Available online 5 July 2023, 101797

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Neuroendocrine neoplasms are rare and heterogenous group of tumors with varying degrees of clinical presentation and involvement of multiple organ systems in the body. In the modern clinical practice somatostatin receptor molecular imaging and targeted radioligand therapy plays a vital role in the diagnosis and management of the disease. Several new and promising radiotracers for NET imaging and theranostics, belonging to various groups and classes are being studied and investigated. This exponential growth of radiotracers poses concerns about the indication, clinical benefit, and safety profile of the agents. We discuss the basis behind these radiotracers clinical use, receptor targeting and intra and inter tumor heterogeneity. Furthermore, role of dual tracer imaging, combination therapy and potential applications of dosimetry in predicting treatment outcome and safety profile is reviewed. Individualized precision medicine with better tumor characterization, maximum therapeutic benefit and minimum toxicity is the way forward for future medicine.

Section snippetsINTRODUCTION

Neuroendocrine neoplasms (NEN) are, rare and heterogeneous group of neoplasms with varying prognoses and clinical presentations and steadily increasing incidence [1], [2], [3].

Pathological grading based on differentiation and proliferation index, as determined by Ki67 score and tumor mitotic index determine the intensity of somatostatin receptor expression on NET cells *[4]. Well-differentiated NET express cell surface somatostatin receptors (SSTR) in 85-90% of the patients, whereas

SOMATOSTATIN RECEPTOR IMAGING

Majority of the tumors with amine precursor uptake and decarboxylation characteristics, express somatostatin receptors (SSTRs), such as gastro-entero-pancreatic tumors, carcinoids, para-gangliomas, medullary thyroid tumors, small cell lung cancers and also meningiomas, neuroblastoma and astrocytoma *[5]. There are at least 5 types of SSTRs,SSTR type 2 is the most common and abundant [6], [7], [8]. Inverse relation of somatostatin receptor expression has been described with G3 NETs or poorly

NON-SSTR TARGETTING PET AGENTS

There are many non-SSTR targeting PET agents under investigation for selected, de-deifferentiated/undifferentiated NET tumors, and dual tracer imaging to better understand the tumor microemvironment, with different modes of uptake. We are providing a brief revirw of most studied and promising non-SSTR agents with potential for imaging and coupled therapeutic use.

TUMOR HETEROGENEITY AND COMBINATION IMAGING AND THERAPY

Most tumors, including NETs, evolve with time and are often secondary to treatment-related microenvironment alterations. This transformation is at both cellular and molecular levels. An example of this transformation and molecular heterogeneity is the coexistence of SSTR and glucose transporters in NETs with varying degrees of differentiation during the course of the disease [65]. Various methods of detection of this heterogeneity have been employed including liquid biopsy, molecular pathology,

ALPHA EMITTING PRRT

SSTR targeting is slowly moving from agonists to antagonists, simultaneously PRRT which as of now primarily relies on beta emitters i.e, Lu-177 and Y-90, is also slowly incorporating other modes of radiation decay i.e, auger electron and alpha particle therapy, the latter being more releveant. Fig. 3, shows different modes of radiation decay, their interaction with matter i.e. tissues in body and effect of such interaction. It has been reported that hypoxic tumor cells could be resistant to

PRRT TOXICITIES

PRRT has emerged as a promising treatment for NETs [77]. While PRRT is generally well tolerated, toxicity remains a concern for clinicians and patients. The most common adverse events associated with PRRT include hematologic toxicity, renal toxicity, and gastrointestinal toxicity [78]. Although very infrequent, serious renal injury has been reported with Y-90 treatment, milder renal toxicities are associated with Lu-177 *[79], [80]. Extensive dosimetric data analysis has been done and is still

UPCOMING CLINICAL TRIALS

There are quite a few ongoing clinical trials being conducted on the NET tumor target imaging, treatment monitoring, tumor heterogeneity, and combination therapies. COMPETE trial [88] [NCT03049189], a prospective multicenter trial, evaluating efficacy and safety of Lu-177 PRRT in GEP-NET patients versus Everolimus. COMPOSE trial [89] [NCT04919226], evaluating Lu-177 versus best standard of care in well-differentiated aggressive G 2 and G 3 GEP-NETs. NETTER-2 trial is also looking at the

SUMMARY

The clinic-pathological management of neuroendocrine tumors has always been challenging for oncologists. The disease can present with varying degrees of differentiation and molecular heterogeneity with remarkable impact on management. New and emerging nuclear medicine radiopharmaceuticals promise to enhance the detection of the disease and better reflect the molecular characteristics of tumors, providing insight of inter-tumor and intra-tumor heterogeneity. A better understanding of tumor’s

Financial Disclosures

No financial support was received for this work. All authors have no relevant financial disclosures.

Conflict of interest

All authors have no conflict of interest with the material presented in this manuscript.

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