What are gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and who do they affect?
GEP-NETs stands for gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). This is a type of rare cancer that is increasing in incidence and prevalence – more on this later.
Neuroendocrine cells are located throughout the whole body. They receive input from nerve cells and, as a consequence, release message molecules (hormones) into the blood. Neuroendocrine tumors are neoplasms of the neuroendocrine cells, located in the intestinal tract and pancreas. The majority of neuroendocrine tumors are from the gastrointestinal system, where a large proportion has a primary origin in the small intestines (midgut).
Since neuroendocrine cells have endocrine functions, neuroendocrine tumors can over-produce certain hormones, or bioactive proteins, resulting in several well-described clinical syndromes. Examples of these clinical syndromes include carcinoid of midgut neuroendocrine tumors and insulinoma or glucagonoma of pancreatic neuroendocrine tumors.
Neuroendocrine tumors do not discriminate; anyone could develop this type of cancer, although people with certain inherited familial syndromes have a higher possibility of developing NET.
What are the main symptoms of GEP-NETs?
Patients with GEP-NETs can have symptoms from the burden or spread of their tumors, as well as symptoms relating to the hormones, or bioactive proteins, being over-produced by their tumors. The neuroendocrine tumors that secrete clinically active proteins or hormones are called functional NETs; whereas, those that do not secrete are non-functional NETs.
Symptoms of non-functional NETs are vague and usually related to the burden of their advanced disease. Examples include abdominal pain, particularly in the upper right quadrant, unintentional weight loss, loss of appetite, and yellowing of the skin (jaundice) or eyes (icteric sclera).
Carcinoid syndrome is a rare clinical manifestation, commonly resulting from metastic or advanced neuroendocrine tumors of the midgut. Symptoms of carcinoid syndrome generally include flushing, diarrhea, wheezing and symptoms of right valvular heart fibrosis.
Pancreatic neuroendocrine tumors can overproduce hormones such as insulin (insulinoma), gastrin (gastrinoma), glucagon (glucagonoma), or vasoactive peptide protein (VIPoma). Typical symptoms of insulinoma include those associated with very low blood sugar, which can include nausea, vomiting, palpitation, weakness and even diaphoresis.
Why do GEP-NETs often take a long time to diagnose?
Many factors contribute to delayed diagnosis of GEP-NETs. There are two main reasons NETs so often take years to diagnose; the symptoms are vague, or generalized, which are not pathogenomic of NETs and NETs are very rare.
As previously mentioned, one of the most common symptoms of carcinoid is diarrhea; therefore, many patients are misdiagnosed with irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). This causes these patients to be empirically or symptomatically treated for many years until a correct diagnosis of NET is made.
Similarly, flushing is frequently attributed to rosacea or menopausal hot flashes for years until the patient is properly diagnosed. Many other symptoms are ubiquitous and generalized; thereby, adding to the confusion. Most physicians do not include NETs on their differential diagnosis for these symptoms because NETs are rarer than conditions such as IBS, IBD or rosacea.
Is it true that the incidence of GEP-NETs has been on the rise in the last few decades?
Incidence measures the number of new NET patients being diagnosed, whereas prevalence measures the number of patients living with NET. The largest SEER database analysis (Yao JC 2008) showed that the incidence of NETs was 5.2 per 100,000 people. Older analyses reported that the incidence of NETs was less than two per 100,000 people; however, these analyses were based on a smaller database and usually from an autopsy series.
Although there is no comparable baseline incidence of NETs, I am convinced that the incidence of NETs has increased over the past few decades. The rate of incidence is not as relevant as the prevalence of NETs. Whether or not the number of new patients being diagnosed with NETs is increasing, there are more and more patients living, and living longer, with NETs. Escalating prevalence of NETs translates to a greater impact on society.
What do you think are the reasons for this increase?
For a long time, there was little information about what neuroendocrine tumors were. It was only in 2010 that the World Health Organization updated the classification of NET to address origin differentiation. Incidence appears to be on the rise, if only because it was not previously calculated accurately. Having a standard definition of the disease will certainly aid in diagnosis. Additionally, advances in diagnostic imaging methods, such as CT scans, have enabled doctors to be more thorough and accurate with their diagnoses.
I also believe this increase is, in part, due to amplified awareness of the disease. Although Steve Jobs’ death was very upsetting for many people, his pancreatic neuroendocrine cancer helped to reveal these previously unknown diseases. It is an unintended legacy but nonetheless, another way he played a part in changing society. If more doctors know about the disease, they will be more likely to recognize it in their patients. Finally, improved treatment options have also contributed to the increase.
Why is there an unmet medical need for GEP-NETs?
Although the incidence, and more importantly the prevalence, of NETs are increasing, treatment options remain limited. To date, there is no FDA approved therapy for disease control in advanced midgut NETs.
I was recently an investigator in the CLARINET study, a phase III trial of 204 NET patients over the course of 96 weeks, that tested the anti-proliferative effects of Somatuline in metastic NETs. There were significant patient results, which were published in the New England Journal of Medicine this past July.
As an outcome from this, last month Somatuline was granted priority review status by the FDA. If it is approved, this could be great news for patients with NET. Of note, Octreotide is only FDA approved to manage symptoms of carcinoid, not treat the tumor itself.
What do you think the future holds for the treatment of GEP-NETs?
This question should be examined in two parts, advanced metastatic NETs and early diagnosis. There is currently no cure for advanced NETs; however, learning more about this disease will benefit future patients in terms of diagnosis and disease management.
Therapeutic development for advanced metastatic NETs, fueled by improved scientific understanding of tumorgenesis, is a very exciting area. More therapies becoming available will mean more options for NET patients. This enables doctors to develop more individualized or “personalized” treatments for their patients. Additionally, more treatment options could result in therapies becoming more affordable.
As we learn more about NETs, this scientific understanding will hopefully allow for earlier detection. I would like to be able to intervene earlier, in the natural course of disease progression, and possibly prevent NETs from developing further in my patients.
About Dr. Alexandria Phan
Dr. Phan is the director of GI Medical Oncology at Houston Methodist. Prior to joining Houston Methodist, Dr. Phan was a clinical specialist at the University of Texas MD Anderson Cancer Center. In 2001, she was recognized with the C.D. Howe Award for Clinical Excellence in Medical Oncology. Dr. Phan received an M.D. degree from the School of Medicine at the University of California, Irvine. Dr. Phan completed at Baylor College of Medicine an internship and residency in Internal Medicine and fellowship in Hematology.