Dataset Information

Safety and efficacy of peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors.

ABSTRACT:

Purpose

Peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate (¹⁷⁷Lu-DOTATATE) is one of the most reliable treatments for unresectable, progressive neuroendocrine tumors (NETs) with somatostatin receptor expression. We have, for the first time, reported the results of the tolerability, safety, pharmacokinetics, dosimetry, and efficacy of this treatment for Japanese patients with NET.

Methods

Patients with unresectable, somatostatin receptor scintigraphy (SRS)-positive NETs were enrolled in this phase I clinical trial. They were treated with 29.6 GBq of ¹⁷⁷Lu-DOTATATE (four doses of 7.4 GBq) combined with amino acid solution infusion plus octreotide long-acting release (LAR) 30 mg. The primary objective of this study was to evaluate the tolerability, safety, pharmacokinetics, and dosimetry of a single administration of this treatment in patients with SRS-positive NETs.

Results

Six Japanese patients (three men and three women; mean age 61.5 years; range 50-70 years) with SRS-positive unresectable NETs were recruited. ¹⁷⁷Lu-DOTATATE was eliminated from the blood in a two-phase manner. Cumulative urinary excretion of radioactivity was 60.1% (range 49.0%-69.8%) within the initial 6 h. The cumulative renal absorbed dose for 29.6 GBq of ¹⁷⁷Lu-DOTATATE was 16.8 Gy (range 12.0-21.2 Gy), and the biological effective dose was 17.0 Gy (range 12.2-21.5 Gy). Administration of ¹⁷⁷Lu-DOTATATE was well tolerated, with no dose-limiting toxicities. Grade 3 lymphopenia occurred in two (33.3%) cases, but there were no other severe toxicities. Four patients achieved partial response (objective response rate, 66.7%), one patient had stable disease, and one patient had progressive disease.

Conclusion

PRRT with ¹⁷⁷Lu-DOTATATE was well-tolerated and showed good outcomes in Japanese patients with unresectable NETs. Peptide receptor radionuclide therapy, ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate .

SUBMITTER: Kobayashi N

PROVIDER: S-EPMC8557155 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeAfter peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with (90)Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [(177)Lu-DOTA(0),Tyr(3)]-Octreotate ((177)Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with (90)Y-radiolabelled somatostatin analogues.MethodsThe annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed.ResultsOf the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5 - 3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (± SD) was 108 ± 5 ml/min and the estimated average annual decrease in CLR (± SD) was 3.4 ± 0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1 ± 4.9 Gy.ConclusionNephrotoxicity in patients treated with (177)Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with (90)Y-labelled somatostatin analogues, does not seem valid for PRRT with (177)Lu-octreotate.

Project description:PURPOSE: Adequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys, the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of the radiopharmaceutical in the blood. This may underestimate the absorbed dose since stem cells express somatostatin receptors. We verified the blood-based method by comparing the activity in the blood with the radioactivity in bone marrow aspirates. Also, we evaluated the absorbed cross-dose from the source organs (liver, spleen, kidneys and blood), tumours and the so-called "remainder of the body" to the bone marrow. METHODS: Bone marrow aspirates were drawn in 15 patients after treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate. Radioactivity in the bone marrow was compared with radioactivity in the blood drawn simultaneously. The nucleated cell fraction was isolated from the bone marrow aspirate and radioactivity was measured. The absorbed dose to the bone marrow was calculated. The results were correlated to the change in platelet counts 6 weeks after treatment. RESULTS: A strong linear correlation and high agreement between the measured radioactivities in the bone marrow aspirates and in the blood was found (r=0.914, p<0.001). No correlation between the calculated absorbed dose in the bone marrow and the change in platelets was found. There was a considerable contribution from other organs and the remainder of the body to the bone marrow absorbed dose. CONCLUSION: (1) After PRRT with [(177)Lu-DOTA(0),Tyr(3)]octreotate, the radioactivity concentration in the bone marrow is identical to that in the blood; (2) There is no significant binding of the radiopharmaceutical to bone marrow precursor stem cells; (3) The contribution of the cross dose from source organs and tumours to the bone marrow dose is significant; and (4) There is considerable variation in bone marrow absorbed dose between patients. These findings imply that for individual dose optimization, individual calculation of the bone marrow absorbed dose is necessary.

Project description:BackgroundThe [177Lu]Lu-DOTA-TATE mediated peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors (NETs) is sometimes leading to treatment resistance and disease recurrence. An interesting alternative could be the somatostatin antagonist, [177Lu]Lu-DOTA-JR11, that demonstrated better biodistribution profile and higher tumor uptake than [177Lu]Lu-DOTA-TATE. Furthermore, treatment with alpha emitters showed improvement of the therapeutic index of PRRT due to the high LET offered by the alpha particles compared to beta emitters. Therefore, [225Ac]Ac-DOTA-JR11 can be a potential candidate to improve the treatment of NETs (Graphical abstract). DOTA-JR11 was radiolabeled with [225Ac]Ac(NO3)3 and [177Lu]LuCl3. Stability studies were performed in phosphate buffered saline (PBS) and mouse serum. In vitro competitive binding assay has been carried out in U2OS-SSTR2 + cells for natLa-DOTA-JR11, natLu-DOTA-JR11 and DOTA-JR11. Ex vivo biodistribution studies were performed in mice inoculated with H69 cells at 4, 24, 48 and 72 h after injection of [225Ac]Ac-DOTA-JR11. A blocking group was included to verify uptake specificity. Dosimetry of selected organs was determined for [225Ac]Ac-DOTA-JR11 and [177Lu]Lu-DOTA-JR11.Results[225Ac]Ac-DOTA-JR11 has been successfully prepared and obtained in high radiochemical yield (RCY; 95%) and radiochemical purity (RCP; 94%). [225Ac]Ac-DOTA-JR11 showed reasonably good stability in PBS (77% intact radiopeptide at 24 h after incubation) and in mouse serum (~ 81% intact radiopeptide 24 h after incubation). [177Lu]Lu-DOTA-JR11 demonstrated excellent stability in both media (> 93%) up to 24 h post incubation. Competitive binding assay revealed that complexation of DOTA-JR11 with natLa and natLu did not affect its binding affinity to SSTR2. Similar biodistribution profiles were observed for both radiopeptides, however, higher uptake was noticed in the kidneys, liver and bone for [225Ac]Ac-DOTA-JR11 than [177Lu]Lu-DOTA-JR11.Conclusion[225Ac]Ac-DOTA-JR11 showed a higher absorbed dose in the kidneys compared to [177Lu]Lu-DOTA-JR11, which may limit further studies with this radiopeptide. However, several strategies can be explored to reduce nephrotoxicity and offer opportunities for future clinical investigations with [225Ac]Ac-DOTA-JR11.

Project description:This study aimed to evaluate the safety and efficacy of multiple cycles of 177Lu-DOTA-Evans blue (EB)-TATE peptide receptor radionuclide therapy (PRRT) at escalating doses in neuroendocrine tumors (NETs). Methods: Thirty-two NET patients were randomly divided into 3 groups and treated with escalating doses. Group A received 1.17 ± 0.09 GBq/cycle; group B, 1.89 ± 0.53 GBq/cycle; and group C, 3.97 ± 0.84 GBq/cycle. The treatment was planned for up to 3 cycles. Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Treatment response was evaluated according to the European Organisation for Research and Treatment of Cancer criteria and modified PERCIST. Results: Administration of PRRT was well tolerated, without life-threatening adverse events (CTCAE grade 4). CTCAE grade 3 hematotoxicity was recorded in 1 patient (16.6%) in group B (thrombocytopenia) and 3 patients (21.4%) in group C (thrombocytopenia in 3, anemia in 1). CTCAE grade 3 hepatotoxicity (elevated aspartate aminotransferase) was recorded in 1 patient in group A (8.3%) and 1 patient in group C (7.1%). No nephrotoxicity was observed. According to the criteria of the European Organisation for Research and Treatment of Cancer, the overall disease response rates were similar in groups A, B, and C (50.0%, 50.0%, and 42.9%, respectively), and the overall disease control rates were higher in groups B (83.3%) and C (71.5%) than in group A (66.7%). According to modified PERCIST, a lower disease response rate but a similar disease control rate were found. When a comparable baseline SUVmax ranging from 15 to 40 was selected, the percentage change in SUVmax increased slightly in group A (2.1% ± 40.8%) but decreased significantly in groups B and C (-38.7% ± 10.0% and -14.7% ± 20.0%, respectively) after the first PRRT (P = 0.001) and decreased in all 3 groups after the third PRRT (groups A, B, and C: -6.9% ± 42.3%, -49.2% ± 30.9%, -11.9% ± 37.9%, respectively; P = 0.044). Conclusion: Dose escalations of up to 3.97 GBq/cycle seem to be well tolerated for 177Lu-DOTA-EB-TATE. 177Lu-DOTA-EB-TATE doses of 1.89 and 3.97 GBq/cycle were effective in tumor control and more effective than 1.17 GBq/cycle.

Project description:Rationale: This study aimed to assess the safety, efficacy, and survival of 177Lu-DOTA-EB-TATE in patients with metastatic neuroendocrine tumors (NETs). Methods: Thirty patients with metastatic NETs were prospectively enrolled and treated with 177Lu-DOTA-EB-TATE (3 intended cycles at 8 to 12-week intervals, 3.7 GBq/cycle). Treatment-related adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The treatment response was graded according to RECIST 1.1 and PERCIST 1.0 criteria. Kaplan-Meier analysis was performed to calculate progression-free survival (PFS) and overall survival (OS). Results: Patients tolerated therapy well without acute adverse effects. During peptide receptor radionuclide therapy (PRRT), no grade 4 toxicity was observed in any of the patients; grade 3 hematotoxicity was recorded in 4 patients, including grade 3 thrombocytopenia in 4 patients (13.3%) and grade-3 anemia in 1 patient (3.3%); grade 3 hepatotoxicity was recorded in 1 (3.3%) patient, and no grade 2/3/4 nephrotoxicity was observed. On long-term follow-up, none of the patients developed grade 4 hematotoxicity or nephrotoxicity of any grade, reversible grade 3 hematotoxicity (thrombocytopenia) occurred in 1 patient. There was no incidence of leukemia or myelodysplastic syndrome for the duration of follow-up. Of 27 patients with RECIST-measurable disease, partial response and stable disease were seen in 9 and 14 patients, respectively, resulting in a response rate of 33.3% and disease control rate of 85.2%. Of 29 patients evaluable for response on 68Ga-DOTATATE PET/CT, 14 had partial response and 11 had stable disease, with a response rate of 48.3% and disease control rate of 86.2%. The follow-up period ranged from 5 to 57 months after the first 177Lu-DOTA-EB-TATE PRRT with a median follow-up of 46 months. The median PFS was 36 months, and the median OS was not reached. Ki-67 index of greater than 10% was associated with poorer PFS (P = 0.012). Conclusions: Our results suggest that PRRT with approximately 3.7 GBq 177Lu-DOTA-EB-TATE has acceptable toxicity profile and is effective in treating metastatic NET with high disease control rate. In addition, 177Lu-DOTA-EB-TATE achieved a favorable survival outcome with encouraging PFS.

Dataset Information

Safety and efficacy of peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors.

Purpose

Methods

Results

Conclusion

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Dataset Information

Safety and efficacy of peptide receptor radionuclide therapy with 177Lu-DOTA0-Tyr3-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors.

Purpose

Methods

Results

Conclusion

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Safety and efficacy of peptide receptor radionuclide therapy with ¹⁷⁷Lu-DOTA⁰-Tyr³-octreotate in combination with amino acid solution infusion in Japanese patients with somatostatin receptor-positive, progressive neuroendocrine tumors.