In this edition of our Guideline Spotlight, we will explore the key insights and takeaways from the American Society of Clinical Oncology’s (ASCO) comprehensive guideline, Systemic Therapy for Tumor Control in Metastatic Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs). This guideline offers evidence-based recommendations for the treatment of advanced or metastatic GEP-NETs, a rare group of tumors that typically originate in the pancreas or gastrointestinal tract.

The authors highlight that the age-adjusted incidence rate for neuroendocrine tumors (NETs) was 6.98 per 100,000 in the United States in 2012. Incidence rates for NETs in North America, Europe, and Asia are on the rise, attributed to improvements in diagnosis, stage migration, and more frequent incidental findings.

Please be aware that this summary does not cover all major points. For a comprehensive list of recommendations, please refer to the summary provided here or access the full text guideline located here. Let’s get started!

Key Takeaways
  • Initial Treatment Approach
    • Somatostatin Analogs (SSAs):
      • First-line treatment for metastatic well-differentiated GEP-NETs that are symptomatic or progressing is the use of somatostatin analogs (SSAs), such as octreotide and lanreotide.
      • SSAs are shown to be helpful for symptom control related to hormone overproduction (e.g., carcinoid syndrome) and can also slow tumor progression in some cases.
      • These therapies are well-tolerated and offer symptom relief (e.g., flushing, diarrhea) by reducing the secretion of hormones like serotonin and insulin.
  • Targeted Therapy and Chemotherapy
    • Targeted Therapies:
      • Everolimus and sunitinib are recommended for progressive metastatic GEP-NETs that are not responsive to SSAs or those with high tumor burden.
      • Everolimus (an mTOR inhibitor) is effective for pancreatic neuroendocrine tumors (PNETs), showing improvement in progression-free survival (PFS).
      • Sunitinib (a tyrosine kinase inhibitor) is recommended for advanced pancreatic neuroendocrine tumors with poor prognosis.
    • Chemotherapy:
      • For high-grade or rapidly progressing tumors, chemotherapy with regimens like streptozocin-based therapy, temozolomide, or capecitabine plus temozolomide can be considered.
      • Temozolomide, often combined with capecitabine, is effective in treating pancreatic NETs, particularly in the context of tumors with DNA mismatch repair defects (e.g., high microsatellite instability or Lynch syndrome).
  • Peptide Receptor Radionuclide Therapy (PRRT)
    • PRRT is an effective second-line treatment for progressive metastatic GEP-NETs.
    • It is recommended for patients with high expression of somatostatin receptors on tumor cells (measured by PET imaging with 68Ga-DOTATATE).
    • PRRT has shown to improve overall survival (OS) and quality of life (QoL) in patients with somatostatin receptor-positive tumors that have progressed on other treatments, such as SSAs.
  • Liver-Directed Therapies
    • Liver-directed therapies, such as trans-arterial chemoembolization (TACE) or radiofrequency ablation (RFA), are useful for patients with liver-dominant metastases.
    • These therapies are intended to control the local tumor burden and symptoms, especially when systemic therapies are not sufficient.
    • TACE and RFA can be considered in select patients as part of a multidisciplinary approach to managing advanced disease.
  • Surveillance and Monitoring
    • Regular monitoring of tumor markers (e.g., chromogranin A) and imaging (e.g., CT or MRI) is critical in assessing treatment response and detecting progression.
    • Functional imaging (e.g., PET scans with somatostatin receptor ligands such as 68Ga-DOTATATE PET/CT) plays a key role in assessing tumor grade, somatostatin receptor expression, and treatment planning.
    • Biomarkers such as chromogranin A and Ki-67 index help guide clinical decision-making, with higher Ki-67 indicating a more aggressive tumor and potential need for more aggressive therapy.
  • Personalized Treatment
    • Personalized treatment should be based on tumor location, somatostatin receptor status, histopathological features, and response to prior therapies.
    • Tumor grade (based on Ki-67 index) and differentiation (well-differentiated vs. poorly differentiated) help guide treatment decisions. High-grade or poorly differentiated tumors may require more aggressive therapies, including chemotherapy or targeted therapies.
  • Patient Selection and Multidisciplinary Care
    • Treatment should be individualized and involve a multidisciplinary team (including endocrinologists, medical oncologists, radiologists, and surgeons) for optimal management.
    • A tailored approach is crucial because of the variability in the clinical course of metastatic GEP-NETs.
    • Decisions about therapy must consider symptom control, tumor progression, side effect profiles, and patient preferences.

The ASCO guideline provides a comprehensive framework for managing metastatic well-differentiated GEP-NETs, emphasizing a personalized, multidisciplinary approach to treatment. With the advent of newer therapies like PRRT, mTOR inhibitors, and targeted agents, patients now have more options for controlling disease progression and managing symptoms, improving both survival rates and quality of life. Regular monitoring and individualized care are essential in achieving optimal outcomes for patients with this rare and complex cancer.

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