Neuroendocrine tumors are rare malignancies that arise in neuroendocrine cells, which can occur throughout the body but are most commonly found in the gastrointestinal tract, lungs, and pancreas. Although most neuroendocrine tumors are indolent and take years to grow, some are aggressive and grow more quickly, which, among other factors, makes them difficult to detect and manage.
Jonathan R. Strosberg, MD
To shed light on the current knowledge and management techniques for this malignancy, The ASCO Post spoke with Jonathan R. Strosberg, MD, Professor of Oncology at Moffitt Cancer Center, who specializes in neuroendocrine malignancies. He leads Moffitt’s Neuroendocrine Tumor Division and Gastrointestinal Department Research Program.
Prognostic Markers
What is the current scientific thinking about why some neuroendocrine tumors grow slowly and others are more aggressive?
Differentiation and grade are the most important prognostic markers. Poorly differentiated neuroendocrine cancers have some pathologic similarities to well-differentiated neuroendocrine tumors, but they are completely different biologically and clinically. Poorly differentiated neuroendocrine cancers are characterized by mutations of the TP53, RB1, and NRAS genes, whereas well-differentiated neuroendocrine tumors are characterized by genes that are involved in chromatin remodeling; in many cases, well-differentiated neuroendocrine tumors have no clear oncogenic mutations.
However, within the world of well-differentiated neuroendocrine tumors, there is still considerable heterogeneity, and it depends a lot on tumor grade and primary site. For example, neuroendocrine tumors of the small bowel tend to grow fairly slowly but also are highly prone to metastasize, whereas rectal neuroendocrine tumors tend to be superficial and benign, but when they do metastasize, they usually are more aggressive. So, we need to think of each primary site as its own unique disease.
“Even though immunotherapy has not played an important role in neuroendocrine tumors to date, I’m encouraged by the work in the lab and in clinical trials.”— Jonathan R. Strosberg, MD
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We are also at the early stages of linking genotype to phenotype. It is becoming more apparent that epigenetic changes also play an important role in oncogenesis. That said, across all sites, differentiation and grade are the most important prognostic markers.
Early Detection: ‘Quite Complicated’
Although certain predisposing genetic syndromes are involved in neuroendocrine tumors, early symptoms seem to be vague. However, when detected early, these tumors have a favorable outcome. Where are we in the early detection of neuroendocrine tumors?
The question of early detection is quite complicated; there is a large reservoir of incidental tumors that never progress and therefore do not cause symptoms. So, given the rarity of clinically significant neuroendocrine tumors, there is no formal screening program to identify asymptomatic or presymptomatic neuroendocrine tumors except, perhaps, for patients with a family history or genetic condition such as von Hippel-Lindau syndrome or multiple endocrine neoplasia.
On the other hand, there is a problem with patients who have advanced, symptomatic disease for many years and are not properly diagnosed. Symptoms such as irritable bowel, chronic diarrhea, or obstructed bowels might be missed or dismissed as unrelated to neuroendocrine tumors. Thus, it would serve patients better if clinicians were more aware of the possible root causes of these symptoms.
Common Sites of Disease and Therapeutic Options
In a nutshell, what is the breakdown of the most common sites of neuroendocrine tumors and their management strategies?
The small intestine is the most common primary site of metastatic disease. The first-line medical treatment in this setting for neuroendocrine tumors that express somatostatin receptors is a somatostatin analog, which also is an important treatment for carcinoid syndrome. Somatostatin analogs are used both for control of tumor growth and for palliation of the carcinoid syndrome.
We also think about the role of debulking surgery in patients with metastatic disease, including resection of the primary tumor, depending on the extent of disease and symptoms. For neuroendocrine tumors in the liver, radiofrequency ablation or hepatic artery embolization is often performed. Second-line therapy usually consists of peptide receptor radiotherapy with lutetium-177 (Lu-177) dotatate. In pancreatic neuroendocrine tumors, we also use a somatostatin analog in patients with metastatic tumors that express somatostatin receptors.
Beyond that, there are multiple treatment options such as everolimus and sunitinib, chemotherapy, or Lu-177 dotatate. However, no completed studies to date have compared these various therapeutic options in patients with progressive disease, so trying to figure out how to sequence treatments can be quite challenging. If the cancer is behaving aggressively, we usually proceed with with capecitabine and temozolomide.
NCCN Guidelines
Since you are a member of the National Comprehensive Cancer Network (NCCN®) Clinical Practice Guidelines in Oncology for Neuroendocrine and Adrenal Tumors panel, can you shed some light on the process involved in developing these Guidelines?
I’ve been on the NCCN Guidelines committee for more than 10 years, and over that time, the Guidelines have improved quite a bit, especially in the setting of metastatic neuroendocrine tumors. When I started on the panel, the Guidelines were just a single page, completely lacking high-level data. However, since then, multiple randomized phase III clinical trials have significantly improved the level of evidence. The details and nuance have improved as well, giving clinicians many more options.
The Guidelines panel convenes at least once a year by either in-person meetings or teleconference. If there is a new practice-changing addition, we might meet on an interim basis and discuss the evidence for or against including it in the Guidelines. In general, I think the NCCN Guidelines are particularly important for rare cancers such as neuroendocrine tumors, where the experience and expertise within the panel may aid oncologists in the community who may be less familiar with the disease.
Clinical Trial Portfolio
Please share a bit about your research.
Having a pretty large population of patients with neuroendocrine tumors, we have a robust clinical trial portfolio, including clinical investigator– and pharma-led trials and cooperative group studies. I’m particularly enthusiastic about a trial we are about to open with lenvatinib plus pembrolizumab for progressive neuroendocrine tumors, and we are also participating in a cooperative group trial evaluating cabozantinib vs placebo.
On a more basic science level, we’re involved in chimeric antigen receptor T-cell therapy research. We’ve published some recent clinical trials on single-agent PD-1 inhibitors, in which the response rates are quite low. That said, there are emerging data on combination immunotherapy with ipilimumab and nivolumab in high-grade neuroendocrine neoplasms. We are awaiting results of data from several trials evaluating combination immunotherapy. Even though immunotherapy has not played an important role in neuroendocrine tumors to date, I’m encouraged by the work in the lab and in clinical trials.
DISCLOSURE: Dr. Strosberg has received honoraria from Novartis; has served as a consultant or advisor to Novartis, Lexicon, and Ipsen; has served on the speakers bureau of Ipsen and Lexicon; and has received research funding from Novartis.
