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neuroendocrine%20tumors
NEUROENDOCRINE TUMORS
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 & primary site as well as the general condition of the patient
  • Optimal therapy by a multidisciplinary team should include surgical & 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 somatostatin receptors to block the release of bioactive peptides & amines
  • Drug of choice in patients with 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 with 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 with metastatic, well-differentiated, midgut NETs & 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 & 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 with metastatic colorectal NETs, especially in cases where radiotracer uptake on octreoscan indicates somatostatin receptor expression
    • Used for chronic management of symptomatic patients with carcinoid syndrome
    • Prevents proliferation in functioning & 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
  • Lantreotide & Octreotide LAR are options for patients with locoregionally advanced &/or metastatic NETs of the gastrointestinal tract
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 with metastatic insulinomas
  • Everolimus is used in patients with advanced carcinoid & malignant pancreatic NETs & for advanced NETs of the gastrointestinal tract, lungs & thymus
  • Everolimus is also used in patients with symptoms & unresectable neuroendocrine pancreatic & carcinoid tumors that initially presents w/ clinically significant disease progression
  • Everolimus is an option for patients with locoregionally advanced &/or metastatic NETs of the gastrointestinal tract
Kinase Inhibitors
  • Eg Sunitinib
  • Studies showed that they may have modest antitumor activity in metastatic gastric & pancreatic NETs
  • Used in patients with symptoms & unresectable neuroendocrine pancreatic tumors that initially present with 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 with somatostatin analogs
    • Combination regimen can enhance antitumor activity
  • Considered in patients with locoregional unresectable disease &/or metastatic carcinoid NETs who are refractory to somatostatin analogs & those with progressive disease
  • IFN-alpha2b can be considered in patients with locoregionally advanced &/or metastatic NETs of the gastrointestinal tract
  • 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 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 & improve the efficacy of other treatment options such as surgery, hepatic arterial infusion, somatostatin analog, Interferon 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, Streptozocin, or Doxorubicin can be considered in patients with locoregionallyadvanced &/or metastatic NETs of the gastrointestinal tract
    • 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
    • May be considered in patients with locoregionally advanced &/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 & pancreatic NETS but toxicity limits its use
    • Dacarbazine-based treatment can also be considered in patients with locoregionally advanced &/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 &/or metastatic NETs of the gastrointestinal tract
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 with 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 with metastatic small-cell lung cancer
    • Considered as primary therapy for patients with intermediate grade/atypical tumors with Ki67 proliferative index & mitotic index in the higher end of the defined spectrum
    • 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 with local-regional extrapulmonary poorly differentiated neuroendocrine carcinomas, particularly if surgical resection is difficult
    • Considered as primary therapy for patients with intermediate grade/atypical tumors with Ki67 proliferative index & mitotic index in the higher end of the defined spectrum
  • 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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