Peptide receptor radionuclide therapy using radiolabeled somatostatin analogs: focus on future developments

Abstract

Peptide receptor radionuclide therapy (PRRT) has been shown to be an effective treatment for neuroendocrine tumors (NETs) if curative surgery is not an option. A majority of NETs abundantly express somatostatin receptors. Consequently, following administration of somatostatin (SST) analogs labeled with γ-emitting radionuclides, these tumors can be imaged for diagnosis, staging or follow-up purposes. Furthermore, when β-emitting radionuclides are used, radiolabeled peptides (radiopeptides) can also be used for the treatment for NET patients. Even though excellent results have been achieved with PRRT, complete responses are still rare, which means that there is room for improvement. In this review, we highlight some of the directions currently under investigation in pilot clinical studies or in preclinical development to achieve this goal. Although randomized clinical trials are still lacking, early studies have shown that tumor response might be improved by application of other radionuclides, such as α-emitters or radionuclide combinations, or by adjustment of radiopeptide administration routes. Individualized dosimetry and better insight into tumor and normal organ radiation doses may allow adjustment of the amount of administered activity per cycle or the number of treatment cycles, resulting in more personalized treatment schedules. Other options include the application of novel (radiolabeled) SST analogs with improved tumor uptake and radionuclide retention time, or a combination of PRRT with other systemic therapies, such as chemotherapy or treatment with radio sensitizers. Though promising directions appear to bring improvements of PRRT within reach, additional research (including randomized clinical trials) is needed to achieve such improvements.

Radiopeptides for Imaging and Therapy: A Radiant Future

“…These include the improvement of pharmacokinetics and in vivo stability, the combination of radionuclides, the combination of PRRT with chemotherapy, the use of a-emitting radionuclides, and the use of novel methods to predict therapy response. Recent developments to increase the therapeutic effects of PRRT have been described in detail by Bison et al (13). Some examples of novel approaches for radionuclide therapy are shown in Figure 3.…”

“…However, careful design of such combination studies is needed, as chemotherapeutics can also alter receptor expression and tumor vascularization. For instance, the DNA alkylating drug temozolomide increased tumor perfusion in a preclinical study (13). Clinical studies combining PRRT using 177 Lu-DOTATATE with several chemotherapeutics have been reported.…”

Comparison of the Therapeutic Response to Treatment with a 177Lu-Labeled Somatostatin Receptor Agonist and Antagonist in Preclinical Models

“…Although results are positive, there is room for improvement of PRRT using SSTR radioligands. Recent developments to improve therapeutic outcome with SSTR radioligands include the use of a combination of 90 Y-and 177 Lu-labeled peptide analogs, PRRT using a-emitters, and the combination of PRRT with other anticancer agents (4). Another recent development is the introduction of SST analogs with receptor antagonistic properties.…”

Evaluation of a Fluorescent and Radiolabeled Hybrid Somatostatin Analog In Vitro and in Mice Bearing H69 Neuroendocrine Xenografts

“…They have been used successfully in diagnosing patients with NET using nuclear imaging technologies, such as SPECT or PET, in combination with CT. They have also been used successfully for peptide receptor radionuclide therapy in patients with metastasized disease (2,3), although surgical resection of the tumor tissue, if possible, is the preferred treatment for NET (4,5).…”