Treatment Options for High Grade (Grade 3) NETS 

Grade 3 well-differentiated neuroendocrine tumors (NETs) present unique clinical challenges, as emphasized by the panel of specialists. Distinguishing these from poorly differentiated carcinomas is essential, as treatment strategies differ markedly. Key factors in management include an accurate Ki-67 proliferation index, somatostatin receptor (SSTR) status, and an understanding of tumor heterogeneity—since clinical behavior and appropriate therapeutic choices may evolve over time. For SSTR-positive grade 3 NETs, peptide receptor radionuclide therapy (PRRT) can be considered early, while temozolomide-based chemotherapy is often preferred for high-burden or SSTR-negative pancreatic NETs. Newer targeted agents like cabozantinib have shown promise, but data remain limited to small subsets. Molecular proﬁling is encouraged, especially in aggressive presentations or unusual sites, to uncover actionable targets such as BRAF mutations. Although newer studies like NETTER-2 and ECOG 2142 provide some guidance, standardization remains incomplete, and treatment often requires nuanced, case-by-case decision making guided by multidisciplinary expertise.

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Doctor Hendifer discusses the diverse therapies for neuroendocrine neoplasms, emphasizing individualized treatment based on patient needs and disease characteristics.

Sequencing of Systemic NETS Treatments 

The discussion highlighted the sequencing of therapies for neuroendocrine tumors (NETs) and emphasized a patient-centered, individualized approach. Dr. Hendifar outlined that treatment decisions are guided primarily by tumor differentiation, grade, and disease burden. For low-grade, low-burden NETs, somatostatin analogs (SSAs) remain ﬁrst-line due to their excellent safety proﬁle and ability to provide disease stability. For intermediate-grade tumors, targeted therapies such as mTOR inhibitors, VEGF tyrosine kinase inhibitors, and peptide receptor radionuclide therapy (PRRT) are often employed. High-grade or poorly differentiated tumors typically require cytotoxic chemotherapy, recognizing its associated toxicities.

Rather than rigid sequencing, the panel emphasized that most patients will eventually receive multiple therapies during their disease course, making exact order less critical. Decisions are informed by patient preferences, comorbidities, treatment tolerability, and healthcare context, reinforcing that NET management is a marathon, not a sprint. This approach ensures therapy balances efficacy, safety, and quality of life.

Experts discuss advanced treatment options for neuroendocrine tumors, highlighting PRRT, mTOR inhibitors, and emerging therapies for improved patient outcomes.

Inadequate Response and Second-Line Treatment of NETS 

The discussion focused on second-line management of neuroendocrine tumors (NETs) following progression on somatostatin analogs (SSAs). Dr. Chauhan highlighted that the expanding range of therapies makes progression a “good problem to have,” though treatment decisions remain site-speciﬁc and biology-driven. Peptide receptor radionuclide therapy (PRRT) is now widely considered a preferred second-line option for SSTR-positive tumors, supported by NETTER-1 and NETTER-2 trials, offering disease control and improved quality of life with limited dosing and infusions. 

For pancreatic NETs, additional options include mTOR inhibitors (everolimus), tyrosine kinase inhibitors (sunitinib, cabozantinib), and chemotherapy with capecitabine-temozolomide, particularly for higher-grade tumors. Clinical trials and emerging therapies, including alpha/beta PRRT are also encouraged. For extra-pancreatic NETs, treatment options are more limited but still include PRRT, capecitabine-temozolomide, and chemotherapy in select aggressive cases. Overall, the panel emphasized the importance of personalizing therapy based on tumor site, grade, receptor status, and patient-speciﬁc factors, reﬂecting the growing complexity and opportunity in NET management.

Oncology treatment decisions hinge on tumor biology and patient factors, emphasizing a multidisciplinary approach for optimal care.

 Inadequate Response and Second-Line Treatment of NETS 

Site of Origin and Treatment of NETS 

The panel underscored that neuroendocrine tumor (NET) management requires a nuanced, multidisciplinary approach, particularly regarding somatostatin receptor (SSTR) expression. Non-expression of SSTR in gastrointestinal NETs is especially concerning, while it’s more common and less worrisome in lung or certain cervical NETs. Dr. Arshad emphasizes balancing evidence-based guidelines with the “art” of oncology—applying patient-speciﬁc factors, tumor biology, clinical presentation, and patient values. Decision-making encompasses tumor site, size, aggressiveness, stage, and presence or absence of functional symptoms, as well as the patient’s age, comorbidities, preferences, and quality-of-life goals. For example, aggressive interventions and attempts at complete resection are prioritized in pancreatic NETs, while small bowel or more indolent NETs often justify a less intensive, sometimes observational approach. Treatment plans are shaped by the therapy’s impact—balancing eOicacy, side effects, and ﬁnancial burden—with ongoing dialogue between specialists and patients to ensure choices align with both the latest evidence and individual patient goals.

Experts discuss treatment strategies for neuroendocrine tumors, emphasizing personalized approaches based on tumor grade, symptoms, and patient health.

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.

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.

Junaid Arshad, MD, MS

Articles

Treatment Options for High Grade (Grade 3) NETS

Sequencing of Systemic NETS Treatments

Inadequate Response and Second-Line Treatment of NETS

Site of Origin and Treatment of NETS

First-Line Treatment and Standard of Care for NETS

Prognostic Factors for Neuroendocrine Tumors

Role of Biomarkers in Diagnosis and Management of NETS

Early Diagnosis of Neuroendocrine Tumors

Imaging Modalities for Neuroendocrine Tumors

Classification of Neuroendocrine Tumors