Navigating Treatment Selection for Advanced NETs

Neuroendocrine tumors (NETs) represent a heterogeneous group of malignancies with distinct clinical behaviors, prognoses, and treatment considerations that continue to evolve as new therapies become available. During a live Case-Based Roundtable event in Washington, DC, Sandy Kotiah, MD, medical oncologist and director of The Neuroendocrine Tumor Center at Mercy Medical Center, discussed the evolving treatment landscape and management considerations for patients with advanced NETs.

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Targeted Oncology: Can you describe the epidemiologic trends of gastrointestinal NETs, and how do clinical features and prognosis differ based on primary tumor site?

Sandy Kotiah, MD: NETs have been increasing in incidence and prevalence for the last 55 years. [Investigators] have done reviews of the Surveillance, Epidemiology, and End Results database and we don't know why it's increasing in incidence; we don't know if it's because there's more environmental [factors] going on…we have better technology, but we've been detecting more NETs over time, and these patients are living longer. When I started the neuroendocrine program 16 years ago, there were only somatostatin analogs that were available, and now we have a whole slew of treatments that are available, so we're helping these patients live even longer.

The site of origin matters, because even though they all look the same under the microscope, they don't all behave the same. I tend to think of pancreatic NETs as behaving a little bit more aggressively for the same differentiation in stage as somebody with a small intestinal tumor. You can catch the rectal NETs earlier; a lot of them get picked up by accident on colonoscopies, they're very small, they remove them….

When they metastasize, the prognosis is a little bit worse, and it's harder to manage, and you'll notice that a lot of the trials don't include a lot of rectal NETs. The tumors of the small intestine and the appendix can produce hormones, but the ones from the colon and the rectum are usually silent—they don't produce any hormones—and they tend to be harder to manage, especially when they metastasize. And then the NETs in the lung, maybe 10% produce carcinoid syndrome.¹ [For] the NETs in the stomach, it's very important to check gastrin levels when you're dealing with gastric NETs. I sometimes see a lot of 5-HIAA testing, a lot of chromogranin A testing, but it's important for the type of organ that you're dealing with, so [for] these you don't have to worry about hormone production.

When [small intestinal NETs] metastasize to the liver, [it] can produce carcinoid syndrome about [10%] of the time.² The pancreatic NETs depend on what hormone producing cell got involved—insulinoma vs glucagonoma vs a VIPoma vs a somatostatinoma, or it could just be nonfunctional most of the time. [For] the stomach NETs, it's always important to check fasting gastrin levels. The type 3 NETs of the stomach are not influenced by gastrin, but [in] type 1 and type 2, there's elevated gastrin. There are type 4 and type 5 now; one of them is caused by structural damage, one of them is caused by long-term proton pump inhibitor use. So it's important to check the gastrin levels. [For] the lung NETs, 5-hydroxytryptophan [is a major pathway], because it can cause atypical flushing, purple flushing, and wheezing. It's not always commercially available, and some of them can produce serotonin.

So they're all a little bit different, and they behave differently. And then survival can be impacted by grade; the well-differentiated tumors do better than poorly differentiated tumors…I think we all know that poorly differentiated NETs do worse, and they need chemotherapy right away, whereas [patients with] well-differentiated tumors usually can live a long time.

What are the treatment options listed in the NCCN Guidelines for grade 1 or grade 2 locoregional advanced and/or distant metastatic pancreatic NETs?

You have a variety of options. You have cabozantinib [Cabometyx], which was approved in April of last year based on the CABINET study [NCT03375320]. Everolimus [Afinitor] was approved in 2016 based on the RADIANT-4 trial [NCT01524783]. Peptide receptor radionuclide therapy was approved in 2018, and then [the use of] octreotide [Sandostatin] was [supported by] the PROMID study [NCT00171873]… and then the CLARINET trial [NCT00353496] happened in 2017 that got lanreotide [Somatuline Depot] approved. All these [agents] are options for your patients.

In terms of pancreatic NETs, the only difference is you can add sunitinib [Sutent], and it's usually given at 37.5 mg daily. I don't usually use a lot of sunitinib, but that's available, and the other addition is you can use capecitabine and temozolomide, because the MGMT expression is higher for pancreatic NETs, so it tends to be an effective regimen. So it's not something that you should give to gastrointestinal NETs because the response rates are [lower], but if you're giving it to your patients with grade 1 or grade 2 pancreatic NETs, you're talking about [a higher] response rate for a Ki-67 index of less than 55%; [for] more than 55%, the response rates go up… You can also do FOLFOX or CAPEOX…and then you can use belzutifan [Welireg] if you have a patient with Von Hippel-Lindau [VHL] disease…but only in patients who have VHL alterations. The study, unfortunately, was negative for patients who have pancreatic NETS without VHL mutations.

DISCLOSURES: Kotiah has previously disclosed serving a consulting or advisory role with Bristol-Myers Squibb and Sanofi and serving on speakers’ bureaus with Amgen, Novartis, and Ipsen.

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REFERENCES

1. Granberg D, Juhlin CC, Falhammar H, Hedayati E. Lung Carcinoids: A Comprehensive Review for Clinicians. Cancers (Basel). 2023;15(22):5440. Published 2023 Nov 16. doi:10.3390/cancers15225440

2. Gonzáles-Yovera JG, Roseboom PJ, Concepción-Zavaleta M, et al. Diagnosis and management of small bowel neuroendocrine tumors: A state-of-the-art. World J Methodol. 2022;12(5):381-391. Published 2022 Sep 20. doi:10.5662/wjm.v12.i5.381