DOTATATE (14). This study was performed on only a few patients, and more systematic clinical studies are needed now to fully evaluate the role of 177 Lu-DOTA-JR11 for therapy of NETs.…”

Repeated 177Lu-Labeled PSMA-617 Radioligand Therapy Using Treatment Activities of Up to 9.3 GBq

“…0.6 Gy/GBq) and red marrow dose (approx. 0.03 Gy/GBq) outperforms the dosimetry of a 177 Lu-labeled PSMA-antibody (9), an 131 I-labeled small molecule PSMA-ligand (10) and the RLT reference compound 177 Lu-DOTA-TATE (11). Based on the available dosimetry data, the 177 Lu-PSMA-617 activities used for the first PSMA-RLTs have been chosen cautiously.…”

Anatomic and functional imaging in the diagnosis of spine metastases and response assessment after spine radiosurgery

“…46 Multiple other agents exist or are in development for other tumor-specific markers, such as radiolabeled bombesin analogs against the gastrin-releasing peptide receptor (GRPr), DOTATATE against the somatostatin receptor, and 18 F-FES against the estrogen receptor. 49,57,58 Primary caveats of this approach are both inter-and intratumoral heterogeneity, alteration of expression of molecular targets after any treatment including SSRS, and applicability largely limited to the research environment. Even more of a concern than with MRI, there is the issue of local availability and cost effectiveness with targeted molecular imaging.…”