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neuroendocrine%20tumors
NEUROENDOCRINE TUMORS
Treatment Guideline Chart
Neuroendocrine tumors are rare, small, slow-growing epithelial neoplasms with predominant neuroendocrine differentiation found in most organs of the body.
They arise from cells throughout the diffuse endocrine system.
Carcinoid tumors and pancreatic neuroendocrine tumors are the most common.
Carcinoid tumors arise from the lungs & bronchi, stomach, small intestine, appendix, rectum or thymus.
Majority of the neuroendocrine tumors are sporadic but some tumors are caused by inherited genetic syndromes such as multiple endocrine neoplasia, Von-Hippel Lindau disease, tuberous sclerosis complex and neurofibromatosis.
They have the ability to store and secrete various peptides and neuroamines.

Neuroendocrine%20tumors Treatment

Principles of Therapy

  • Depends on tumor size and primary site as well as the general condition of the patient
  • Therapeutic management should be based on proliferative activity, SSR expression, tumor growth rate and extent of disease
  • Optimal therapy by a multidisciplinary team should include surgical and medical treatment modalities
Goals
  • Increase survival
  • Symptom control
  • Biochemical control
  • Tumor control
  • Improvement in quality of life

Pharmacotherapy

Somatostatin Analogs
  • Eg Octreotide, Lanreotide
  • They bind selectively to SSRs to block the release of bioactive peptides and amines
  • Drug of choice in patients with symptomatic functional gastroenterohepatic NETs to decrease hormone production, control symptoms, and minimize risk of carcinoid crises
    • 1st-line agents for functional NETs and low- to intermediate-grade small intestinal carcinoids
    • Recommended therapy for locoregional unresectable and metastatic carcinoid tumors with asymptomatic, low to clinically significant tumor burden and carcinoid syndrome
    • Mainstay for the control and relief of symptoms in carcinoid syndrome by decreasing or normalizing 5-HIAA levels
    • Prevent carcinoid crisis during procedures such as surgery or hepatic arterial infusions; thus, Octreotide is given peri-operatively and intraoperatively
    • Improve time to progression among patients with metastatic, well-differentiated, midgut NETs and should be an alternative for tumor stabilization in patients with or without carcinoid syndrome
  • Its use should also be considered in all patients with elevated 5-HIAA levels even if asymptomatic
    • Because increased 5-HIAA is a predictor of cardiac complications and marker of tumor growth or progression
    • Somatostatin analogs decrease circulating serotonin levels and may stabilize progression of carcinoid heart disease
  • Octreotide long-acting release (LAR) is recommended in patients with nonfunctional tumors and an alternative in patients with metastatic colorectal NETs, especially in cases where radiotracer uptake on octreoscan indicates SSR expression
    • Used for chronic management of symptomatic patients with carcinoid syndrome
    • Prevents proliferation in functioning and nonfunctioning small intestinal carcinoids
  • Use with caution in patients with insulinoma because they may worsen hypoglycemia in some cases
  • In long-term therapy of some NETs (eg glucagonomas, somatostatinomas), they may cause symptomatic breakthrough, in which increased dose, more frequent administration, shortened interval, or temporarily discontinuation is needed
  • For Lanreotide and Octreotide LAR:
    • Options for patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract
    • May also used in patients with distant metastases from NETs of bronchus, lung or thymus
    • May be considered in patients with locoregionally advanced and/or metastatic neuroendocrine pancreatic tumors
Mammalian Target of Rapamycin (mTOR) Inhibitors
  • Eg Everolimus, Rapamycin
  • mTOR is a conserved serine/threonine kinase regulating cell growth and metabolism in response to environmental factors and signaling downstream of receptor tyrosine kinases which includes insulin-like growth factor receptor, VEGF receptor, and epidermal growth factor
  • May control hypoglycemia in patients with metastatic insulinomas
  • Everolimus is used in patients with advanced carcinoid and malignant pancreatic NETs and for advanced NETs of the gastrointestinal tract, bronchus, lungs and thymus
  • Everolimus is also used in patients with symptoms and unresectable neuroendocrine pancreatic and carcinoid tumors that initially presents with clinically significant disease progression
  • Everolimus is an option for patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract
Kinase Inhibitors
  • Eg Sunitinib
  • Studies showed that they may have modest antitumor activity in metastatic gastric and pancreatic NETs
  • Used in patients with symptoms and unresectable neuroendocrine pancreatic tumors that initially present with clinically significant disease progression
  • Sunitinib may be used in patients with locoregionally advanced and/or metastatic neuroendocrine pancreatic tumors
Interferon (IFN) alpha
  • IFNs, IFN-alpha2, and IFN-alpha2b bind to specific IFN receptors on neuroendocrine cells activating signal transduction cascade which leads to transcription of multiple tumor suppressor genes
    • Inhibits protein and hormone synthesis in tumor cells, inhibits angiogenesis, and stimulates the immune system
  • Can control symptoms and induce disease stabilization which leads to an objective response
  • Can be utilized for low-proliferating NETs, either as monotherapy or in combination with somatostatin analogs
    • Combination regimen can enhance antitumor activity
  • Considered in patients with locoregional unresectable disease and/or metastatic carcinoid NETs who are refractory to somatostatin analogs and those with progressive disease
  • IFN-alpha is a treatment option for patients with progressive metastatic lung NETs especially if with carcinoid syndrome
  • IFN-alpha2b can be considered in patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract
  • Effective in controlling symptoms in patients with carcinoid syndrome who may be resistant to somatostatin analogs
  • Requires careful monitoring because of common adverse effects such as severe fatigue, anorexia, weight loss and dose-dependent bone marrow toxicity (eg neutropenia, anemia, thrombocytopenia)

Hypoxia-inducible Factor 2 Alpha (HIF-2α) Inhibitor

  • Eg Belzutifan
  • Considered for patients with progressive pancreatic NETs with germline VHL alteration
  • Binds to HIF-2α, blocks the HIF-2α-HIF-1β interaction in conditions of hypoxia or tumor suppressor protein impairment, leading to reduced transcription and expression of HIF-2α target genes

Immunotherapy

  • Nivolumab/Ipilimumab may be used in patients with metastatic poorly differentiated neuroendocrine carcinoma if with progression
  • Pembrolizumab may be considered in patients with locoregional unresectable or metastatic poorly differentiated neuroendocrine carcinoma if with mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) or advanced mutational burden high (TMB-H) that has progressed and no satisfactory alternative treatment is available

Chemotherapy

  • Cytotoxic chemotherapy is used for tumors with high proliferative capacity (Ki67 >5%)
  • They are effective chemotherapeutic agents with sufficient antitumor activity that can be used as monotherapy or as combination regimen
  • Should only be used when it will most likely have an effect so as to minimize or avoid its toxic side effects
    • Consider only in patients with clinically advanced aggressive tumors who have no other treatment options
  • May decrease the proliferative capacity of highly proliferative disease and improve the efficacy of other treatment options such as surgery, hepatic arterial infusion, somatostatin analog, IFN-alpha, or radioisotope therapy

Monotherapy

  • 5-Fluorouracil, Streptozocin or Doxorubicin
    • Monotherapy with 5-Fluorouracil, Streptozocin, or Doxorubicin has only modest response rates in patients with metastatic carcinoid tumors
    • Monotherapy with 5-Fluorouracil or Streptozocin can be considered in patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract
    • 5-Fluorouracil may be used at radiosensitizing doses for thymic carcinoid tumors after surgery, and for metastatic carcinoid tumors
  • Capecitabine
    • May be used at radiosensitizing doses for thymic carcinoid tumors after surgery, and for metastatic carcinoid tumors
    • May be considered in patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract
  • Cisplatin or Carboplatin
    • May be used after surgery in patients with atypical or poorly differentiated thymic carcinoid tumors
  • Dacarbazine
    • Can be an option to Streptozocin-based therapy in carcinoid and pancreatic NETS but toxicity limits its use
    • Dacarbazine-based treatment can also be considered in patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract and patients with lung NETs
  • Oxaliplatin
    • May be considered in patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract
  • Temozolomide
    • Commonly used as monotherapy or in combination with Capecitabine, Temozolomide is a promising agent for pancreatic NETs
    • Either regimen is acceptable since there are no studies that compare the efficacy of Temozolomide monotherapy to combination therapy
    • May also be considered as a treatment option for metastatic or unresectable thymic/lung/bronchial NETs
    • Can be considered in patients with locoregionally advanced and/or metastatic NETs of the gastrointestinal tract
Combination Therapy
  • Capecitabine/Oxaliplatin (CAPEOX)
    • Studies have shown good response rates (23-30%) in patients with poorly differentiated NETs and well-differentiated disease
    • May be an option in patients with locoregionally advanced and/or metastatic neuroendocrine pancreatic tumors
  • Carboplatin/Etoposide
    • Also used in patients with local-regional extrapulmonary poorly differentiated neuroendocrine carcinomas, particularly if surgical resection is difficult
    • Considered as primary therapy for patients with bronchopulmonary or thymus NETs with intermediate grade/atypical tumors with Ki67 proliferative index and mitotic index in the higher end of the defined spectrum
    • May be considered in distant metastases from NETs of bronchus, lung or thymus
  • Carboplatin/Irinotecan
    • May be used in patients with locoregional and metastatic extrapulmonary poorly differentiated neuroendocrine carcinomas, particularly if surgical resection is difficult
  • Cisplatin/Etoposide or its analog
    • Has good response rate but short response duration and poor prognosis of 2-year survival rate of <20% in patients with poorly differentiated pancreatic NETs
    • Considered as primary therapy for patients with bronchopulmonary or thymus NETs with intermediate grade/atypical tumors with Ki67 proliferative index and mitotic index in the higher end of the defined spectrum
    • Recommended as 1st-line therapy for metastatic poorly differentiated neuroendocrine carcinomas
    • Considered in patients with local-regional extrapulmonary poorly differentiated neuroendocrine carcinomas, especially when there is difficult surgical resection
  • Cisplatin/Irinotecan
    • May be used in patients with locoregional and metastatic extrapulmonary poorly differentiated neuroendocrine carcinomas, particularly if surgical resection is difficult
  • Cyclophosphamide/Vincristine/Dacarbazine
    • Responses are usually short and in only few of the patients
    • Preferred in patients with negative MIBG scintigraphy and those with rapidly progressive tumors
  • Leucovorin/Fluorouracil/Oxaliplatin (FOLFOX)
    • May be an option in patients with locoregionally advanced and/or metastatic neuroendocrine pancreatic tumors
    • Also used in patients with locoregional and metastatic extrapulmonary poorly differentiated neuroendocrine carcinomas, particularly if surgical resection is difficult
  • Leucovorin/Fluorouracil/Irinotecan (FOLFIRI)
    • May be used in patients with resectable, locoregional unresectable and metastatic extrapulmonary poorly differentiated neuroendocrine carcinomas
  • Leucovorin/Fluorouracil/Irinotecan/Oxaliplatin (FOLFIRINOX)
    • May be used in patients with resectable, locoregional unresectable and metastatic extrapulmonary poorly differentiated neuroendocrine carcinomas
  • Streptozocin/Doxorubicin, Streptozocin/Fluorouracil, Streptozocin/Doxorubicin/Fluorouracil
    • Most effective and commonly used combination therapy in well-differentiated pancreatic NETs
    • May be an option in patients with locoregionally advanced and/or metastatic neuroendocrine pancreatic tumors
    • Streptozocin/Doxorubicin/Fluorouracil regimen showed a good overall response rate and median survival of 37 months in patients with locally advanced or metastatic pancreatic NETs
    • Streptozocin-based treatment may be considered in patients with metastatic gastric NETs
    • Studies with combination therapy in patients with metastatic carcinoid tumors have not shown superiority to monotherapy and are associated with significant toxicity
    • May be considered in distant metastases from NETs of bronchus, lung or thymus
  • Temozolomide/Capecitabine, Temozolomide/Thalidomide, Temozolomide/Everolimus
    • Showed beneficial results
    • Temozolomide-based treatment may be considered in patients with metastatic gastric NETs and an acceptable alternative to Streptomycin-based therapy in patients with advanced pancreatic NETs
    • For Temozolomide/Capecitabine
      • May be considered in patients with metastatic large- or small-cell lung cancer
      • May also be considered in patients with distant metastases from NETs of bronchus, lung or thymus
      • May be used in patients with locoregionally advanced and/or metastatic neuroendocrine pancreatic tumors
      • May be used in patients with locoregional and metastatic extrapulmonary poorly differentiated neuroendocrine carcinomas, particularly if surgical resection is difficult
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