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.

Principles of Therapy

  • Depends on tumor size & primary site as well as the general condition of the patient
  • Optimal therapy by a multidisciplinary team should include surgical & medical treatment modalities
  • Increase survival
  • Symptom control
  • Biochemical control
  • Tumor control
  • Improvement in quality of life


Somatostatin Analogs
  • Eg Octreotide, Lanreotide
  • They bind selectively to somatostatin receptors to block the release of bioactive peptides & amines
  • Drug of choice in patients w/ symptomatic functional gastroenterohepatic NETs to decrease hormone production, control symptoms, & minimize risk of carcinoid crises
    • First-line agents for functional NETs & low to intermediate-grade small intestinal carcinoids
    • Recommended therapy for locoregional unresectable & metastatic carcinoid tumors w/ asymptomatic, low to clinically significant tumor burden & carcinoid syndrome
    • Mainstay for the control & 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 & intraoperatively
    • Improve time to progression among patients w/ metastatic, well-differentiated, midgut NETs & should be an alternative for tumor stabilization in patients w/ or w/o carcinoid syndrome
  • Its use should also be considered in all patients w/ elevated 5-HIAA levels even if asymptomatic
    • Because increased 5-HIAA is a predictor of cardiac complications & marker of tumor growth or progression
    • Somatostatin analogs decrease circulating serotonin levels & may stabilize progression of carcinoid heart disease
  • Octreotide long-acting release (LAR) is recommended in patients w/ nonfunctional tumors & an alternative in patients w/ metastatic colorectal NETs, especially in cases where radiotracer uptake on octreoscan indicates somatostatin receptor expression
    • Used for chronic management of symptomatic patients w/ carcinoid syndrome
    • Prevents proliferation in functioning & nonfunctioning small intestinal carcinoids
  • Use w/ caution in patients w/ 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
Mammalian Target of Rapamycin (mTOR) Inhibitors
  • Eg Everolimus, Rapamycin
  • mTOR is a conserved serine/threonine kinase regulating cell growth & metabolism in response to environmental factors & signaling downstream of receptor tyrosine kinases which includes insulin-like growth factor receptor, VEGF receptor, & epidermal growth factor
  • May control hypoglycemia in patients w/ metastatic insulinomas
  • Everolimus is used in patients w/ advanced carcinoid & malignant pancreatic NETs & for advanced NETs of the GI tract, lungs & thymus
  • Everolimus is also used in patients w/ symptoms & unresectable neuroendocrine pancreatic & carcinoid tumors that initially presents w/ clinically significant disease progression
Kinase Inhibitors
  • Eg Sunitinib
  • Studies showed that they may have modest antitumor activity in metastatic gastric & pancreatic NETs
  • Used in patients w/ symptoms & unresectable neuroendocrine pancreatic tumors that initially present w/ clinically significant disease progression
Interferon (IFN) alpha
  • IFNs, IFN-alpha2, & 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 & hormone synthesis in tumor cells, inhibits angiogenesis, & stimulates the immune system
  • Can control symptoms & induce disease stabilization which leads to an objective response
  • Can be utilized for low-proliferating NETs, either as monotherapy or in combination w/ somatostatin analogs
    • Combination regimen can enhance antitumor activity
  • Considered in patients w/ locoregional unresectable disease &/or metastatic carcinoid NETs who are refractory to somatostatin analogs & those w/ progressive disease
  • Effective in controlling symptoms in patients w/ carcinoid syndrome who may be resistant to somatostatin analogs
  • Requires careful monitoring because of common adverse effects such as severe fatigue, anorexia, weight loss & dose-dependent bone marrow toxicity (eg neutropenia, anemia, thrombocytopenia)
  • Cytotoxic chemotherapy is used for tumors w/ high proliferative capacity (Ki67 > 5%)
  • They are effective chemotherapeutic agents w/ 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 w/ clinically advanced aggressive tumors who have no other treatment options
  • May decrease the proliferative capacity of highly proliferative disease & improve the efficacy of other treatment options such as surgery, hepatic arterial infusion, somatostatin analog, Interferon alpha, or radioisotope therapy
  • 5-Fluorouracil, Streptozocin or Doxorubicin
    • Monotherapy w/ 5-Fluorouracil, Streptozocin, or Doxorubicin has only modest response rates in patients w/ metastatic carcinoid tumors
    • 5-Fluorouracil may be used at radiosensitizing doses for thymic carcinoid tumors after surgery, & for metastatic carcinoid tumors
  • Capecitabine
    • May be used at radiosensitizing doses for thymic carcinoid tumors after surgery, & for metastatic carcinoid tumors
  • Cisplatin or Carboplatin
    • May be used after surgery in patients w/ atypical or poorly differentiated thymic carcinoid tumors
  • Dacarbazine
    • Can be an option to Streptozocin-based therapy in carcinoid & pancreatic NETS but toxicity limits its use
    • Dacarbazine-based treatment can also be considered in patients w/ metastatic gastric NETs
  • Temozolomide
    • Commonly used as monotherapy or in combination w/ 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
Combination Therapy
  • Streptozocin/Doxorubicin, Streptozocin/Fluorouracil, Streptozocin/Doxorubicin/Fluorouracil
    • Most effective & commonly used combination therapy in well-differentiated pancreatic NETs
    • Streptozocin/Doxorubicin/Fluorouracil regimen showed a good overall response rate & median survival of 37 months in patients w/ locally advanced or metastatic pancreatic NETs
    • Streptozocin-based treatment may be considered in patients w/ metastatic gastric NETs
    • Studies w/ combination therapy in patients w/ metastatic carcinoid tumors have not shown superiority to monotherapy & are associated w/ significant toxicity
  • Cisplatin/Etoposide or its analog
    • Has good response rate but short response duration & poor prognosis of 2-year survival rate of < 20% in patients w/ poorly differentiated pancreatic NETs
    • Used in patients w/ metastatic small-cell lung cancer
    • Recommended as first-line therapy for metastatic poorly differentiated neuroendocrine carcinomas
    • Considered in patients w/ local-regional extrapulmonary poorly differentiated neuroendocrine carcinomas, especially when there is difficult surgical resection
  • Carboplatin/Etoposide
    • Also used in patients w/ local-regional extrapulmonary poorly differentiated neuroendocrine carcinomas, particularly if surgical resection is difficult
  • Temozolomide/Capecitabine, Temozolomide/Thalidomide, Temozolomide/Everolimus
    • Showed beneficial results
    • Temozolomide-based treatment may be considered in patients w/ metastatic gastric NETs & an acceptable alternative to Streptomycin-based therapy in patients w/ advanced pancreatic NETs
  • Cyclophosphamide/Vincristine/Dacarbazine
    • Responses are usually short & in only few of the patients
    • Preferred in patients w/ negative MIBG scintigraphy & those w/ rapidly progressive tumors
  • Capecitabine/Oxaliplatin
    • Studies have shown good response rates (23-30%) in patients w/ poorly differentiated NETs & well-differentiated disease
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