Neuroendocrine Tumor Treatment: Current and Emerging Therapies for NETs

Types of Neuroendocrine Tumors
Neuroendocrine tumors (NETs) originate from neuroendocrine cells found throughout the body. While NETs can develop in many organs, the most common primary sites include the lungs, pancreas, small intestine, appendix, and rectum. NETs are divided into two main categories based on the primary tumor site and characteristics:

Gastrointestinal NETs
Gastrointestinal NETs develop in the gastrointestinal tract and pancreas. These account for the majority of NET cases diagnosed each year.NETs of the small intestine, also known as carcinoid tumors, are the most prevalent type of gastrointestinal NET. Other common sites include the rectum, appendix, and pancreas. Symptoms often depend on the specific tumor location and may include abdominal pain, gastrointestinal bleeding, jaundice, and changes in bowel habits.

Lung NETs
Pulmonary (lung) NETs arise from Neuroendocrine Tumor Treatment cells in the lungs. There are two main types - typical carcinoid tumors and atypical carcinoid tumors. Typical carcinoids tend to grow and spread more slowly while atypical carcinoids have a worse prognosis. Symptoms can include cough, chest pain, and hemoptysis (coughing up blood). Lung NETs may secrete hormones causing conditions like Cushing's syndrome.

Staging and Grading NETs
Staging examines spread beyond the primary tumor site using imaging tests like CT scans. The TNM system evaluates tumor size (T), nearby lymph node involvement (N), and metastases (M). Higher TNM stages indicate more advanced disease.

Grading relies on histologic examination to evaluate how abnormal the tumor cells appear under a microscope. Grading is reported using a scale of G1, G2, or G3. G1 and G2 NETs are considered low grade while G3 are high grade, indicating faster growth and worse prognosis.

Surgery for Localized NETs
Surgery offers the best chance of cure for NETs contained to the primary site without metastases. The type of surgery depends on tumor location but may involve resection of affected organs, portions of the gastrointestinal tract, or lung lobes/segments. Lymph node dissection helps determine spread for staging purposes. For gastrointestinal NETs, minimizing postoperative complications from surgery is important given many patients require lifelong management.

Systemic Therapies for Advanced NETs
For NETs that have spread beyond the original site, systemic therapies aim to slow tumor growth and alleviate symptoms from excessive hormone production. Several treatment options are used based on tumor characteristics, prior therapies, and individual factors.

Somatostatin Analogs
Somatostatin analogs (SSAs) like octreotide and lanreotide bind to somatostatin receptors on NET cell surfaces. This inhibits secretion of hormones and other substances from the tumors, relieving symptoms in around 60-70% of patients. SSAs may also modestly reduce tumor growth. Common side effects include diarrhea, nausea, and injection site reactions.

Targeted Therapy
The targeted drug sunitinib malate (Sutent) inhibits multiple tyrosine kinase receptors important for angiogenesis and tumor growth. For pancreatic NETs, sunitinib was shown to delay tumor progression compared to placebo in a pivotal clinical trial. Additional targeted therapies under investigation include everolimus (Afinitor) and combinations of targeted agents.

Chemotherapy
For high grade, rapidly progressing lung and gastrointestinal NETs, platinum-based chemotherapy may provide response rates around 35-50%. The alkylating agent streptozocin is also used for pancreatic NETs. However, chemotherapy carries more substantial side effects than other systemic options.

Radionuclide Therapy
Radionuclide therapy delivers radioactive particles that selectively irradiate and damage NET cells. Two common agents are lutetium-177 (177Lu) dotatate (Lutathera) and yttrium-90 (90Y) dotatate (Dotatate). Both bind to somatostatin receptors for targeted delivery. In advanced midgut NETs, 177Lu dotatate was shown to significantly prolong progression-free survival compared to high-dose octreotide alone. Radionuclide therapy is generally well-tolerated with few severe side effects reported.

Emerging Strategies in NET Treatment
Research is evaluating new agents and combinations that build upon existing systemic therapies for NETs. Areas of ongoing investigation include:

- Immunotherapy drugs like pembrolizumab and nivolumab that enable the body's own immune response against tumor cells. Early results indicate potential for certain lung and gastrointestinal NET subtypes.

- Multi-kinase inhibitors beyond sunitinib that target additional deregulated pathways in NET growth. Cabozantinib, lenvatinib, and vandetanib are examples under study.

- Peptide receptor radionuclide therapy (PRRT) using beta-emitting radiolabeled somatostatin analogs as mentioned previously, potentially as adjuvant treatment after resection of metastatic disease.

- Combination strategies pairing drugs that target different cancer cell signaling networks, such as sunitinib plus everolimus or chemotherapy in select patients. Synergistic effects may outweigh individual agent toxicity.

- Alternative hormone-suppressing agents beyond somatostatin analogs when resistance develops, including serotonin and dopamine receptor antagonists.

- Novel targeted drugs based on genomic profiling to elucidate “driver” mutations fueling individual patient's NET. Molecularly-guided therapy tailored using precision medicine approaches.

Emerging data from clinical trials will hopefully advance treatment into less toxic yet more effective options capable of controlling advanced NETs over the long term for many patients. Continued research remains crucial for improving outcomes.

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