Treatments for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs) fall into different therapeutic categories, including SSAs, targeted therapies, PRRT, chemotherapy, and locoregional liver-directed therapies. Experts in neuroendocrine oncology describe a treatment paradigm that is largely dominated by sequential therapy rather than combination therapy, albeit with some notable exceptions (eg, capecitabine plus temozolomide).

As broad categories, we typically think of SSAs as a single class. Within the systemic therapies, I think that most of us group the targeted therapies together (eg, everolimus, sunitinib, and cabozantinib). And we separate those from, say, PRRT, and we separate PRRT from chemotherapy. Aside from all of those, we also think about locoregional therapies, whether that be surgical resection, vascular or nonvascular interventions, embolotherapy, SIRT, histotripsy, or any of the new technologies that we have for liver-directed therapy. I would group them all in that locoregional framework.

In my mind, the big question that arises when thinking about combinations is: Do I really know whether I am going to help the patient by combining the toxicities of these 2 approaches at the same time? Do we have evidence about using therapies in parallel vs in series? How do we think about the relative merits of combinatorial therapy, outside of a few rarer situations? There is not a large number of studies showing clear and convincing evidence of a benefit with a combination as opposed to an individual agent. Of course, there are exceptions. For example, in the ECOG-ACRIN Cancer Research Group E2211 study, led by Dr Kunz, it is very clear that capecitabine plus temozolomide was better than single-agent temozolomide. However, many other studies have struggled to demonstrate that it is significantly better to use therapies together vs one after the other.

A final thought on the topic of multimodal therapy and sequencing pertains to a question that sometimes arises regarding the possible benefit of liver-directed therapy prior to PRRT. Proponents reason that, in the case of bulkier hepatic metastases that are, say, larger than 3 to 4 cm, reducing that bulk might preempt or mitigate a potential tumor sync effect in subsequent PRRT. This is debated, but, to my knowledge, it has not been shown that liver-directed therapy prior to PRRT increases the benefits of PRRT.

When using combination therapy, there should be evidence that the combination provides benefit over single-agent therapy or the sequential use of therapies. Not many studies have established a benefit with combination therapy, and there is also added toxicity when using agents together. Therefore, unless there is a clear advantage to using a combination strategy, I tend to take a sequential approach to treatment.

Questions often arise regarding whether to continue SSA therapy after disease progression develops on SSAs. For patients who have carcinoid syndrome or functional NETs, we tend to continue SSA therapy in combination with other agents 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 in combination with other therapies, and practices can vary. A prospective clinical trial would, ideally, address this issue.

I agree with my colleagues, and I would add that the decision to continue SSA therapy with lutetium dotatate for patients with nonfunctional NETs is a bit controversial. Although the NETTER-1 trial required concurrent SSA therapy for all patients, we may need to tailor these decisions to our patients with nonfunctional NETs. Patients with nonfunctional NETs, defined as those who do not have symptoms of hormone excess, may derive antitumor benefit from SSAs when used in the first-line setting. If they progress on an SSA, I do not continue it beyond progression or with lutetium dotatate after progression. It is a matter of debate within the community, and we need more data to inform this decision.

Returning to the idea of multimodal therapy, I believe that multidisciplinary care is critical in cancer care and is especially critical for patients with NETs because they have the potential to interact with so many different specialties. Many of our institutions have tumor boards that provide a forum for multidisciplinary discussions, whether it is medical oncology, surgical oncology, interventional oncology, or nuclear medicine. At these multidisciplinary tumor board meetings, we make complex treatment decisions as a team so that these options can be presented to patients through shared decision making.