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Published on: April 17, 2019
Therapy of neuroendocrine tumors with radiolabeled somatostatin-analogues
M De Jong1, W A Breeman, H F Bernard
1Department of Nuclear Medicine, University Hospital and Erasmus University, Rotterdam, The Netherlands.
Unlabelled:
Peptide receptor scintigraphy with the radioactive somatostatin-analogue [111In-DTPA0]octreotide (DTPA = diethylenetriaminepentaacetic acid) is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localised. A new application is the use of peptide receptor radionuclide therapy, administrating high doses of 111In- or 90Y-labeled octreotide-analogues. PRECLINICAL: We investigated the radiotherapeutic effect of 90Y- and 111In-labeled [DOTA0,Tyr3]octreotide (DOTA = tetraazacyclododecanetetraacetic acid) or [111In-DTPA0]octreotide in Lewis rats bearing the somatostatin receptor-positive rat pancreatic tumor CA20948 in A) the flank or B) in the liver.
Patients:
Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with [111In-DTPA0]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase 1 trial. PRECLINICAL RESULTS: A) Flank model: at least two 111MBq injections of [111In-DOTA0,Tyr3]octreotide were needed to reach tumor response, in 40% of the animals complete tumor remission was found after a follow-up period of 10 months. One or two injections of [90Y-DOTA0,Tyr3] octreotide yielded transient stable disease. B) Liver model: we found that peptide receptor radionuclide therapy is only effective if somatostatin receptors are present on the tumors, and is therefore receptor-mediated. High radioactive doses of 370 MBq [111In-DTPA0]octreotide or 93 MBq [90Y-DOTA0,Tyr3]octreotide can inhibit the growth of somatostatin receptor-positive metastases.
Clinical Results:
There were no major clinical side effects after up to 2 years treatment, except that a transient decline in platelet counts and lymphocyte subsets can occur. Promising beneficial effects on clinical symptoms, hormone production and tumor proliferation were found. Of the 21 patients with progressive disease at baseline and who received a cumulative dose of more than 20 GBq [111In-DTPA0]octreotide, 8 patients showed stabilisation of disease and 6 other patients a reduction in size of tumors. There is a tendency towards better results in patients whose tumors have a higher accumulation of the radioligand.
Conclusion:
Radionuclide therapy with octreotide-derivatives is feasible, both with 111In and 90Y as radionuclides.
Insights
Peptide receptor radionuclide therapy using [111In-DTPA0]octreotide and [90Y-DOTA0,Tyr3]octreotide shows promise for treating neuroendocrine tumors. This therapy is feasible and demonstrates beneficial effects on tumor growth and patient symptoms.
Area of Science:
- Nuclear Medicine
- Oncology
- Radiopharmaceutical Therapy
Background:
- Peptide receptor scintigraphy utilizes radioactive somatostatin analogues like [111In-DTPA0]octreotide for tumor localization.
- Peptide receptor radionuclide therapy (PRRT) involves administering high doses of radiolabeled octreotide analogues for therapeutic purposes.
- Neuroendocrine cancers and other tumor types expressing somatostatin receptors are targets for this diagnostic and therapeutic approach.
Purpose of the Study:
- To investigate the radiotherapeutic effects of 90Y- and 111In-labeled octreotide analogues in preclinical models.
- To evaluate the efficacy of [111In-DOTA0,Tyr3]octreotide and [90Y-DOTA0,Tyr3]octreotide in Lewis rats with somatostatin receptor-positive pancreatic tumors.
- To assess the feasibility and clinical outcomes of PRRT in patients with progressing neuroendocrine tumors.
Main Methods:
- Preclinical studies involved administering [111In-DOTA0,Tyr3]octreotide or [90Y-DOTA0,Tyr3]octreotide to Lewis rats bearing flank or liver tumors.
- A Phase 1 clinical trial treated 30 patients with end-stage, progressing neuroendocrine tumors using [111In-DTPA0]octreotide up to a cumulative dose of 74 GBq.
- Tumor response, remission rates, disease stabilization, and tumor size reduction were assessed in both preclinical and clinical settings.
Main Results:
- In the flank tumor model, [111In-DOTA0,Tyr3]octreotide achieved complete tumor remission in 40% of animals after 10 months, while [90Y-DOTA0,Tyr3]octreotide resulted in transient stable disease.
- PRRT efficacy was confirmed to be receptor-mediated, requiring somatostatin receptor presence on tumors.
- In patients, 8 out of 21 with progressive disease receiving >20 GBq [111In-DTPA0]octreotide showed disease stabilization, and 6 had tumor size reduction. Higher radioligand accumulation correlated with better outcomes.
Conclusions:
- Peptide receptor radionuclide therapy with octreotide derivatives labeled with either 111In or 90Y is a feasible treatment modality.
- The therapy demonstrated promising beneficial effects on clinical symptoms, hormone production, and tumor proliferation.
- PRRT offers a potential treatment option for patients with somatostatin receptor-positive tumors, particularly neuroendocrine cancers.