For nonresectable small-bowel NETs with radiographic progression on SSA therapy, the first step when deciding on the appropriate treatment approach is to determine whether the disease is liver dominant. If it is, treatment will often start with a liver-directed therapy, which is primarily liver embolization and usually bland embolization. If the disease is more systemic, treatment will typically incorporate the peptide receptor radionuclide therapy (PRRT) with lutetium-177 dotatate, as almost all small-bowel NETs express somatostatin receptors. 

Of course, there are exceptions to these basic guidelines. For example, patients with peritoneal carcinomatosis with extensive mesenteric disease are at a higher risk for bowel obstruction, which can be quite severe—especially if the mesenteric disease is tethering the small bowel. So, we are quite careful in those with peritoneal carcinomatosis. We will sometimes prescribe steroids prophylactically to prevent obstruction, or we may avoid treating these patients altogether. It is important to note, however, that this is a small minority of patients in whom treatment is contraindicated.

It is the nature of cancer to become resistant, but there are 2 different aspects of treatment resistance in NETs with carcinoid syndrome that one should be aware of: refractory hormonal symptoms and radiographic progression. For patients with refractory symptoms such as diarrhea or flushing, it should be determined whether the symptoms are attributable to a hormonal syndrome. If an individual's serotonin level or urine 5-hydroxyindoleacetic acid level is rising on an SSA, increasing the dose or frequency of the SSA injections may help. The serotonin inhibitor telotristat may be an option for refractory diarrhea. PRRT can also improve hormone-related symptoms.

For clinically significant radiographic progression, the primary strategies are either liver embolization or PRRT. In some cases, the mammalian target of rapamycin inhibitor everolimus may also be considered. Chemotherapy does not tend to work very well for small-bowel NETs, although in scenarios involving high-grade tumors, capecitabine or temozolomide might be used. 

Retreatment with lutetium 177 dotatate is an option. Typically, the standard course is 4 treatments, and you can consider additional treatments for patients who experience response or stable disease for at least 1 year after treatment but then subsequently progress. Retreatments typically consist of 2 cycles, so we will give 2 more cycles and then rescan. The maximum lifetime dose has not been well established.