Somatostatin receptor-targeted radionuclide therapy of tumors: Preclinical and clinical findings

de Jong, Marion; Valkema, Roelf; Jamar, Francois; Kvols, Larry K.; Kwekkeboom, Dik J.; Breeman, Wout A.P.; Bakker, Willem H.; Smith, Chuck; Pauwels, Stanislas; Krenning, Eric P.

doi:10.1053/snuc.2002.31027

« Previous Next »Seminars in Nuclear Medicine
Volume 32, Issue 2 , Pages 133-140, April 2002

Somatostatin receptor-targeted radionuclide therapy of tumors: Preclinical and clinical findings

Marion de Jong
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
- Address reprint requests to M. de Jong, PhD, Department of Nuclear Medicine, Erasmus University Center Rotterdam, 3015 GD Rotterdam, The Netherlands.
Roelf Valkema
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
Francois Jamar
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
Larry K. Kvols
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
Dik J. Kwekkeboom
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
Wout A.P. Breeman
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
Willem H. Bakker
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
Chuck Smith
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
Stanislas Pauwels
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA
Eric P. Krenning
- Department of Nuclear Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands, USA
- Universitaire Catholique Louvain, Brussels, Belgium, USA
- Lee Moffitt Cancer Center, University of South Florida, Tampa, FL, USA
- Novartis Pharmaceutical Corporation, East Hanover, NJ, USA

In preclinical studies in rats we evaluated biodistribution and therapeutic effects of different somatostatin analogs, [¹¹¹In-DTPA]octreotide, [⁹⁰Y-DOTA, Tyr³]octreotide and [¹⁷⁷Lu-DOTA, Tyr³]octreotate, currently also being applied in clinical radionuclide therapy studies. [Tyr³]octreotide and [Tyr³] octreotate, chelated with DTPA or DOTA, both showed high affinity binding to somatostatin receptor subtype 2 (sst₂) in vitro. The radiolabelled compounds all showed high tumor uptake in sst₂-positive tumors in vivo in rats, the highest uptake being reached with [¹⁷⁷Lu-DOTA, Tyr³]octreotate. In preclinical therapy studies in vivo in rats, excellent, dose dependent, tumor size responses were found, responses appeared to be dependent on tumor size at therapy start. These preclinical data showed the great promise of radionuclide therapy with radiolabelled somatostatin analogues. They emphasised the concept that especially the combination of somatostatin analogs radiolabeled with different radionuclides, like ⁹⁰Y and ¹⁷⁷Lu, is most promising to reach a wider tumor size region of high curability.

Furthermore, different phase I clinical studies, using [¹¹¹In-DTPA]octreotide, [⁹⁰Y-DOTA, Tyr³]octreotide or [¹⁷⁷Lu-DOTA, Tyr³]octreotate are described. Fifty patients with somatostatin receptor-positive tumors were treated with multiple doses of [¹¹¹In-DTPA⁰]octreotide. Forty patients were evaluable after cumulative doses of at least 20 GBq up to 160 GBq. Therapeutic effects were seen in 21 patients: partial remission in 1 patient, minor remissions in 6 patients, and stabilization of previously progressive tumors in 14 patients. The toxicity was generally mild bone marrow toxicity, but 3 of the 6 patients who received more than 100 GBq developed a myelodysplastic syndrome or leukemia. Radionuclide therapy with [⁹⁰Y-DOTA, Tyr³]octreotide started in 3 different phase I trials. Overall, antimitotic effects have been observed: about 20% partial response and 60% stable disease (N=92) along with complete symptomatic cure of several malignant insulinoma and gastrinoma patients. Maximum cumulative [⁹⁰Y-DOTA, Tyr³]octreotide dose was about 26 GBq, without reaching the maximum tolerable dose. New is the use of [¹⁷⁷Lu-DOTA, Tyr³]octreotate, which shows the highest tumor uptake of all tested octreotide analogs so far, with excellent tumor-to-kidney ratios. Radionuclide therapy with this analog in a phase 1 trial started recently in our center in 63 patients (238 administrations), Interim analysis of 18 patients with neuroendocrine tumors was performed very recently. According to the WHO, toxicity criteria no dose limiting toxicity was observed. Minor CT-assessed tumor shrinkage (25%–50% reduction) was noticed in 6% of 18 patients and partial remission (50%–100% reduction, SWOG criteria) in 39%. Eleven percent of patients had tumor progression and in 44% no changes were seen.

These data show that radionuclide therapy with radiolabelled somatostatin analogs, like [DOTA, Tyr³]octreotide and [DOTA, Tyr³]octreotate is a most promising new treatment modality for patients who have sst₂-positive tumors.

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