A growing number of agents are US Food and Drug Administration (FDA) approved for the treatment of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Although having additional treatment options has improved patient outcomes, it can make decisions regarding the optimal sequencing of therapies for an individual patient more complicated.

Well-differentiated NETs are quite heterogeneous in their presentation and responsiveness to therapy, so treatment plans must be individualized for patients. As we make decisions, we must take into account both patient- and tumor-related factors, including patient comorbidities and goals of treatment, primary tumor site, tumor grade, pace of tumor growth, bulk of disease, presence of hormone-related symptoms, and SSTR expression.

For patients with extensive disease or symptoms who might benefit from a reduced disease burden, we may aim to use chemotherapy if the primary tumor arises in the pancreas, or we may aim to use PRRT; we can see higher objective response rates with these treatments. On the other hand, if our goal is to achieve stable disease, we often consider using SSAs in the frontline setting. SSAs have been shown to slow disease progression and have favorable side-effect profiles. After progression on SSAs, options include PRRT, targeted agents, or chemotherapy, depending on patient- and tumor-related factors.

Determining the optimal sequencing of therapy can be challenging because we have not had very many randomized trials comparing one active agent to another, and we have had very few trials comparing different sequences of treatment. There are ongoing trials comparing PRRT with chemotherapy or targeted agents. In the future, we will hopefully have the results of these trials to help us understand the relative efficacy of these treatments and to help with treatment selection and sequencing.

Patient comorbidities and choosing treatments that we think patients will be able to tolerate are important when selecting therapy. Other important factors to consider are patient preferences regarding potential side effects, the treatment schedule, and the impact of treatment on quality of life and functioning. It is important to integrate patient preferences and to discuss all options that can be considered while keeping in mind goals of treatment.

Questions often arise regarding whether to continue SSA therapy after disease progression develops on SSAs. For patients who have carcinoid syndrome or a functional NET, we tend to continue SSA therapy with the goal of reducing hormone secretion and symptoms related to excess hormone. For patients with nonfunctional NETs, there are only limited data regarding the benefits of continuing SSAs beyond progression, and practices can vary.

For patients with liver-predominant NETs, disease can be treated with liver-directed therapies, including hepatic artery embolization. Bland hepatic artery embolization, chemoembolization, and radioembolization are acceptable approaches. For patients with SSTR-positive disease who may be candidates for future PRRT, we have become more reluctant to use radioembolization when using a liver-directed approach because of concerns regarding liver toxicity with radioembolization of the liver before or after PRRT. Therefore, in patients who may be candidates for PRRT, we are more likely to take a bland embolization or chemoembolization approach. Ongoing trials are evaluating which of these approaches is the optimal strategy.