Peptide Receptor Radionuclide Therapy Targeting the Somatostatin Receptor: Basic Principles, Clinical Applications and Optimization Strategies

Abstract

Peptide receptor radionuclide therapy (PRRT) consists of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. The only target that is currently used in clinical practice is the somatostatin receptor (SSTR), which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review provides a summary of the treatment efficacy (e.g., response rates and symptom-relief), impact on patient outcome and toxicity profile of PRRT performed with different generations of SSTR-targeting radiopharmaceuticals, including the landmark randomized-controlled trial NETTER-1. In addition, multiple optimization strategies for PRRT are discussed, i.e., the dose–effect concept, dosimetry, combination therapies (i.e., tandem/duo PRRT, chemoPRRT, targeted molecular therapy, somatostatin analogues and radiosensitizers), new radiopharmaceuticals (i.e., SSTR-antagonists, Evans-blue containing vector molecules and alpha-emitters), administration route (intra-arterial versus intravenous) and response prediction via molecular testing or imaging. The evolution and continuous refinement of PRRT resulted in many lessons for the future development of radionuclide therapy aimed at other targets and tumor types.

Preclinical Evaluation of [155/161Tb]Tb-Crown-TATE—A Novel SPECT Imaging Theranostic Agent Targeting Neuroendocrine Tumours

“…The majority of advanced, progressive NETs show overexpression of somatostatin receptors (SSTRs) on the cell surface and are therefore attractive targets for radionuclide imaging and therapy [ 1 , 2 ]. In humans, SSTRs are comprised of five subtypes (SSTR1-5), which are expressed in numerous organ systems including the gastrointestinal tract, pancreas, lungs, and renal organs.…”

“…Peptide receptor radionuclide therapy (PRRT) with complementary diagnostic imaging is a highly effective approach for the treatment of advanced neuroendocrine tumours (NETs) and has shown high response rates in patients previously refractory to conventional somatostatin therapy [ 1 , 2 , 3 ]. This approach involves the systemic administration of therapeutic radiopharmaceuticals which enable the selective localisation of ionising radiation to tumour sites through peptide-based molecular recognition of cell-surface receptors.…”

Peptide Receptor Radionuclide Therapy in Thyroid Cancer

“…These cells are present in several organs, including the bronchi, pancreas, and the gastrointestinal tract. Based on the site of origin, NETs can be pancreatic NETs (PNETs), gastroenteropancreatic NETs (GEP-NETs), carcinoids, small cell lung cancer, or large cell neuroendocrine carcinoma ( 53 ). Other tumors of neuroendocrine origin include pheochromocytoma and paraganglioma (PPGL), MTC, neuroblastoma, meningioma, and Merkel cell carcinoma ( 53 ).…”

“…Based on the site of origin, NETs can be pancreatic NETs (PNETs), gastroenteropancreatic NETs (GEP-NETs), carcinoids, small cell lung cancer, or large cell neuroendocrine carcinoma ( 53 ). Other tumors of neuroendocrine origin include pheochromocytoma and paraganglioma (PPGL), MTC, neuroblastoma, meningioma, and Merkel cell carcinoma ( 53 ). In a landmark phase 3 clinical trial (NETTER-1), 177 Lu-DOTATATE therapy in addition to long-acting repeatable (LAR) octreotide in patients with SSTR+ well-differentiated, metastatic midgut NETs resulted in substantially longer PFS compared to treatment with LAR octreotide alone ( 33 ).…”

Neuroendocrine Tumors: Treatment and Management

“…The only target currently used in clinical practice in NET patients is the somatostatin receptor, and one of the most interesting associations is 68 Ga-DOTATATE and 177 Lu-DOTATATE (somatostatin-analogues-based PRRT), with very promising results. Ahmadi Bidakhvidi et al [ 12 ] provide a didactical review focusing on the basic principles and clinical applications of PRRT, discussing several PRRT-optimization strategies in patients with NETs. Moreover, Theiler et al [ 13 ] report the results of PRRT in a cohort of elderly NET patients (>79 years old), resulting in a valid therapeutic option with similar toxicity and non-inferior survival compared to matched younger patients.…”