Multidisciplinary care is especially important with NETs—perhaps even more so than with many other cancers. Medical oncologists prescribe medical treatments. Advanced disease surgeons play an important role, not only for patients with localized or local-regional tumors but also for patients with metastatic tumors. Interventional radiologists perform liver embolizations, including bland embolizations, chemoembolizations, and radioembolizations. And then there are nuclear medicine physicians for peptide receptor radionuclide therapy and gastroenterologists for the initial diagnosis and management of gastric or rectal NETs. Endocrinologists manage challenging endocrine syndromes such as Cushing syndrome, and cardiologists manage carcinoid heart disease. So, there are multiple specialties involved.

For advanced, well-differentiated, gastroenteropancreatic (GEP)–NETs, there are several considerations for planning treatment, including the primary site, presence of somatostatin receptors (SSTRs), tumor grade, symptom burden, and tumor burden. We also need to consider whether the patient has a hormonal syndrome. Most GEP-NETs express SSTRs. If they originate in the small bowel, they often produce hormones such as serotonin, which may result in carcinoid syndrome. So, somatostatin analogues (SSAs) are typically used as first-line treatment for both control of disease growth and control of hormonal syndromes. 

Beyond that, if a patient has a metastatic small-bowel NET that is progressing beyond the liver, the typical second-line therapy will be peptide receptor radionuclide therapy with lutetium Lu 177 dotatate. If the disease is progressing mostly in the liver, liver-directed therapy such as hepatic embolization can be considered, assuming that the patient does not have surgically resectable disease. Everolimus is also an option, but one that is generally only marginally effective for patients with metastatic small-bowel NETs and carcinoid syndrome. 

For patients with uncontrolled carcinoid syndrome diarrhea on an SSA (typically small-bowel primary), the oral serotonin inhibitor telotristat (in addition to the SSA) has been shown to improve the number of daily bowel movements and reduce the levels of urine 5-hydroxyindoleacetic acid.  

There are more options for pancreatic NETs. Both of the targeted agents everolimus and sunitinib can stabilize disease and were shown to inhibit tumor growth compared with placebo (ie, everolimus in NCT00510068 and sunitinib in NCT00428597), although objective response rates are very rare. Chemotherapy regimens are effective, both in terms of tumor shrinkage and progression-free survival. Kunz et al reported a response rate of approximately 40% and a median progression-free survival of nearly 2 years with the combination of capecitabine and temozolomide in patients with advanced pancreatic NETs. We can also use lutetium Lu 177 dotatate in those with advanced pancreatic NETs that are progressing systemically with SSTR-expressive metastatic receptors.

It really does take a strategic approach to treat these patients optimally from the beginning. Individuals with advanced, low-grade GI-NETs often live for years with this disease, and many patients go through most of the treatments at some point in their life. Treatment decisions should be made by a comprehensive care team. A lot of cancers are multidisciplinary, and many disciplines are involved in the care of patients with this disease, even in the metastatic setting. As Dr Strosberg noted, this is one of the areas of cancer care that may be even more multidisciplinary than a lot of other cancers.

Patients with localized disease undergo a resection, which generally rids them of their symptoms. My approach to individualizing care for those with metastatic disease is to determine the primary tumor location and grade. I put the patients with pancreatic NETs in a different category than the patients with bowel NETs. Those with bowel NETs are more likely than those with pancreatic NETs to suffer from carcinoid syndrome. We always want to know the grade of disease, or at least if the patient has well-differentiated vs poorly differentiated tumors.

Then it is a matter of determining if the patient has a functional or a nonfunctional tumor, with the functional tumors being those manifesting carcinoid syndrome. What is the severity of their symptoms? Are they just experiencing mild flushing or are they experiencing out-of-control diarrhea? Do they have cardiac carcinoid disease? 

Generally speaking, those with functional tumors are more on the well-differentiated, lower end of the spectrum—generally patients with grade 1 or grade 2 NETs. And patients with grade 1 and grade 2 are treated similarly. For individuals with nonfunctional tumors, the standard frontline treatment is SSA therapy. When I have newly diagnosed patients with very minimal disease burden, I may not start them on anything right away. Rather, I watch them, and then I will start treating them with the SSA if they progress. If they have carcinoid syndrome, regardless of the degree of disease burden, I will start the SSA therapy. For patients with extensive disease, particularly those with a tumor burden in the liver, we may consider liver-directed therapy combined with SSA therapy, especially if they have carcinoid syndrome. We do this in an effort to debulk them, which, in turn, decreases their degree of hormone production and carcinoid syndrome. 

I think that my colleagues hit all of the highlights. We have to establish the anatomical origin of the tumor because pancreatic NETs have different responses to treatment than small-bowel NETs. Then we need to think of the symptoms and remember that embolization or intravascular therapy can be very effective in relieving the symptoms of carcinoid syndrome, and even the symptoms of rare functional tumors in the liver, such as metastatic insulinoma. There are several approaches to treatment, which is why it is best discussed in a multidisciplinary tumor board environment. 

Individualizing treatment based on symptoms is not always straightforward in patients with carcinoid syndrome. For example, there are multiple potential causes of diarrhea. Exocrine pancreatic insufficiency can start after the initiation of SSA therapy, with a change in bowel habits consistent with worsening carcinoid syndrome, including diarrhea and loose stool, but with light-colored, greasy bowels that float with an oil slick in the water. It is treated with digestive pancreatic enzymes. Another possibility is bile acid diarrhea, which typically occurs in patients who have had small-bowel resection. These individuals are very symptomatic. You can dramatically change their quality of life by putting them on bile acid–binding drugs such as colestipol or cholestyramine. So, attention to whether seemingly syndromic symptoms are truly from carcinoid syndrome is another important aspect of patient care.