What is NET Cancer? Neuroendocrine tumors are a relatively rare and diverse form of cancer that arise from neuroendocrine cells that are located in multiple sites of the body, including the gastrointestinal tract, lung, and other organs. They are characterized by variable but often indolent (or slow-growing) behavior.

How is it different from other cancers?

Neuroendocrine tumors are unique because of their ability to secrete hormones. Most neuroendocrine tumors are non-functional tumors, which means that they are not associated with symptoms from hormone secretion. However, some neuroendocrine tumors (10-30%) produce hormones. Symptoms that a patient experiences will depend on which hormone is produced.

Neuroendocrine tumors, particularly ones that start in the small intestine or appendix, can produce hormones such as serotonin, which leads to symptoms including flushing or diarrhea. These symptoms are referred to as carcinoid syndrome.

Some pancreatic neuroendocrine tumors can also produce a variety of hormones such as gastrin, insulin, glucagon, vasoactive intestinal peptide, somatostatin, and ACTH.

Why is it hard to diagnose? 

Neuroendocrine tumors can be difficult to diagnose because many of the symptoms are non-specific and can be associated with many non-cancerous conditions. Because neuroendocrine tumors are relatively rare, a diagnosis of neuroendocrine tumor may not be considered.

Neuroendocrine tumors are also hard to diagnose because there is not a widely available screening test, such as mammogram for breast cancer or PSA blood test for prostate cancer.

What symptoms should serve as red flags for patients and primary care physicians? 

Symptoms that should lead to consideration of a diagnosis of neuroendocrine tumor include unexplained flushing or diarrhea or unexplained symptoms that are associated with hormone-producing neuroendocrine tumors.

Many patients may not have hormone-producing NETs–these tumors are often diagnosed during the evaluation of symptoms, including pain, related to the tumor.

What is the standard treatment for NET when it is discovered early? What is the prognosis when it is caught early?

When neuroendocrine tumors are diagnosed at an early stage–before spread has occurred–standard management includes surgery. For neuroendocrine tumors that are completely removed with surgery, the prognosis is good, and the surgery is often curative. Some smaller tumors can be removed with endoscopic techniques.

What is the prognosis when it is caught late?

When disease is more advanced, the treatment approach is individualized to each patient and depends on many factors such as tumor grade and extent of disease, organ where the disease started, symptoms related to disease, and how much growth has occurred.

Prognosis will also vary from person to person and depends on factors related to the grade and biology of disease, extent of disease, and the health of each patient. Many patients with advanced low to intermediate-grade disease can live many years.

One important factor that can affect prognosis is tumor grade. Grade is an assessment of the tumor that takes into account markers of cell proliferation seen by the pathologist on a biopsy. Tumors can be categorized as low, intermediate, or high-grade. Low-grade tumors are slow-growing; high-grade tumors are faster-growing.

What is the standard treatment for NET when it is not discovered early for patients with low-to-moderate grade tumors? 

Treatment options can include systemic therapy, which is treatment that can reach and affect the whole body, or therapy that is directed specifically to where the tumors is located. Systemic therapy can be administered in a variety of ways, such as pills by mouth or injections given intravenously, intramuscularly, or under the skin.

For some patients, surgery to remove all or most sites of disease can be considered.

If surgery is not an option and there is limited disease without any disease-related symptoms, some patients may be candidates for close observation. This is the case since some patients with low-grade disease may have very slow-growing disease that may not grow significantly for some time. Treatment can be started at the time of progression or development of symptoms.

For patients with symptoms related to hormone production, somatostatin analogs can help symptoms by reducing hormone production. The medications octreotide and lanreotide are examples of somatostatin analogs.

Somatostatin analogs also have been shown to slow growth of advanced gastrointestinal and pancreatic neuroendocrine tumors. Somatostatin analogs are commonly used as an initial therapy for patients with advanced neuroendocrine tumors.

For patients with advanced pancreatic neuroendocrine tumors, systemic treatment options also include everolimus, sunitinib, and chemotherapy. Everolimus and sunitinib are two oral targeted therapies approved by the FDA for patients with advanced pancreatic NET; both have been shown to slow growth in pancreatic NET.

Pancreatic NETs can also be sensitive to chemotherapy. Temozolomide and streptozocin are examples of chemotherapy drugs that are active against pancreatic NET.

For patients with predominantly liver metastases, treatment directed at the liver can be considered. Hepatic (liver)-directed therapies include surgery, hepatic artery embolization, or ablation.

We continue to study new therapies for patients with neuroendocrine tumors. Clinical trials investigating new therapies may be an option for some patients with advanced disease.

For patients with advanced high-grade, poorly differentiated neuroendocrine carcinomas, platinum-based chemotherapy is often used.

As the disease progresses, what kinds of things do patients experience, physically and mentally?

For some patients, there are no symptoms even when CT scans or MRIs show tumor growth.

For some patients, however, there may be development of symptoms such as fatigue, loss of appetite, weight loss, or pain. Some patients may experience an increase in hormone-related symptoms if there is an increase in hormone production that correlates with disease progression.

Disease progression can also be emotionally challenging. Depression might occur. Patients benefit from the support of family, friends and their health care team. The health care team can consist of many individuals, including oncologists, nurses, social workers, psychiatrists and therapists, and nutritionists.

Can NETs lead to heart issues?

Some patients with carcinoid syndrome can develop carcinoid heart disease. The heart valves, primarily those on the right side of the heart, can become thickened and work less well due to exposure to hormones such as serotonin. Heart failure can develop when the heart valves do not work well, and patients can experience leg swelling, shortness of breath, fatigue.

What is the greatest challenge we face in dealing with this disease from a patient standpoint?

From a patient standpoint, it can be challenging to find a team of health care providers with knowledge and expertise in managing NET. A multidisciplinary approach is critical to the care of patients NET since NETs are a diverse group of tumors, and our approach needs to be individualized.

Depending on the situation, there may be a role for surgery, interventional radiology or nuclear medicine techniques, or medical therapy. When to start and how to sequence therapy may also need to be decided. These are complicated issues, and it is helpful to have multiple people thinking together about each patient.

What is the greatest challenge we face in dealing with this disease from a medical standpoint?

From a medical standpoint, education and raising awareness about NET remains extremely important. With early diagnosis and intervention, we can hopefully cure more patients and improve outcomes. It is also critical that we expand our treatment options for patients with advanced disease. Compared to many years ago, patients with NET are now living much longer. However, we still need better treatments to control disease and help with symptoms related to disease so that patients can live long, productive lives with good quality of life.

How have things changed with NETs over the last year? 

In September 2015, the results of three large randomized placebo-controlled trials related to neuroendocrine tumors were announced.  All three had positive results that are practice-changing and will expand possible treatment options for patients with NET.

1) The TELESTAR study was a randomized study of telotristat etiprate, an oral agent that blocks the activity of tryptophan hydroxylase– the rate limiting step in the synthesis of serotonin.  Telotristat was associated with reduction in bowel movement frequency in patients with uncontrolled diarrhea despite standard doses of octreotide.

24-hour urine 5-HIAA levels were lower in patients receiving telotristat–indicating effective inhibition of tryptophan hydroxylase and reduction in serotonin production due to this agent.

2) The RADIANT-4 study demonstrated improved progression-free survival with everolimus in patients with advanced non-functional NET of lung and GI origin.

3) The NETTER-1 study demonstrated improved progression-free survival with the radiolabeled somatostatin analog 177-Lu-Dotatate in patients with progressive mid-gut neuroendocrine tumors.

The results of the RADIANT-4 study and NETTER-1 study are particularly exciting and promising because historically, patients with advanced non-pancreatic neuroendocrine tumors have had limited systemic treatment options.  Both of these studies show that growth can, in fact, be slowed and will expand possible treatment options for patients with NET.

What is the most promising thing you see on the near horizon?

Recent translational research has also provided new insight into the biology of neuroendocrine tumors. For example, a recent gene sequencing study suggests that dysregulation of the cell cycle may be important in the etiology of small bowel NET.

As we understand more about the factors that drive the development and growth of neuroendocrine tumors, we hopefully will be able to find new targets for therapy.

Additional research also needs to be done to better understand why some people do and do not respond to certain therapies. Results from this investigation may help us to select the most appropriate therapy for each individual patient.

• Dr. Jennifer Chan, head of clinical trials for the Program in Neuroendocrine and Carcinoid tumors wrote the answers above. the questions were posed by Harry Proudfoot, Chairman of Walking with Jane.
• This information is available in pamphlet form from Walking with Jane. Contact us at walkingwithjane@gmail.com if you are interested.