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A patient with well-differentiated duodenal NET (G1, Ki67 < 2%) underwent 68 Ga-DOTATATE for the assessment of suitability for 177 Lu-DOTATATE. 68 Ga-DOTATATE PET CT and PET/CT (A) showed no uptake in the hepatic metastases (brackets). 68 Ga-DOTA-Exendin-4 PET, CT and PET/CT (B) showed intense uptake in the hepatic metastases (brackets)
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Neuroendocrine neoplasia (NEN) is an umbrella term that includes a widely heterogeneous disease group including well-differentiated neuroendocrine tumours (NETs), and aggressive neuroendocrine carcinomas (NECs). The site of origin of the NENs is linked to the intrinsic tumour biology and is predictive of the disease course. It is understood that NE...
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Context 1
... receptors are widespread within the gastrointestinal tract and pancreas, and overexpressed in various NETs (Fig. 10), particularly in high density in almost all benign insulinomas [79]. Exendin-4 is a longacting GLP-1 analog used for the treatment of type 2 diabetes and as the precursor to be radiolabeled with a variety of gamma-emitting radionuclides including In and 99m Tc, as well as PET radionuclides such as 68 Ga, 64 Cu, 18 F and 89 Zr. PET ...
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Introduction. Neuroendocrine tumors (NETs) have increased expression of somatostatin receptors (SSTR), where subtype 2 and 5 are the most common. Overexpression of the SSTR is an outstanding molecular target for inoperable and metastatic NETs that enables a unique approach of targeted diagnosis and treatment. In addition to SSTRs, neuroendocrine tu...
Citations
... Preoperative PET imaging with the positron (β + )-emitting somatostatin analog [ 68 Ga]Ga-DOTA-(Tyr 3 )octreotate (TATE) is recommended in the guidelines for NENs and was FDA (Food and Drug Administration)-approved in 2016 in the Unites States [13][14][15][16]. [ 68 Ga]Ga-DOTA-TATE detects primary and metastatic lesions of NENs with high sensitivity and specificity of over 80%, as demonstrated in multiple studies [17][18][19]. ...
... There are two main strategies for enhancing the efficacy of conventional radionuclide therapies: increasing the absorbed radiation dose (dose maximization), or enhancing the tumor's susceptibility to the biophysical and radiobiological effects of ionizing radiation (radiosensitization). The absorbed dose of a target-specific radiopharmaceutical can be improved by (i) optimizing treatment schemes and sequences, e.g., via personalized fractionating and dosing [49]; (ii) minimizing off-target retention, in particular in kidneys, thereby allowing for increased total applied doses of the radiopharmaceutical [16,50,51]; (iii) upregulating molecular targets for radiopharmaceuticals in tumors, e.g., through epigenetic modifiers [52][53][54][55]; (iv) increasing the bound fraction of radiopharmaceuticals in tumors, e.g., using albumin binder conjugates providing increased blood circulation times [56] or receptor antagonists [57,58]; and (v) attaching alternative radionuclides with suitable chemical properties for radiolabeling as well as favorable decay properties providing radiation with high ionization densities such as α particles, Auger electrons and/or high-energy βparticles, and half-lives compatible with the pharmacologic properties of the targeting vectors, e.g. 225 Ac, 213 Bi,211 At, 212 Pb, 161 Tb, and 67 Cu [59][60][61]. ...
Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [¹³¹I]MIBG and [¹⁷⁷Lu]Lu-DOTA-TATE are routinely used for the treatment of a subset of NENs, including pheochromocytomas, paragangliomas and gastroenteropancreatic tumors. Some patients suffering from other forms of NENs, such as medullary thyroid carcinoma or neuroblastoma, were shown to respond to radionuclide therapy; however, no general recommendations exist. Although [¹³¹I]MIBG and [¹⁷⁷Lu]Lu-DOTA-TATE can delay disease progression and improve quality of life, complete remissions are achieved rarely. Hence, better individually tailored combination regimes are required. This review summarizes currently applied radionuclide therapies in the context of NENs and informs about recent advances in the development of theranostic agents that might enable targeting subgroups of NENs that previously did not respond to [¹³¹I]MIBG or [¹⁷⁷Lu]Lu-DOTA-TATE. Moreover, molecular pathways involved in NEN tumorigenesis and progression that mediate features of radioresistance and are particularly related to the stemness of cancer cells are discussed. Pharmacological inhibition of such pathways might result in radiosensitization or general complementary antitumor effects in patients with certain genetic, transcriptomic, or metabolic characteristics. Finally, we provide an overview of approved targeted agents that might be beneficial in combination with radionuclide therapies in the context of a personalized molecular profiling approach.
... Lesion uptake higher than the liver, as indicated by a Krenning score of ≥3, is typically used to define SSTR positivity and eligibility for RLT. The Krenning score was originally based on [ 111 ln]ln-pentetreotide scintigraphy (as used in the pivotal NETTER-1 trial of 177 Lu-DOTATATE) [11], and a similar threshold-based approach has been adapted for SSTR PET [9,12,13]. As the Krenning scale is visually dependent on planar images and limited by semi-quantitative scoring metrics, efforts have been made to develop other imaging surveillance techniques with better sensitivity and specificity for tumor burden. ...
... Pre-RLT imaging should thus incorporate SSTR PET along with multiphasic, contrast-enhanced anatomic imaging of the abdomen, including the liver and pancreas. Functional imaging with 2-[ 18 F] fludeoxyglucose (FDG) PET also complements SSTR PET and has the potential to elucidate disease heterogeneity and improve patient selection for RLT [8,13]. This approach is especially useful in patients with grade 3 GEP-NETs or grade 1/2 GEP-NETs with mismatch lesions between SSTR PET and anatomic imaging. ...
Simple Summary
Radioligand therapy with [¹⁷⁷Lu]Lu-DOTA-TATE is a therapeutic option for adult patients with somatostatin-receptor–positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Patients undergoing radioligand therapy require diligent monitoring and surveillance. While published guidelines can provide guidance on general approaches to care, GEP-NETs are heterogeneous and the guidelines can be difficult to apply in individual and complex cases. In this article, we discuss emerging evidence on imaging, clinical biochemistry, and tumor assessment criteria in the management of patients receiving radioligand therapy for GEP-NETs as well as our own best practices. We offer practical guidance on how to effectively implement monitoring and surveillance measures to aid patient-tailored clinical decision-making.
Abstract
Radioligand therapy (RLT) with [¹⁷⁷Lu]Lu-DOTA-TATE is a standard of care for adult patients with somatostatin-receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Taking advantage of this precision nuclear medicine approach requires diligent monitoring and surveillance, from the use of diagnostic SSTR-targeted radioligand imaging for the selection of patients through treatment and assessments of response. Published evidence-based guidelines assist the multidisciplinary healthcare team by providing acceptable approaches to care; however, the sheer heterogeneity of GEP-NETs can make these frameworks difficult to apply in individual clinical circumstances. There are also contradictions in the literature regarding the utility of novel approaches in monitoring and surveilling patients with GEP-NETs receiving RLT. This article discusses the emerging evidence on imaging, clinical biochemistry, and tumor assessment criteria in the management of patients receiving RLT for GEP-NETs; additionally, it documents our own best practices. This allows us to offer practical guidance on how to effectively implement monitoring and surveillance measures to aid patient-tailored clinical decision-making.
... The development of molecular imaging and tracers provides insights into intratumoral or intertumoral heterogeneity and shows the advantage of uncovering spatiotemporal heterogeneity (35). Understanding this remarkable biological heterogeneity helps us to gain insight into the clinical manifestations and disease course, which can guide clinical treatment decisions and assist in evaluating prognoses (36). Due to the differences in radiopharmaceutical avidity and imaging modalities in our case, the cervical lesions (Ki-67 5%) showed mild FDG uptake but significantly intense DOTATATE uptake. ...
... Another 18 F labeled PSMA-specific small molecule imaging agent, 2-(3-[45]-ureido)-pentanedioic acid ([ 18 F]DCFPyL), has also been developed based on the Glu-urea-Lys motif. This molecule is characterized by high affinity and favorable pharmacokinetics in vivo [23,45,46], thus allowing the earlier detection of local recurrence, even at lower PSA levels [47]. The novel probe, JK-PSMA-7, was identified by screening multiple DCFPyL analogs, with the main difference being the addition of a methoxy group to the pyridine ring. ...
... 68 Ga-labeled DOTA-TOC and DOTA-TATE have been widely used for the PET imaging of tumors. Additionally, peptide receptor radionuclide therapy (PRRT) with [ 90 Y]Y-DOTA-TOC and [ 177 Lu]Lu-DOTA-TATE can improve treatment efficacy for NETs [4,45]. ...
... FDG is a glucose analog that shows a high level of uptake by cells with high glycolysis rates. [ [45,84]. Studies have demonstrated that NEPC cells show increased glucose uptake owing to the increased expression of glucose transporters. ...
Radiopharmaceuticals targeting prostate-specific membrane antigens (PSMA) are essential for the diagnosis, evaluation, and treatment of prostate cancer (PCa), particularly metastatic castration-resistant PCa, for which conventional treatment is ineffective. These molecular probes include [68Ga]PSMA, [18F]PSMA, [Al18F]PSMA, [99mTc]PSMA, and [89Zr]PSMA, which are widely used for diagnosis, and [177Lu]PSMA and [225Ac]PSMA, which are used for treatment. There are also new types of radiopharmaceuticals. Due to the differentiation and heterogeneity of tumor cells, a subtype of PCa with an extremely poor prognosis, referred to as neuroendocrine prostate cancer (NEPC), has emerged, and its diagnosis and treatment present great challenges. To improve the detection rate of NEPC and prolong patient survival, many researchers have investigated the use of relevant radiopharmaceuticals as targeted molecular probes for the detection and treatment of NEPC lesions, including DOTA-TOC and DOTA-TATE for somatostatin receptors, 4A06 for CUB domain-containing protein 1, and FDG. This review focused on the specific molecular targets and various radionuclides that have been developed for PCa in recent years, including those mentioned above and several others, and aimed to provide valuable up-to-date information and research ideas for future studies.
... A dissociated or mixed response is seen when some lesions respond to therapy while others do not (Fig 15). A dissociated response is also seen with conventional cytotoxic therapy; this results from inherent interlesion heterogeneity, the exis-tence of synchronous malignancies, or the treatment-induced emergence of resistant tumor clones (3,53,54). This response pattern with immune checkpoint inhibitor therapy likely reflects the interlesional heterogeneity whereby select tumors acquire resistance to specific immune-targeting pathways by way of additional genetic mutations (55). ...
Response is the logical outcome measure of a treatment in a clinical or research setting. Objective response assessment involves the use of a test to segregate patients who are likely to experience improved survival from those who are not. Early and accurate response assessment is critical for determining therapy effectiveness in clinical settings, for effective trial designs comparing two or more therapies, and for modulating treatment on the basis of response (ie, response-adapted therapy). 2-[fluorine 18]fluoro-2-deoxy-d-glucose (FDG) PET/CT can provide both functional and structural information about a disease process. It has been used at several stages of patient management, including imaging-based tumor response assessment, for various malignancies. FDG PET/CT can be used to differentiate patients with lymphoma who have a residual mass but no residual disease after treatment (ie, complete responders) from those who have a residual mass and residual disease after treatment. Similarly, in solid malignancies, the functional changes in glucose uptake and metabolism precede the structural changes (commonly seen as tumor shrinkage) and necrosis. Response assessment criteria have been developed on the basis of findings on FDG PET/CT images and are continuously being revised to ensure standardization and improve their predictive performance. Published under a CC BY 4.0 license. Quiz questions for this article are available through the Online Learning Center.
... The expression of SSTRs on imaging could therefore be more accurate in the assessment of tumour heterogeneity in comparison to tumour sampling (i.e., assessment of Ki-67 on tumour biopsy), as imaging can assess all primary and secondary lesions (spatial and morphological heterogeneity), and can be repeated to assess changes in tumour biology over time (temporal heterogeneity) [52]. Pre-treatment 68Ga-DOTA-peptides PET/CT, however, does not always correlate with a response to PRRT, as target lesion heterogeneity may affect the response [53]. The quality of SSTR expression on baseline 68Ga-DOTA-peptides PET/CT prior to PRRT has been proposed as a parameter to evaluate intra-tumour heterogeneity in grade 1 and grade 2 NETs. ...
... SUVmax on 68Ga-DOTATATE imaging has been found to be higher in patients with bone metastases from NENs of different sites; generally bone metastases in NENs represent a poor prognostic factor [65]. The inconsistent correlation between SUV changes and outcomes could be due to the presence of spatial and temporal SSTR heterogeneity that may lead to a divergent appearance after treatment on morphologic (CT or magnetic resonance imaging-MRI) versus receptor-based imaging [53]. ...
... 18F-FDG-PET might be a useful addition to SSTR-based imaging in NENs with higher mitotic rates but well-differentiated morphology, i.e., for grade 3 GEP-NETs [66]. They might help in predicting response to PRRT, as standardised uptake values on 18F-FDG-PET seem to correlate more clearly than 68Ga-DOTA-peptides PET/CT with higher histological grades and poorer overall survival [53,[67][68][69][70][71][72][73]. In a retrospective analysis of grade 3 GEP-NETs, patients who showed increased 18F-FDG uptake in comparison to 68Ga-DOTATOC had significantly lower survival than patients who displayed increased uptake with receptor-based imaging. ...
Tumour heterogeneity is a common phenomenon in neuroendocrine neoplasms (NENs) and a significant cause of treatment failure and disease progression. Genetic and epigenetic instability, along with proliferation of cancer stem cells and alterations in the tumour microenvironment, manifest as intra-tumoural variability in tumour biology in primary tumours and metastases. This may change over time, especially under selective pressure during treatment. The gastroenteropancreatic (GEP) tract is the most common site for NENs, and their diagnosis and treatment depends on the specific characteristics of the disease, in particular proliferation activity, expression of somatostatin receptors and grading. Somatostatin receptor expression has a major role in the diagnosis and treatment of GEP-NENs, while Ki-67 is also a valuable prognostic marker. Intra- and inter-tumour heterogeneity in GEP-NENS, however, may lead to inaccurate assessment of the disease and affect the reliability of the available diagnostic, prognostic and predictive tests. In this review, we summarise the current available evidence of the impact of tumour heterogeneity on tumour diagnosis and treatment of GEP-NENs. Understanding and accurately measuring tumour heterogeneity could better inform clinical decision making in NENs.
