First-Line Treatment and Standard of Care for NETS 

The discussion focused on frontline management of newly diagnosed neuroendocrine tumor (NET) patients, emphasizing the heterogeneity of these tumors and the need for individualized care. For grade 1–2, low-burden, nonfunctional tumors, observation is often appropriate to assess disease biology and pace. Functional tumors, even if low-volume, typically require somatostatin analogs (SSAs) to control symptoms. Surgery and local therapies are highlighted as frontline options for liver-dominant or debulkable disease, offering potential long-term beneﬁt. For higher-burden or symptomatic tumors, systemic therapies like capecitabine-temozolomide may be considered, especially in pancreatic NETs. A key challenge discussed is low-grade tumors lacking somatostatin receptor (SSTR) expression, where SSA use is controversial and decisions may rely on FDG PET, functional symptoms, and tumor site. Site of origin (small bowel, pancreas, lung) also inﬂuences imaging interpretation, SSTR expression likelihood, and treatment selection, reinforcing that NET management requires careful, patient-speciﬁc decision-making rather than a one-size-ﬁts-all approach.

Videos

Explore the complexities of treating neuroendocrine tumors, focusing on patient-specific strategies and the role of somatostatin analogs.

Prognostic Factors for Neuroendocrine Tumors 

The discussion focused on the key prognostic factors guiding management of neuroendocrine tumors (NETs). Dr. Arshad emphasized tumor diferentiation and Ki-67 proliferation index as the two most critical determinants of prognosis, highlighting how well-differentiated tumors with organized morphology and low atypia generally behave more indolently than poorly differentiated ones. Dr. Hendifar and others agreed that pathologic classiﬁcation is fundamental but added that disease pace of growth rate observed on serial imaging provides essential real-world insight into tumor aggressiveness—especially given the heterogeneity of NETs that a single biopsy may not capture. Dr. Shaheen noted that somatostatin receptor (SSTR) expression is another powerful prognostic and predictive marker, for grade 1–2 and select grade 3 tumors, as it inﬂuences treatment options like PRRT. Dr. Chauhan added burden of disease, particularly liver involvement, as a key prognostic factor, explaining that patients with >50% hepatic disease often have worse outcomes due to risk of liver failure despite low tumor grade.

Experts discuss key factors influencing disease prognosis, emphasizing differentiation, growth pace, and disease burden in treatment decisions.

Role of Biomarkers in Diagnosis and Management of NETS 

The discussion centered on the evolving and often confusing role of biomarkers in neuroendocrine tumors (NETs)—described by Dr. Shaheen as the “wild west” of oncology. Experts agreed that histologic biomarkers remain foundational, distinguishing well- from poorly differentiated tumors through morphology and molecular markers such as chromogranin, synaptophysin, ATRX, DAXX, TP53, and RB. Ki-67 continues to be essential for grading and prognostication, while somatostatin receptor (SSTR) expression serves as both a diagnostic and predictive biomarker guiding the use of somatostatin analogs and radioland therapy. Next-generation sequencing (NGS) is mainly reserved for neuroendocrine carcinomas and select higher-grade NETs, performed upfront in grade 3 or when tumor behavior suggests progression or atypia; rarely is it used routinely in grade 1/2 NETs, except for speciﬁc cases like thoracic or thymic neoplasms. Chromogranin, though widely ordered in the past, is now discouraged for routine use due to poor speciﬁcity; imaging and advanced molecular markers are preferred for monitoring and management decisions.

Experts discuss the evolution of neuroendocrine tumor classification, highlighting its clinical implications and the importance of standardized treatment approaches.

Early Diagnosis of Neuroendocrine Tumors

In this discussion, neuroendocrine tumor specialists address the persistent challenge of delayed diagnosis in patients with functional NETs, notably those with carcinoid syndrome. Dr. Andrew Hendifar emphasizes that vague, slowly-progressing symptoms—such as ﬂushing, diarrhea, hypoglycemia, or even hypertension—often lead to extensive diagnostic delays, with many patients identiﬁed only at advanced, sometimes incurable stages. Contrastingly, functional tumors with more severe, acute symptoms, like insulinomas, are diagnosed earlier due to their pronounced clinical presentation. The panel highlights the ever-expanding spectrum of neuroendocrine tumor manifestations, mentioning tumor-induced, non-islet cell hypoglycemia as a rare but important entity, especially in the context of high tumor burden. Recognizing this diverse symptomatology is difficult for busy primary care providers, who manage numerous patients with overlapping, nonspeciﬁc complaints. Specialists agree that ongoing education for clinicians and patients is essential, encouraging heightened vigilance and early diagnostic strategies to improve timely detection and management of functional neuroendocrine tumors.

Experts discuss the evolution of neuroendocrine tumor classification, highlighting its impact on diagnosis, treatment, and clinical implications.

Imaging Modalities for Neuroendocrine Tumors

The discussion among neuroendocrine tumor specialists highlighted major advances in imaging that have transformed diagnosis and disease management. Dr. Chauhan emphasized two main imaging approaches: anatomic imaging (CT and MRI) and molecular imaging (DOTATATE PET). Anatomic imaging remains essential for baseline staging, assessing disease burden, and monitoring treatment response—CT is preferred for chest imaging, while MRI or liver protocols are more sensitive for hepatic lesions. DOTATATE PET provides high sensitivity and specificity (≈95–97%) for detecting neuroendocrine tumors, even small or obscure lesions, and determines somatostatin receptor expression—crucial for selecting targeted therapies. When following indolent NET patients, a sudden change in disease biology may warrant repeating a DOTA scan to assess for loss of somatostatin receptor expression, indicating possible disease progression or transformation. This approach offers a non-invasive alternative to biopsy.

Classification of Neuroendocrine Tumors

In this episode, panelists discussed classification of neuroendocrine neoplasms. Over the years, the classification of neuroendocrine neoplasms has evolved significantly, improving diagnostic accuracy and guiding clinical management. The 2010 WHO classification first introduced a universal, proliferation-based grading system using Ki-67 to categorize tumors into grades 1–3, providing a reproducible metric for prognosis and treatment selection. In 2017, the system was updated to recognize well-differentiated grade 3 neuroendocrine tumors (NETs) as distinct from poorly differentiated neuroendocrine carcinomas, with implications for therapy—such as differentiating between platinum-based and temozolomide-based regimens. By 2019, this dual-axis model of grade and differentiation was standardized across all gastroenteropancreatic NENs, improving consistency in diagnosis and imaging approaches. The 2022 WHO update further refined terminology, integrated molecular features (e.g., TP53, RB, DAXX, ATRX), and expanded classification to other endocrine organs. These updates have enhanced uniformity in pathology reporting and supported more precise, personalized treatment decisions.

Andrew E. Hendifar, MD, medical oncology lead for the Gastrointestinal Disease Research Group, Cedars-Sinai Medical Center, discusses the future treatment landscape for patients with neuroendocrine tumors (NETs).

The change in the treatment of NETs has been quite substantial over the last 5 years, explains Hendifar. However, there has been an immense number of breakthroughs in the last several years, and new treatments have been developed.

There are many types of treatments, such as peptide-receptor radionuclide therapy, targeted treatments, and new somatostatin analog treatments. According to Henfidar, there are things that we can do to help patients, and it seems like we are getting closer to achieving a better understanding of how to sequence treatments.

There are still remaining questions that need to be answered in the future, explains Hendifar. When does a patient need to see a multidisciplinary tumor team? When is the optimal time of surgery? Sequencing and synthesis of care, and putting these great new discoveries together in a certain treatment paradigm, is what physicians are going to be working on in the next few years.

Dr. Hendifar Discusses the Future Treatment of NETs

Andrew E. Hendifar, MD, medical oncology lead for the Gastrointestinal Disease Research Group, Cedars-Sinai Medical Center, discusses a 92-gene assay of patients with neuroendocrine tumors (NETs).

This 92-gene assay is a molecular classification of NETs, says Hendifar. The original validation set looked at over 2,000 tumors and sequenced over 22,000 genes to create this reference set of 92 genes.

Hendifar says this assay was done in an effort to better understand and characterize NETs that are diagnosed as an unknown primary.

Dr. Hendifar Discusses a 92-Gene Assay of NETs

Andrew E. Hendifar, MD, medical oncology lead for the Gastrointestinal Disease Research Group, Cedars-Sinai Medical Center, discusses the current treatment landscape in pancreas cancer.

Pancreas cancer treatment is changing, say Hendifar, and the disease is treatable with combination chemotherapy.

Additionally, the community is beginning to understand the different subtypes of this disease, including BRCA and microsatellite instable. Stromal targeting therapies also look promising.

Dr. Hendifar on the Current Treatment Landscape in Pancreas Cancer

Andrew E. Hendifar, MD, medical oncology lead for the Gastrointestinal Disease Research Group, Cedars-Sinai Medical Center, discusses HALO-202 in metastatic pancreatic ductal adenocarcinoma.

HALO-202 is phase II study that randomized previously untreated patients with metastatic pancreatic ductal adenocarcinoma to PEGPH20 in addition to standard gemcitabine and abraxane versus standard gemcitabine and abraxane alone.

View more from the 2017 World Congress on GI Cancer

Andrew E. Hendifar, MD

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