lutetium-lu-177-dotatate and Carcinoma--Small-Cell

Small cell cancers (SmCC), whether pulmonary (SCLC) or extrapulmonary, have a poor prognosis unless localised at diagnosis. Given a proportion of these cancers express somatostatin receptor subtype 2 (SSTR2), we aimed to investigate the efficacy of targeted peptide receptor chemoradionuclide therapy (PRCRT).. In this preclinical study, we used a SCLC xenograft mouse model with high expression of SSTR2 to investigate the effect of peptide receptor radionuclide therapy (PRRT) with chemotherapy compared to either alone. We subsequently explored the clinical utility in a patient with SmCC with high SSTR expression treated with PRCRT.. Robust expression of SSTR2 in NCI-H69 SCLC xenografts was documented by (68)Ga-DOTA-octreotate (GaTate) (tumour to background uptake ratio = 35). The combination of PRRT using (177)Lu-DOTA-octreotate (LuTate) with carboplatin/etoposide (C/E) chemotherapy was more effective than either LuTate or C/E alone for regression of the NCI-H69 model (p value < 0.05). PRCRT was associated with significantly prolonged survival versus PRRT (p value = 0.0001) or chemotherapy alone (p value = 0.0058). In the subsequent case study, a patient with relapsed SmCC with high SSTR2 expression on GaTate PET underwent PRCRT with radiosensitising etoposide with evidence of a complete metabolic response for 4 months.. Given the limited treatment options in this setting, PRCRT is a promising therapeutic option for SSTR2-expressing SmCC.

Topics: Animals; Antineoplastic Agents; Carboplatin; Carcinoma, Small Cell; Cell Line, Tumor; Etoposide; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Octreotide; Organometallic Compounds; Radiopharmaceuticals; Receptors, Somatostatin; Small Cell Lung Carcinoma; Translational Research, Biomedical

(177)Lu-DOTA-Tyr(3)-octreotate is a candidate radiopharmaceutical for the therapy of somatostatin receptor (sstr)-positive small cell lung cancer (SCLC). Scintigraphy of lung tumors is made with 2 alternative somatostatin analogs, (111)In-DTPA-octreotide or (99m)Tc-depreotide. The aim of this study was to compare the biodistribution of these 3 radiopharmaceuticals in SCLC xenografted to nude mice.. Nude mice, bearing tumors from the human SCLC cell line NCI-H69, were intravenously injected with 10 MBq (2.4 microg) (99m)Tc-depreotide and 2 MBq (0.5 microg) (111)In-DTPA-octreotide simultaneously. The activity concentration (%IA/g) was measured in tumor and normal tissue at 2, 4, and 24 hours postinjection (hpi). The results were compared with earlier published biodistribution data of 3 MBq (0.7 microg) (177)Lu-DOTA-Tyr(3)-octreotate in the same animal model.. The activity concentration of (111)In-DTPAoctreotide in tumor was higher than the activity concentration of (99m)Tc-depreotide at 2-24 hpi, p < 0.05. The highest tumor uptake at 24 hpi was, however, found for (177)Lu-DOTA-Tyr(3)-octreotate. The activity concentration of (99m)Tc-depreotide was significantly higher in the heart, lungs, liver, the salivary glands, spleen, and bone marrow than for (111)In-DTPA-octreotide at 2-24 hpi. Saturation of the somatostatin receptors may have influenced the uptake in tumor and sstr-positive normal tissues.. The low tumor-to-lung and tumor-to-liver activity concentration ratios for (99m)Tc-depreotide could result in a lower detection rate of SCLC with this compound versus (111)In-DTPA-octreotide. (177)Lu-DOTA-Tyr(3)-octreotate gave the highest tumor-activity concentration, and has, thus, the best properties for therapy.

Topics: Animals; Carcinoma, Small Cell; Cell Line, Tumor; Disease Models, Animal; Humans; Indium Radioisotopes; Liver; Lung; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Octreotide; Organometallic Compounds; Organotechnetium Compounds; Pentetic Acid; Radiopharmaceuticals; Somatostatin; Time Factors; Tissue Distribution

Small cell lung cancer (SCLC) is a tumor of neuroendocrine (NE) origin with very low survival rate. Somatostatin receptor scintigraphy using 111In-DTPA-octreotide (DTPA is diethylenetriaminepentaacetic acid) is a well-established method for the visualization of somatostatin receptor-expressing NE tumors. Recently, new combinations of radionuclides and somatostatin analogs have been investigated for therapeutic purposes. In this study, the somatostatin analog DOTA-Tyr3-octreotate (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid), labeled with the medium-energy electron emitter 177Lu (maximal electron energy = 498 keV, half-life = 6.6 d), was used for radiation therapy of human SCLC in an animal model.. Nude mice, bearing tumors from the human SCLC cell line NCI-H69, were injected intravenously with 177Lu-DOTA-Tyr3-octreotate. Groups of animals (n = 5 or 6) were injected with 45-, 60-, and 120-MBq fractions and two 45-MBq fractions 48 h apart. Furthermore, 1 control group was treated with unlabeled DOTA-Tyr3-octreotate and another control group was not treated.. In both control groups, the tumor volumes were increased 2-fold in approximately 5 d. Treatment with 177Lu-DOTA-Tyr3-octreotate resulted in marked tumor regression with statistically significant tumor volume reduction after 1 wk (P < 0.001). The tumor growth delay time was dependent on the amount of injected activity for the groups with single injections, 26 d for 60 MBq and 40 d for 120 MBq. The best therapeutic effect was obtained in mice injected with 2 fractions of 45 MBq. The relative tumor volume after 1 mo was 0.004 +/- 0.004.. Radiation therapy with 177Lu-DOTA-Tyr3-octreotate on SCLC-bearing mice was successful. Since the experiments were performed on a human SCLC cell line xenografted to nude mice, the results may be clinically relevant and treatment with 177Lu-DOTA-Tyr3-octreotate could be a treatment alternative in this tumor disease that normally has a dismal prognosis.

Topics: Animals; Carcinoma, Small Cell; Disease Models, Animal; Injections, Intravenous; Lung Neoplasms; Male; Metabolic Clearance Rate; Mice; Mice, Inbred BALB C; Mice, Nude; Octreotide; Organ Specificity; Organometallic Compounds; Radiopharmaceuticals; Tissue Distribution; Treatment Outcome

In this study the biodistribution of a somatostatin analogue, (177)Lu-[DOTA(0),Tyr(3)]octreotate, was investigated in an animal model, as a possible therapeutic radiopharmaceutical.. (177)Lu-[DOTA(0),Tyr(3)]octreotate was injected i.v. into nude mice bearing somatostatin receptor-positive tumors of the human small cell lung cancer (SCLC) cell line NCI-H69. In addition, nontumor bearing mice were injected i.v. with (177)LuCl(3). The activity concentration in tumor and normal tissues was measured and dosimetric estimations for tumor tissue were made.. The tumor had higher activity concentration of (177)Lu-[DOTA(0),Tyr(3)]octreotate compared to all measured normal tissues at all time points. The activity concentration in the tumor tissue was 3.7 %IA/g, 2.1 %IA/g, and 1.2 %IA/g after 24 h, 3 days and 7 days, respectively. The mean absorbed dose to a 1 g tumor was 0.3 Gy/MBq. The highest activity concentration of (177)LuCl(3) was observed in the bone marrow and increased with time.. This study shows that (177)Lu-labeled [DOTA(0),Tyr(3)]octreotate has therapeutic potential for SCLC. The study also points out the importance of optimal labeling efficiency since the high bone marrow uptake of free lutetium ions can be controlled by a high peptide-bound fraction.

Topics: Algorithms; Animals; Carcinoma, Small Cell; Cell Line, Tumor; Humans; Lutetium; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Octreotide; Organometallic Compounds; Radioisotopes; Radiopharmaceuticals; Radiotherapy; Radiotherapy Dosage; Somatostatin; Time Factors; Tissue Distribution