Malignant neuroendocrine tumors (NETs) represent a rare entity with a rising incidence comprising 3% of all tumors diagnosed in western world countries.
NETs arise from the neuroendocrine cells which are widespread in the body and may differ along the following attributes:
- site of origin
- stage, grade
- Ki67 labelling index (Ki67 LI, an indication of aggressiveness)
- growth pattern (locally versus metastatic) and
- response to treatment.
The clinical symptoms of NETs depend largely on whether these tumors produce and release in the blood biologically active substances (called neuroamines and peptides) or not. Based on this characteristic, they are called “functional neuroendocrine tumors” and “non-functional neuroendocrine tumors”.
- Functional neuroendocrine tumors account for approximately 10% of the cases. They produce and release substances which may induce clinically detectable hormonal syndromes at an early stage of the disease. The most characteristic example of functional syndromes is the carcinoid syndrome in which the substance serotonin is released in the blood. This particular syndrome consists of several symptoms such as perspiration, hot flushes, increased heart rate, redness in the face etc.
- Non-functional neuroendocrine tumors constitute the vast majority of cases. These tumors do not produce and release substances, and therefore are undetectable in their early stage. At later stages they become symptomatic due to local enlargement and metastatic invasion (mainly of the liver).
Regarding the site of origin in the body, approximately 70% of NETs develop in the gastrointestinal tract, 25% in the lung and a minority in other sites such as skin, kidney, thymus, ovaries and larynx.
NETs share many common biological and clinical features regardless of the site of origin. However, lung, gastrointestinal and pancreatic NETs are considered distinct clinical entities.
NETs comprise a spectrum of malignancies, ranging from well differentiated (i.e. slow growing), to poorly differentiated (i.e. with far more aggressive tumors).
The most recently approved NET classification system divides NETs into three groups of malignancies, according to their differentiation grade and Ki67 labelling index (LI) estimation:
- Grade 1 NETs (well differentiated, Ki67<2%),
- Grade 2 NETs (moderately differentiated, Ki67:3-20%), and
- Grade 3 neuroendocrine carcinomas (NECs) (poorly differentiated, Ki67>20%).
The diagnosis of neuroendocrine tumors is made via biopsy.
The staging of the disease (i.e. the extent of the tumor) is done through CT (Computed Tomography) and MRI (Magnetic Resonance Imaging) scans, as well as with Octreoscan (a test based on nuclear medicine).
The response to treatment and the follow up is facilitated by monitoring of tumor markers such as Chromogranin A and Neuron specific enolase.
There are several theories regarding the pathogenesis of neuroendocrine tumors. One theory is based on Somatostatin.
Somatostatin is a hormone secreted normally by a variety of normal cells of the gastrointestinal tract, and has multiple biological effects on bowel motility and absorption. Somatostatin has mainly an antisecretory effect as it inhibits the release of hormones such as glucagon, insulin and gastrin etc.
Somatostatin exerts its action through specific cellular membrane receptors. These receptors are expressed in 90% of NET tumors (mainly well differentiated), while they are not commonly expressed in highly aggressive (undifferentiated) tumors.
Other, non-somatostatin related mechanisms involved in the pathogenesis of NETs include the over-activation of factors that promote blood supply to feed the tumors. This activity is mediated in the cell through a specific pathway called the “mTOR pathway”.
Treatment of NETs is broadly divided into 4 major groups
- Surgical treatment
- Local therapy (such as chemoembolization)
- Medical treatment
- Nuclear treatment
The primary goal of surgical treatment for NETs is complete surgical excision, particularly for localized disease that ranges from well differentiated to moderately differentiated, as this offers the best chance for cure.
In patients with more histologically aggressive or extensive disease, surgery is not the ideal approach. Surgery may still have a role after neoadjuvant (preoperative) medical treatment that decreases tumor load.
Additionally, surgery has an important role in removing lesions that may compress surrounding organs. Also, it can reduce tumor load with procedures such as liver metastasectomy (surgical excision of metastasis) and intraoperative radiofrequency ablation (metastasis destroyed by radiofrequency).
Complementary, well established methods, to decrease tumor load without surgery are applicable to disease localized in one organ. Such methods are transdermal radiofrequency ablation, chemoembolization and embolization.
Medical treatment may be used in addition to surgery, or as a primary therapy when surgery is not feasible. Its main goals are to decrease the size of the tumor and control the disease symptoms.
Medical treatment is composed of
- Somatostatin analogues
- chemotherapy and
- molecular targeted agents such as Everolimus and Sunitinib
Somatostatin analogues (SA)
Somatostatin analogues (such as the long-acting depot injections octreotide LAR and lanreotide Autogel) can be used for treating the disease and its symptoms.
These new compounds can help stabilize the disease, palliate symptoms and control tumor markers in NET patients.
Altogether, Somatostatin analogues have been shown to be well tolerated and safe in all available forms. Patients may experience infrequent side effects such as bile stones due to the inhibitory effects of octreotide on gallbladder contractility.
Interferon may be used on its own, or combined with somatostatin analogues, with variable response rates. Although improvements in the tumor markers and symptoms of NET patients have been reported, significant tumor shrinkage is rarely seen.
Side-effects of interferon alpha are significant and include
- flu-like syndrome
- chronic fatigue
- weight loss
- leukopenia and
- generation of autoantibodies in 15% of patients.
α-Interferon is not commonly used.
Chemotherapy has variable results in NET patients mainly due to the large variability of biological features among the disease subgroups. The most commonly applied chemotherapeutics for NETs include 5-fluorouracil, doxorubicin, streptozotocin, etoposide, cisplatin and the newer agents docetaxel and temozolomide.
Overall, patients with advanced NETs do not benefit as much from single agent chemotherapy, while combination chemotherapy exhibits a significant response rate.
The main predictive factors for chemotherapy are
- Grade of differentiation and
- Ki67 LI (Labelling Index)
Chemotherapy in well differentiated, functional, advanced NETS with Ki67 <2% has limited efficacy.
The response rate improves for tumors with higher Ki67 LI, but again differs according to the grade of differentiation.
Moderately differentiated NETs with Ki67 <55% will respond better to temozolomide.
Anaplastic (i.e. poorly differentiated) NETs, independently of the primary site location, are responsive to combination chemotherapy including etoposide and cisplatin. Conversely, well differentiated tumors were unresponsive to this combination. Side-effects of this regimen can be severe and include vomiting, leucopenia, thrombocytopenia, anemia, alopecia, and neuropathy.
Newer therapies: Molecular targeted therapies
The more thorough understanding of molecular biology has led to the clinical investigation of small molecules targeting relevant pathways. These molecules are everolimus and sunitinib.
Everolimus is an oral medication, which is an inhibitor of the so-called “mTOR pathway”. Based on the observations of one phase II and two phase III clinical trials, it was granted approval for its use in progressive well differentiated pancreatic NETs.
The most common side-effect reported was mucositis. Other toxicities observed included: anemia, thrombocytopenia, mucous membrane ulcer (mouth), diarrhea, edema, fatigue, hypoglycemia, nausea, pain, and rash.
Sunitinib is an oral medication; it is scientifically described as a multi-tyrosine kinase inhibitor with anti-angiogenic and antiproliferative activity. Based on two recent clinical trials, it was granted authorization for the treatment of advanced well-differentiated pancreatic NETs progressing after a first line therapy.
The most common side-effects are anorexia, oral changes, hand-foot syndrome and other skin toxicity, thyroid dysfunction, myelotoxicity, hypertension, cardiotoxicity and thromboembolic events.
Nuclear treatment is based on nuclear medicine and represents a recent treatment option for advanced NETs.
More specifically, as the majority of these tumors express a variety of somatostatin receptors, nuclear treatment can be effective radiating these receptors with 90Yttrium-DOTATOC or 177Lutetium-DOTATE.
Agents such as somatostatin analogues (SAs), interferon A and chemotherapy have extensively been used for treatment of neuroendocrine tumors. Recently, based on the findings of phase III studies, molecular targeted agents such as everolimus and sunitinib are new treatment options for neuroendocrine tumors. Finally, nuclear medicine is another recent development.
While the sequential use of some of the older agents may prolong the survival of NET patients, it is expected that the inclusion of all these novel therapies will prolong it even further.
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