Comparison of 111In-[DTPA0]Octreotide Versus Non Carrier Added 177Lu- [DOTA0,Tyr3]-Octreotate Efficacy in Patients With GEP-NET Treated Intra-arterially for Liver Metastases.

AIM: In patients with progressive, metastatic neuroendocrine tumors (NET), intra-arterial radionuclide infusions with high activities of In-[DTPA]-octreotide and more recently with non-carrier added (nca) Lu-[DOTA,Tyr]-octreotate have been performed with encouraging results. However, the affinity profiles (IC50) of these radiopeptides for human sst2 receptors are markedly different (In-[DTPA]-octreotide, 22 ± 3.6 nM and nca Lu-[DOTA,Tyr]-octreotate, 1.5 ± 4.0 nM). The total administered activity is determined by organ dose limits (kidneys and bone marrow), and our aim therefore was to compare and evaluate the therapeutic efficacy of both radiopeptides in metastatic NETs. METHODS: Thirty patients with gastroenteropancreatic (GEP) somatostatin-positive NETs with liver metastases confirmed on biopsy and In-pentetreotide scan were included. They were treated with In-[DTPA]-octreotide (n = 17) or nca Lu-[DOTA,Tyr]-octreotate (n = 13). Blood samples were collected 2, 4, 8, and 24 hours postadministration to calculate residence time in blood and in red marrow. The maximum percentage uptake in organs and tumors was estimated by region of interest analysis, and tumor dosimetry calculations were performed using OLINDA/EXM/ 1.0 software. RESULTS: ncaLu-[DOTA,Tyr3]-octreotate blood radioactivity, expressed as a percentage of the injected dose, was significantly lower than In-[DTPA]-octreotide (P < 0.05), as clearly depicted from the time-activity curves; the background-corrected tumor uptake was significantly higher than In-[DTPA]-octreotide but without any significant difference in other organs (spleen, kidneys, and liver). CONCLUSIONS: Using Lu-[DOTA,Tyr]-octreotate, a 3-fold higher absorbed dose to tumor tissue was achieved compared with In-[DTPA] octreotide. Residence time of nca Lu-[DOTA,Tyr]-octreotate results in a significantly higher absorbed dose to bone marrow compared with In-[DTPA]-octreotide. However, a drawback of In-[DTPA]-octreotide therapy is that the number of administrations would need to be almost doubled to achieve an equal therapeutic outcome as compared with Lu-[DOTA,Tyr]-octreotate.

Super-selective hepatic arterial infusions as established technique ('ARETAIEION' Protocol) of [177Lu]DOTA-TATE in inoperable neuroendocrine liver metastases of gastro-entero-pancreatic (GEP) tumors.

AIM: Aim of this study was to evaluate the effectiveness of non-carrier added (n. c. a.) [177Lu]DOTA-TATE in inoperable liver metastases, positive for sst2 receptor overexpression (verified by Octreoscan and confirmed by biopsy) due to neuroendocrine gastroenteropancreatic (GEP) tumors. [177Lu]DOTA-TATE has been infused after selective catheterization of the hepatic artery, minimising in parallel the toxicity of non-target tissues. METHODS: The dose per session administered to each patient (12 cases in total) was 7400 MBq (200 mCi). Repetitions did not exceed 6-fold with treatment intervals of 5-8 weeks. Response assessment was classified according to the therapeutic benefit. Absorbed doses delivered to metastases, kidneys and red marrow were calculated according to OLINDA 1.1 program and the derived values were correlated to the Response Evaluating Criteria in Solid Tumors (RECIST). CT/MRI scans were performed as baseline before, during and after the end of treatment and monthly ultrasound images for follow-up estimation and measurements. Toxicity (World Health Organization criteria) was measured using blood and urine tests of renal, hepatic and bone marrow function. RESULTS: None of the patients resulted complete response (0.0%); partial response was assessed in 8 (66.7%), disease stabilization in 3 (25%) and progressive disease in 1(8.3%). A 14-month median survival time was estimated for all patients, so far. Eight of 12 (66.7%) showed a mean target diameter shrinkage ranging from 33% to 45%. The organ average radiation dose estimation was found as follows: a) liver tumor 20.8 mGy/MBq; b) liver 0.14 mGy/MBq; c) kidneys 0.41 mGy/MBq; d) spleen 1.4 mGy/MBq; and f) bone marrow 0.022 mGy/MBq. The average absorbed dose per session to a tumor for a spherical mass of 20 g was estimated to be 20.8 mGy/MBq, depending on the histotype of the tumor. WHO toxicity grade 2 to 3 erythro-, leuko- and thrombo-cytopenia occurred in 9 (75%) cases observed about after the third session. CONCLUSION: In unresectable metastatic liver lesions positive for somatostatin receptors repeated, trans-hepatic high doses of [177Lu]DOTA-TATE resulted in a more than promising therapeutic outcome with a partial response in 75% of the treated patients. Given the loco-regional modality character of the administration technique, no nephro-toxicity has been so far observed whereas a remarkable myelotoxicity was noticed.