NETs: Clinical Strategies for Diagnosis and Management
Key Points
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Tumor differentiation and Ki-67 index are critical first steps in selecting an appropriate treatment pathway for neuroendocrine tumors (NETs).
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Somatostatin analogs (SSAs) remain a foundational therapy, particularly for patients who are symptomatic.
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Immunotherapy has an evolving role in NET treatment, whereas next-generation sequencing (NGS) plays a limited role due to the low mutational burden of these tumors.
An Evolving Treatment Paradigm
The treatment of NETs follows a multifactorial algorithm that incorporates tumor differentiation, Ki-67 index, site of origin, functional status, symptom burden, and disease extent. In an episode of the Oncology Brothers podcast, Thor Halfdanarson, MD, of Mayo Clinic, discussed current options and how he approaches these tumors with cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center.
The treatment paradigm includes SSAs, radioligand therapy, and other targeted therapies. However, Dr. Halfdanarson explained that it’s not a one-size-fits-all approach.
Steps to Staging NETs
The most important step when selecting a treatment is to determine the Ki-67 index and tumor differentiation. Poorly differentiated neuroendocrine carcinomas (NECs) feature highly abnormal cells and are aggressive, whereas well-differentiated NETs closely resemble normal cells and are typically grade 1–2 with a better prognosis.
Determining primary tumor site is also critical, as pancreatic and lung NETs often require different therapeutic strategies compared with small bowel NETs, Dr. Halfdanarson said.
At diagnosis, cross-sectional imaging and somatostatin receptor PET should be performed to assist in accurate staging, particularly in metastatic disease, he explained.
Dr. Halfdanarson also explained the significance of functional versus non-functional NETs. While functional NETs require a dual focus on symptom control and tumor growth suppression, non-functional NETs prioritize disease control.
Determining Treatment Route
For patients who are symptomatic, a good option is to begin with SSA therapy. However, data from the NETTER-2 study demonstrated that radioligand therapy is a viable option for select patients with Ki-67 levels between 10% and 55%, Dr. Halfdanarson said.
The phase 3 trial showed a substantial progression-free survival benefit with first-line lutetium Lu 177 dotatate plus long-acting octreotide (22.8 months) compared with high-dose octreotide alone (8.5 months) in patients with newly diagnosed, high-grade (grade 2–3), well-differentiated gastroenteropancreatic NETs.
For nonfunctional NETs, Dr. Halfdanarson said there is a role for SSA therapy as long as the tumor lights up on imaging. He recommends starting with a standard dose, then discussing any adverse effects with patients about a month after treatment initiation. That’s when he assesses if he needs to shorten the medication dose.
Symptoms, such as wheezing, chronic diarrhea, and carcinoid heart disease, may affect the dosing and frequency of SSAs.
Their discussion also covered when drugs, such as everolimus, capecitabine/temozolomide, and cabozantinib, may be appropriate. It’s crucial to keep comorbidities in mind, Dr. Halfdanarson said.
Surveillance in NET Management
Monitoring strategies are based on disease burden and whether the disease is metastatic. These include imaging and tumor markers like 5-HIAA and chromogranin. Cross-sectional imaging, sometimes with liver contrast, is preferred by Dr. Halfdanarson. For metastatic disease, he does not repeat gallium dotatate more than 1 year or every other year, except for patients with bone-only disease.
On the Horizon
NGS will play a limited role in managing high-grade NETs, as these are characterized by low mutational burden. Recent data have identified targeted mutations in ALK and HER, but this is still very early on, Dr. Halfdanarson said.
The role of immunotherapy within the treatment of NETs continues to evolve, he explained. Studies, such as SWOG S2012, are investigating its efficacy in patients with poorly differentiated NECs. In heavily pretreated populations, the combination of ipilimumab and nivolumab has demonstrated modest activity, with response rates of 15%-20%. However, Dr. Halfdanarson emphasized the lack of Level 1 randomized data.
For community oncologists, he shared available resources like the North American Neuroendocrine Tumor Society and the European Neuroendocrine Tumor Society. When possible, multidisciplinary care and referral of patients with resectable metastatic disease to a high-volume center is advisable, he explained.
“I think with new, fancy drugs, we sometimes forget the things that work really well,” Dr. Halfdanarson said.