A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management

Abstract

The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

Current Concepts in 68Ga-DOTATATE Imaging of Neuroendocrine Neoplasms: Interpretation, Biodistribution, Dosimetry, and Molecular Strategies

“…Previously, chromogranin A was considered useful, but rigorous assessment over the last decade has led to decreased enthusiasm about its use, because of normal levels in about 30%-40% of NENs and falsely elevated levels in patients with renal failure, cardiac disease, or proton pump inhibitor therapy (59). Moreover, alterations in circulating chromogranin A levels are often nonconcordant with imaging, and prospective studies have not confirmed a role for chromogranin A in predicting or defining progression (55). To better reflect not only the mere secretory activity but also the complex biologic activities of an evolving neoplasm (cell proliferation, growth factor signaling, and others) that constitute the hallmarks of cancer, and to provide more relevant information on tumor behavior, new approaches have been introduced, including whole-genome sequencing, circulating micro-RNA, and tumor transcripts (60).…”

Paraneoplastic endocrine syndromes

“…This is partially due to the pathobiological diversity of non-endocrine neoplasia and its generally more aggressive biological behaviour (Oberg et al 2016). In endocrine neoplasia, particularly in NETs, certain markers developed based on specific tumour-secreted compounds can improve chances of tumour detection (Oberg et al 2016).…”

“…This is partially due to the pathobiological diversity of non-endocrine neoplasia and its generally more aggressive biological behaviour (Oberg et al 2016). In endocrine neoplasia, particularly in NETs, certain markers developed based on specific tumour-secreted compounds can improve chances of tumour detection (Oberg et al 2016). Besides traditional biomarkers developed for the detection of endocrine malignancy, there is currently a considerable interest in areas such as blood transcript analysis, circulating tumour cells (NetTest) and miRNA measurement, although yet there are significant limitations before application into general clinical practice is likely (Modlin et al 2016).…”

“…However, occasionally, in the presence of highly aggressive tumours or extensive disease burden, management of these syndromes may be difficult and their presence can contribute to the morbidity and mortality of the underlying disease (Kaltsas et al 2010). As currently available therapies for a number of neoplasms evolve and highly specific diagnostic modalities become widely used, patients with tumours will live longer, and thus the prevalence of PNS will likely also increase (Oberg et al 2016). In the present review only endocrine PNS will be considered, excluding those related to different pathophysiological processes and/or exhibiting manifestations in other systems.…”

Molecular challenges of neuroendocrine tumors (Review)

“…Among the 5 types of SSTRs, SSTR2 is the predominant receptor in NETs (61). The SSTR 2 has the highest density and proved to be associated with overall survival (62)(63)(64). Pasireotide (SOM230), a novel somatostatin analog also was reported to have antitumor properties (65).…”