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

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.

[1]  R. Salem,et al.  Blood measurement of neuroendocrine gene transcripts defines the effectiveness of operative resection and ablation strategies , 2016 .

[2]  I. Modlin,et al.  Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms , 2016, Nature Reviews Clinical Oncology.

[3]  S. Asa,et al.  Diagnosis and management of gastrointestinal neuroendocrine tumors: An evidence-based Canadian consensus. , 2016, Cancer treatment reviews.

[4]  S. Severi,et al.  Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors , 2016, European Journal of Nuclear Medicine and Molecular Imaging.

[5]  James C Yao,et al.  Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study , 2016, The Lancet.

[6]  I. Modlin,et al.  Chromogranin A: any relevance in neuroendocrine tumors? , 2016, Current opinion in endocrinology, diabetes, and obesity.

[7]  E. Krenning,et al.  ENETS Consensus Guidelines Update for Neuroendocrine Neoplasms of the Jejunum and Ileum , 2016, Neuroendocrinology.

[8]  R. Kianmanesh,et al.  ENETS 2016 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update , 2016, Neuroendocrinology.

[9]  R. Jensen,et al.  ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors , 2016, Neuroendocrinology.

[10]  I. Modlin,et al.  Circulating Transcript Analysis (NETest) in GEP-NETs Treated With Somatostatin Analogs Defines Therapy. , 2015, The Journal of clinical endocrinology and metabolism.

[11]  I. Drozdov,et al.  Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status. , 2015, Endocrine-related cancer.

[12]  T. Mukhtar,et al.  Consensus Recommendations for the Diagnosis and Management of Pancreatic Neuroendocrine Tumors: Guidelines from a Canadian National Expert Group , 2015, Annals of Surgical Oncology.

[13]  R. Agarwala,et al.  A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase. , 2015, Gastroenterology.

[14]  I. Drozdov,et al.  The Clinical Utility of a Novel Blood-Based Multi-Transcriptome Assay for the Diagnosis of Neuroendocrine Tumors of the Gastrointestinal Tract , 2015, The American Journal of Gastroenterology.

[15]  S. Severi,et al.  Gene transcript analysis blood values correlate with 68Ga-DOTA-somatostatin analog (SSA) PET/CT imaging in neuroendocrine tumors and can define disease status , 2015, European Journal of Nuclear Medicine and Molecular Imaging.

[16]  Mohid S. Khan,et al.  Somatostatin Analogs Treated Small Intestinal Neuroendocrine Tumor Patients Circulating MicroRNAs , 2015, PloS one.

[17]  A. Frilling,et al.  Therapeutic strategies for neuroendocrine liver metastases , 2015, Cancer.

[18]  M. Dowsett,et al.  Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer , 2015, Breast Cancer Research.

[19]  James C Yao,et al.  A tale of two tumors: treating pancreatic and extrapancreatic neuroendocrine tumors. , 2015, Annual review of medicine.

[20]  I. Drozdov,et al.  Decoding the Molecular and Mutational Ambiguities of Gastroenteropancreatic Neuroendocrine Neoplasm Pathobiology , 2015, Cellular and molecular gastroenterology and hepatology.

[21]  G. Vitale,et al.  Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment. , 2014, Endocrine-related cancer.

[22]  I. Drozdov,et al.  A PCR blood test outperforms chromogranin A in carcinoid detection and is unaffected by proton pump inhibitors , 2014, Endocrine connections.

[23]  I. Drozdov,et al.  Neuroendocrine Tumor Biomarkers: Current Status and Perspectives , 2014, Neuroendocrinology.

[24]  I. Modlin,et al.  The Status of Neuroendocrine Tumor Imaging: From Darkness to Light? , 2014, Neuroendocrinology.

[25]  E. Wang,et al.  Predictive genomics: a cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data. , 2014, Seminars in cancer biology.

[26]  I. Drozdov,et al.  Blood transcript analysis and metastatic recurrent small bowel carcinoid management , 2014, BMC Cancer.

[27]  I. Drozdov,et al.  A multianalyte PCR blood test outperforms single analyte ELISAs (chromogranin A, pancreastatin, neurokinin A) for neuroendocrine tumor detection. , 2014, Endocrine-related cancer.

[28]  I. Drozdov,et al.  Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors , 2014, BMC Genomics.

[29]  M. Lubberink,et al.  Quantitative and Qualitative Intrapatient Comparison of 68Ga-DOTATOC and 68Ga-DOTATATE: Net Uptake Rate for Accurate Quantification , 2014, The Journal of Nuclear Medicine.

[30]  James C. Yao,et al.  Molecular pathology and genetics of gastrointestinal neuroendocrine tumours , 2014, Current opinion in endocrinology, diabetes, and obesity.

[31]  Mohid S. Khan,et al.  Combination of Cross-Sectional and Molecular Imaging Studies in the Localization of Gastroenteropancreatic Neuroendocrine Tumors , 2014, Neuroendocrinology.

[32]  A. Sundin,et al.  Gastrointestinal neuroendocrine tumors (NETs): new diagnostic and therapeutic challenges , 2014, Cancer and Metastasis Reviews.

[33]  J. Kinross,et al.  Metabonomic profiling: a novel approach in neuroendocrine neoplasias. , 2013, Surgery.

[34]  P. Kuppen,et al.  The prognostic value of apoptotic and proliferative markers in breast cancer , 2013, Breast Cancer Research and Treatment.

[35]  I. Drozdov,et al.  Gut neuroendocrine tumor blood qPCR fingerprint assay: characteristics and reproducibility , 2013, Clinical chemistry and laboratory medicine.

[36]  I. Steffen,et al.  Evaluation of radiological prognostic factors of hepatic metastases in patients with non-functional pancreatic neuroendocrine tumors. , 2013, European journal of radiology.

[37]  O. Dekkers,et al.  Low accuracy of tumor markers for diagnosing pancreatic neuroendocrine tumors in multiple endocrine neoplasia type 1 patients. , 2013, The Journal of clinical endocrinology and metabolism.

[38]  R. Murthy,et al.  Can imaging patterns of neuroendocrine hepatic metastases predict response yttruim-90 radioembolotherapy? , 2013, World journal of radiology.

[39]  E. Wieben,et al.  The genomic landscape of small intestine neuroendocrine tumors. , 2013, The Journal of clinical investigation.

[40]  I. Drozdov,et al.  The Identification of Gut Neuroendocrine Tumor Disease by Multiple Synchronous Transcript Analysis in Blood , 2013, PloS one.

[41]  M. Kulke,et al.  Targeted therapies in neuroendocrine tumors (NET): clinical trial challenges and lessons learned. , 2013, The oncologist.

[42]  D. Metz,et al.  Consensus guidelines for the management and treatment of neuroendocrine tumors. , 2013, Pancreas.

[43]  H. Amthauer,et al.  Quantification in 68Ga-DOTA(0)-Phe(1)-Tyr(3)-Octreotide Positron Emission Tomography/Computed Tomography: Can We Be Impartial about Partial Volume Effects? , 2013, Neuroendocrinology.

[44]  M. Broder,et al.  Systemic Treatment in Unresectable Metastatic Well-Differentiated Carcinoid Tumors: Consensus Results From a Modified Delphi Process , 2013, Pancreas.

[45]  Mohid S. Khan,et al.  Circulating tumor cells as prognostic markers in neuroendocrine tumors. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[46]  A. Sundin,et al.  Therapeutic Monitoring of Gastroenteropancreatic Neuroendocrine Tumors: The Challenges Ahead , 2012, Neuroendocrinology.

[47]  K. Öberg Neuroendocrine tumors of the digestive tract: impact of new classifications and new agents on therapeutic approaches , 2012 .

[48]  J. Shay,et al.  Cancer and Telomeres—An ALTernative to Telomerase , 2012, Science.

[49]  Sven Diederichs,et al.  The hallmarks of cancer , 2012, RNA biology.

[50]  M. Ronot,et al.  Imaging response in neuroendocrine tumors treated with targeted therapies: the experience of sunitinib , 2012, Targeted Oncology.

[51]  M. Pavel Translation of Molecular Pathways into Clinical Trials of Neuroendocrine Tumors , 2012, Neuroendocrinology.

[52]  B. Wiedenmann,et al.  ENETS 2011 Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Tumors: An Update , 2011, Neuroendocrinology.

[53]  James C Yao,et al.  Chromogranin A and neuron-specific enolase as prognostic markers in patients with advanced pNET treated with everolimus. , 2011, The Journal of clinical endocrinology and metabolism.

[54]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[55]  Michael A. Choti,et al.  DAXX/ATRX, MEN1, and mTOR Pathway Genes Are Frequently Altered in Pancreatic Neuroendocrine Tumors , 2011, Science.

[56]  I. Modlin,et al.  The clinical relevance of chromogranin A as a biomarker for gastroenteropancreatic neuroendocrine tumors. , 2011, Endocrinology and metabolism clinics of North America.

[57]  L. Ellis,et al.  Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  Mohid S. Khan,et al.  Circulating Tumor Cells and EpCAM Expression in Neuroendocrine Tumors , 2011, Clinical Cancer Research.

[59]  A. Metspalu,et al.  Metagenes Associated with Survival in Non-Small Cell Lung Cancer , 2011, Cancer informatics.

[60]  R. Salazar,et al.  Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[61]  P. Cumming,et al.  68Ga-DOTATATE PET/CT for the Early Prediction of Response to Somatostatin Receptor–Mediated Radionuclide Therapy in Patients with Well-Differentiated Neuroendocrine Tumors , 2010, The Journal of Nuclear Medicine.

[62]  W. Oyen,et al.  Procedure guidelines for PET/CT tumour imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[63]  I. Modlin,et al.  Chromogranin A—Biological Function and Clinical Utility in Neuro Endocrine Tumor Disease , 2010, Annals of Surgical Oncology.

[64]  M. Washington,et al.  Pathology Reporting of Neuroendocrine Tumors: Application of the Delphic Consensus Process to the Development of a Minimum Pathology Data Set , 2010, The American journal of surgical pathology.

[65]  Marion de Jong,et al.  Somatostatin-receptor-based imaging and therapy of gastroenteropancreatic neuroendocrine tumors. , 2010, Endocrine-related cancer.

[66]  R. Bale,et al.  68Ga-DOTA-Tyr3-Octreotide PET for Assessing Response to Somatostatin-Receptor–Mediated Radionuclide Therapy , 2009, Journal of Nuclear Medicine.

[67]  S. Mane,et al.  Predicting neuroendocrine tumor (carcinoid) neoplasia using gene expression profiling and supervised machine learning , 2009, Cancer.

[68]  T. Sing,et al.  Gene expression profiles differentiating between breast cancers clinically responsive or resistant to letrozole. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[69]  Manal M. Hassan,et al.  One hundred years after "carcinoid": epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[70]  Hirotoshi Kikuchi,et al.  Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis. , 2008, Endocrine-related cancer.

[71]  Haesun Choi,et al.  Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[72]  R. Bale,et al.  68Ga-DOTA-Tyr3-Octreotide PET in Neuroendocrine Tumors: Comparison with Somatostatin Receptor Scintigraphy and CT , 2007, Journal of Nuclear Medicine.

[73]  M. Rothmund,et al.  Prospective Evaluation of Imaging Procedures for the Detection of Pancreaticoduodenal Endocrine Tumors in Patients with Multiple Endocrine Neoplasia Type 1 , 2004, World Journal of Surgery.

[74]  U. Jaeger,et al.  Monitoring minimal residual disease in AML: the right time for real time , 2003, Annals of Hematology.

[75]  J. Crisp,et al.  The Delphi method? , 1997, Nursing research.

[76]  Murray Turoff,et al.  The Delphi Method: Techniques and Applications , 1976 .

[77]  A. Grossman,et al.  Appendiceal neuroendocrine neoplasms: diagnosis and management. , 2016, Endocrine-related cancer.

[78]  E. Mittra,et al.  177-Lu-Dotatate Significantly Improves Progression-Free Survival in Patients with Midgut Neuroendocrine Tumors : Results of the Phase III NETTER-1 Trial , 2016 .

[79]  A. Scarpa,et al.  Genetics and Epigenetics of Pancreatic Neuroendocrine Tumors and Pulmonary Carcinoids. , 2015, Frontiers of hormone research.

[80]  J. Berlin,et al.  Neuroendocrine tumors, version 1.2015. , 2015, Journal of the National Comprehensive Cancer Network : JNCCN.

[81]  E. D. de Vries,et al.  EUS is superior for detection of pancreatic lesions compared with standard imaging in patients with multiple endocrine neoplasia type 1. , 2015, Gastrointestinal endoscopy.

[82]  R. Schilsky,et al.  Recommendations for management of patients with neuroendocrine liver metastases. , 2014, The Lancet. Oncology.

[83]  Arkady Tsinober,et al.  On the Status , 2014 .

[84]  M. Luster,et al.  European Journal of Nuclear Medicine and Molecular Imaging Eanm Dosimetry Committee Series on Standard Operational Procedures for Pre-therapeutic Dosimetry Ii. Dosimetry Prior to Radioiodine Therapy of Benign Thyroid Diseases , 2022 .

[85]  J. Stockman,et al.  Everolimus for Advanced Pancreatic Neuroendocrine Tumors , 2012 .

[86]  K. Oberg,et al.  Neuroendocrine tumors of the digestive tract: impact of new classifications and new agents on therapeutic approaches , 2012, Current opinion in oncology.

[87]  F. Bosman,et al.  WHO Classification of Tumours of the Digestive System , 2010 .

[88]  A. Kjaer,et al.  F-Fluorodeoxyglucose Positron Emission Tomography Predicts Survival of Patients with Neuroendocrine Tumors , 2010 .

[89]  L. Schwartz,et al.  New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). , 2009, European journal of cancer.

[90]  金子 文成,et al.  長時間歩行時の下肢筋の活動状態:[ 18 F]fluorodeoxyglucoseを用いたPositron Emission Tomographyによる検討 , 2008 .

[91]  R. Jensen,et al.  Gastroenteropancreatic neuroendocrine tumours. , 2008, The Lancet. Oncology.

[92]  E. Somers International Agency for Research on Cancer. , 1985, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.