Abstract
Simple SummaryNeuroendocrine neoplasms (NENs) are a rare and diverse group of malignancies which are rising in incidence. Several treatments have been devised for unresectable or metastatic tumors, including peptide receptor radionuclide therapy (PRRT). PRRT specifically targets cells that express high levels of somatostatin receptors, such as well-or moderately differentiated NENs, to enable precise delivery. This article highlights the journey of PRRT from inception to the present day, where it is now integral in clinical practice guidelines worldwide. It also provides an overview of NENs and a history of somatostatin receptor imaging, which facilitates the selection of patients for PRRT. Practical considerations relating to appropriate use, treatment administration and side-effects are discussed, and perspectives on future directions to boost efficacy are detailed.Peptide receptor radionuclide therapy (PRRT) has been one of the most successful and exciting examples of theranostics in nuclear medicine in recent decades and is now firmly embedded in many treatment algorithms for unresectable or metastatic neuroendocrine neoplasms (NENs) worldwide. It is widely considered to be an effective treatment for well- or moderately differentiated neoplasms, which express high levels of somatostatin receptors that can be selectively targeted. This review article outlines the scientific basis of PRRT in treatment of NENs and describes its discovery dating back to the early 1990s. Early treatments utilizing Indium-111, a γ-emitter, showed promise in reduction in tumor size and improvement in biochemistry, but were also met with high radiation doses and myelotoxic and nephrotoxic effects. Subsequently, stable conjugation of DOTA-peptides with β-emitting radionuclides, such as Yttrium-90 and Lutetium-177, served as a breakthrough for PRRT and studies highlighted their potential in eliciting progression-free survival and quality of life benefits. This article will also elaborate on the key trials which paved the way for its approval and will discuss therapeutic considerations, such as patient selection and administration technique, to optimize its use.
Highlights
Neuroendocrine neoplasms (NENs) are a diverse group of malignancies, derived from multipotent stem cells, which have migrated primarily from the endoderm to tissues throughout the body [1]
A later study of 25 patients treated with either 177Lu-DOTATATE or 90Y-DOTATATE showed a median progression-free survival of 17 months, which is comparable if not favorable to other systemic therapies [166] but larger trial data are required [167] and a phase 2 trial comparing it to everolimus in bronchial neuroendocrine tumor (NET) is due to recruit [168]
A pre-clinical study reported that combination treatment with 177Lu-DOTATATE and carboplatin/etoposide chemotherapy in mouse models with SSTR expressing small cell lung cancer was more effective than either treatment alone [169] and this is to be translated to human studies
Summary
Neuroendocrine neoplasms (NENs) are a diverse group of malignancies, derived from multipotent stem cells, which have migrated primarily from the endoderm to tissues throughout the body [1] They are a heterogenous group of neoplasms with a wide range of clinical presentations, with some producing symptoms depending on their location and others remaining dormant for extended periods. The most recent classification has clarified previous semantic issues, using NEN as an all-encompassing term for both well- and poorly-differentiation tumors of neuroendocrine cells, whilst the term neuroendocrine tumor (NET) is reserved for well-differentiated neoplasm and neuroendocrine carcinoma (NEC) is defined as a poorly differentiated neoplasm Another important change is the inclusion of a high-grade category for well differentiated NETs (defined as a mitotic rate >20 per 2 mm or Ki-67 >20%) which are distinct from poorly differentiated NECs. Staging is performed using formal TNM-based systems independently produced by the American Joint Committee on Cancer (most recently the 8th edition) [10] and the ENETS, which are separated by tumor location. Curative surgical resection is only an option in a subset of patients; somatostatin analogues are central in treatment pathways for patients with NENs
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