Each year in the US, approximately 8000 patients are diagnosed with neuroendocrine tumors.
These cancers are distinguished by metabolic processes that enable them to metabolize certain amines into hormonal peptides.
The term applied is APUD and stands for amine precursor uptake and decarboxylation. From this, the term APUDoma has been coined.
These cancers can arise in the gastrointestinal tract including stomach, small intestine, appendix, colon, rectum, and pancreas but also in the lung, ovary or skin.
Depending upon the site of origin and the particular chemistry, neuroendocrine tumors have different features.
The most common form of neuroendocrine tumor arises in the small intestine and is known as a gastro-intestinal neuroendocrine tumor or GI-NET. These relatively low-grade tumors arise in the ileum or appendix and were known historically as carcinoid tumors.
Related tumors arising in the pancreas, known as pancreatic neuroendocrine tumors or P-NET can behave Like GI-NETs. Other low-grade NET tumors can be found in the bronchus of the lung or in other parts of the gastrointestinal tract.
Between 20% and 50% of patients diagnosed with neuroendocrine tumor of the gastrointestinal tract have metastatic disease at presentation.
The classic carcinoid syndrome associated with excess serotonin production leads to flushing, diarrhea, wheezing and in some cases hypotension, even loss of consciousness. Patients can experience these carcinoid flares intermittently, but they almost always reflect liver involvement, as it is only after growth in the liver that the amount of serotonin becomes clinically significant and symptomatic.
The term neuroendocrine cancer can apply to other forms of tumors, including the somewhat more aggressive neuroendocrine tumors known as large cell. These large cell tumors can arise in the gastrointestinal tract, lung, or other sites, are more likely to metastasize and are not as responsive to therapy.
The most aggressive form of neuroendocrine tumor is called small cell, or oat cell, carcinoma of the lung.
While it shares some biochemical features with the lower grade types of cancers, it is more aggressive, metastasizes rapidly and must be treated immediately. Small cell lung cancers are commonly associated with cigarette smoking and are generally highly symptomatic with a tendency to spread to the brain.
Another form of neuroendocrine tumor arises in the skin and is known as a Merkel cell tumor. These can often be treated with local surgery and/or radiation but can spread requiring chemotherapy. Recently Merkel cell tumors have been found responsive to immune checkpoint inhibitors.
A rare form of neuroendocrine tumor is known as a pheochromocytoma.
This tumor arising in the adrenal medulla, is associated with the over-production of epinephrine and norepinephrine that can lead to hypertension, sweating, tachycardia, weight loss and irritability. It can present as a benign tumor that can be cured surgically or in rare cases as a malignant tumor.
Some neuroendocrine tumors arise as part of familial syndromes known as multiple endocrine neoplasia syndrome or MEN associated with medullary thyroid carcinoma and pheochromocytoma. These are familialy transmitted and are often picked up by family history as well as clinical presentation.
Depending upon the site, stage, and biology of neuroendocrine tumors, a number of different treatments can be considered.
The low grade GI-NETs and the pancreatic NETs are treated with medications known as somatostatin receptor antagonists and include octreotide and lanreotide. These drugs reduce symptoms, can slow progression and provide a survival advantage. They are administered as monthly subcutaneous injections and are generally well tolerated. Objective response rates, however, are usually low.
Patients with GI-NETs of the small intestine, large bowel and pancreas can be treated with surgery. Centers around the world have established expertise in the conduct of tumor, lymph node and partial liver resections combined with somatostatin antagonists, chemotherapy, and most recently peptide receptor radionuclide therapy, or PRRT.
PRRT, pioneered in the past 1-2 decade, uses the fact that NETs over express somatostatin receptors to target radioactive isotopes like yttrium, indium or recently lutetium to selectively deliver radiation directly to the site of disease. This approach has shown very good outcomes and with the publication of a large series using lutetium, the US FDA has approved lutetium-177 PRRT therapy in the US.
Patients presenting with evidence of a neuroendocrine tumor require a biopsy.
The biopsy is studied with special stains for synaptophysin, chromogranin and neuron-specific enolase.
Blood tests, including serotonin, chromogranin, pancreastatin, neurokinin, and 5-HIAA can also be followed. Some patients express high levels of CEA or CA-19.9.
One of the most common tests for this type of cancer is a urinary collection to measure the 24-hour output of 5-HIAA, a principal byproduct of serotonin metabolism.
Further workup includes CT scan, MRI and a type of scan known as an octreotide scan that uses a small amount of radioactivity to track the sites of disease in the body and lights up on nuclear medicine scan not unlike a bone or a PET scan.
Once staging is complete, the patient's management may be systemic, or it may rely upon surgery to reduce the volume of disease.
There has been a growing movement to use surgery early in this disease, even if this disease has spread, as reducing the total tumor volume can provide survival advantage.
All patients must be carefully evaluated due to the known side effects of the neuroendocrine tumors that include liver function abnormalities, changes in glucose and lipid metabolism, and a characteristic type of valvular heart disease confirmed by echocardiogram.
Once staging is complete a consultation with a neuroendocrine center is warranted.
Depending upon the type of neuroendocrine tumor, treatments differ.
Patients who present with the most aggressive form, small cell cancer of the lung, receive a combination of platinum-based chemotherapy and radiation.
Gastrointestinal and pancreatic neuroendocrine tumors are treated with a combination of octreotide or lanreotide, surgery and may require PRRT or chemotherapy.
Among the most widely used chemotherapy combinations today is capecitabine plus temozolomide, known as CAPTEM. Other platinum or alkylator-based regimens can also be considered.
Patients can become niacin deficient, as nicotinamide is over-utilized and can lead to deficiency in some patients. Patients should be supplemented with oral niacin.
Systemic therapy for neuroendocrine tumors has advanced using targeted agents.
It is now well known that sunitinib and everolimus have activity against these tumors.
Sunitinib, a VEGF inhibitor, influences tumor biology by changing vascular endothelial growth factor. Everolimus, an inhibitor of metabolism at the level of mTOR, has also been shown to provide favorable outcome in patients with advanced disease.
Related agents such as pazopanib can also be considered. Beyond these agents, new areas of investigation suggest that other metabolic signals and the MYC oncogene may be targets in the future.
Some patients respond to classic chemotherapies like platinum-based treatment, the taxanes and antimetabolites.
In collaboration with co-investigators, we examined a large number of GI neuroendocrine tumors to explore how chemotherapy, signal transduction inhibitors and vascular endothelial inhibitors contribute to treatment.
Results were reported at the European Neuroendocrine Tumor Society (ENETS) in Barcelona in 2013.
Neuroendocrine tumors constitute a somewhat rare class of cancers that are increasing in incidence.
Treatment has improved as specialists have expanded the use of cytoreductive surgery combined with systemic therapies to provide durable remissions.
Many patients with the GI-NETs and PNETs can live long and productive lives with appropriate management.
Symptom control with somatostatin receptor inhibitors like octreotide and lanreotide, combined with other modalities have made life with neuroendocrine tumors demonstrably better and longer for many patients.
"Within a week, my local oncologist had the report from Rational Therapeutics (now Nagourney Cancer Institute), which identified two chemo agents, that we had not yet tried, as the most promising – and more effective than the two agents of the standard protocol that I had completed in February 2014."
— Valerie Leighty