Assessment of Hepatic Toxicity from Treatment with ⁹⁰Y-SMT 487 (OctreoTher™) in Patients with Diffuse Somatostatin Receptor Positive Liver Metastases

Abstract

The purpose of this study was to determine whether there is evidence for hepatocellular radiation injury following treatment with (90)Y-SMT487 ((90)Y-DOTA-tyr3-octreotide, OctreoTher(TM)) in patients with extensive liver metastases from neuroendocrine tumors. Patients reported in this study participated in a Phase II trial of efficacy and safety of (90)Y-SMT487. The trial design called for three treatment cycles of 120 mCi each (4400 MBq) of (90)Y-SMT487. (111)In-pentetreotide SPECT images were used to determine the extent of liver metastases. Serum AST, ALT, and alkaline phosphatase levels were obtained at baseline and following each cycle of therapy. Least squares fit was applied to the serial liver enzyme measurements in patients with extensive liver metastases. Post-therapy liver enzyme measurements were also evaluated using WHO common toxicity criteria. Repeated-measures ANOVA and paired t-test were applied to the serial enzyme measures. There were 21 subjects. Fifteen of these had hepatic metastases with 12 demonstrating extensive (defined as 25% or more) liver involvement. In only 4 of these 15 did any of the three enzyme levels increase in WHO toxicity grade from baseline to final follow-up. We conclude that patients with diffuse SSTR positive hepatic metastases can be treated with a cumulative administered activity of 360 mCi (90)Y-SMT487 with only a small chance of developing mild acute or subacute hepatic radiation injury.

Nuclear Uptake and Dosimetry of 64Cu-Labeled Chelator Somatostatin Conjugates in an SSTr2-Transfected Human Tumor Cell Line

“…Here we address whether the nuclear localization of 64 Cu from a 64 Cu-labeled chelator-somatostatin conjugate is related to the dissociation of the radio-copper from its chelator. The 64 Cu complex of 1,4,8,4,8, has demonstrated instability in vivo, whereas 64 Cu-CB-TE2A (CB-TE2A is 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane) was highly stable. Methods: Receptor binding, nuclear uptake, internalization, and efflux assays were performed to characterize the interaction with the somatostatin receptor and the intracellular fate of 64 Cu-labeled chelator-peptide conjugates in A427-7 cells.…”

“…Gamma scintigraphy with 111 In-diethylenetriaminepentaacetic acidoctreotide ( 111 In-DTPA-octreotide; OctreoScan, Mallinckrodt) has become the standard method to image neuroendocrine tumors (1,2) and is clinically approved in Europe and the United States. Somatostatin analogs labeled with 111 In, 90 Y, 177 Lu, and 64 Cu have been evaluated for targeted radiotherapy of cancer in animal models (3)(4)(5)(6)(7), and clinical trials have been performed with 90 Y-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid tyrosine 3 -octreotide ( 90 Y-DOTATOC) and 177 Lu-DOTA-tyrosine 3 -octreotate ( 177 Lu-DOTATATE) in patients with neuroendocrine tumors with promising results (8)(9)(10)(11). 64 Cu (half-life 5 12.7 h; b 1 [17.4%]; b 2 [41%]) emits both b 1 and b 2 radiation, allowing for the use of this radionuclide in both PET and targeted radiotherapy of cancer.…”

Peptide Receptor Radionuclide Therapy with Somatostatin Analogues in Neuroendocrine Tumors

“…A significant increase in liver enzymes after the administration of 90 Y-DOTATOC was reported in two studies [32,129]. Valkema et al reported one transient grade 3 toxicity in a group of 60 patients treated with 90 Y-DOTATOC in a phase I study [32].…”

Zielgerichtete, rezeptorvermittelte Radionuklidtherapie (Radiopeptidtherapie) neuroendokriner Tumoren

“…Alle 3 Patienten hatten eine Infiltration der Leber durch Tumorgewebe von über 75 %. Ein signifikanter Anstieg der Leberenzyme nach der Administration von 90 Y-DOTATOC wurde in zwei Studien berichtet [41,67]. Valkema et al publizierten eine Transiente-Grad-3-Toxizität in einer Gruppe von 60 Patienten, die mit 90 Y-DO-TATOC im Rahmen einer Phase-I-Studie behandelt wurden [41].…”

“…Valkema et al publizierten eine Transiente-Grad-3-Toxizität in einer Gruppe von 60 Patienten, die mit 90 Y-DO-TATOC im Rahmen einer Phase-I-Studie behandelt wurden [41]. In einer Studie in der 15 Patienten mit neuroendokrinen Tumoren und bekannten Lebermetastasen (12 mit extensivem Leberbefall > 25 %) mit 3 Zyklen von je 120 mCi (4,4 GBq) 90 Y-DOTATOC behandelt wurden [67] zeigten 4 eine signifikante Erhöhung von mindestens einem Leberenzym zwischen Ausgangswert und Nachsorge 4-6 Wochen nach der Therapie. Es wurde daraus geschlossen, dass auch Patienten mit diffuser sst-positiver hepatischer Metastasierung mit 360 mCi (13,2 GBq) 90 Y-DO-TATOC behandelt werden können und lediglich ein geringes Risiko einer Leberschädigung besteht.…”