Classifying NETs Versus NECs in Gastrointestinal Cancer

Jennifer Eads, MD

Patients with gastrointestinal cancers who have aggressive grade 3 (G3) neuroendocrine neoplasms can have either neuroendocrine tumors (NETs) or neuroendocrine carcinomas (NECs), which should be specifically classified as 2 separate entities, according to Jennifer Eads, MD.

“Determining the pathologic differentiation status of these G3 tumors can have a significant impact on the prognosis and treatment decision of the patient,” says Eads.

Appropriate classification can lead to more precise therapeutic approaches. There is a phase II study (NCT02595424) investigating cisplatin, carboplatin, and etoposide versus temozolomide and capecitabine in patients with metastatic GI NECs. Certain NECs may respond better to treatments other than the current standard of care, which is a regimen of cisplatin and etoposide. The primary objective of the study is to determine the progression-free survival (PFS) of platinum-based therapy and etoposide versus the PFS of temozolomide and capecitabine in this patient population. This trial is currently accruing patients.

OncLive: What is the current classification of NETs?

Can you discuss those characteristics and how they present differently?

In an interview with OncLive, Eads, an assistant professor of medicine, senior clinical instructor, Department of Medicine, University Hospitals Cleveland Medical Center, discusses the classification of NETs versus NECs.Eads: Within the neuroendocrine population of patients, there is an aggressive category that is grade 3. Within that subcategory, there are NETs and NECs. The current classification system for NETs includes many tumors in the G3 category that are heterogeneous and should be classified as 2 separate entities. The features of G3 NETs and NECs, such as the pathology, genetics, and clinical presentation distinguish a less aggressive, well-differentiated G3 tumor from a more aggressive or poorly differentiated G3 tumor.The current classification scheme for GI neuroendocrine neoplasms involves using both the tumor histology, Ki-67, and the mitotic index as parameters for placing a tumor within a category and guiding us in terms of what to do. There is a separate classification scheme that is used for neuroendocrine neoplasms of the lung, which uses mitotic index and the presence or absence of necrosis as their main distinguishing features. Their classification system does not include Ki-67.

We hope to understand how Ki-67 contributes to the GI component. What the pathologic and clinical studies have indicated is that the tumor differentiation status is the most important factor when determining if a patient is likely to be in the less aggressive G3 category versus the more aggressive G3 category. It makes a difference in terms of patient presentation because, often, the patients with more aggressive G3 tumors do not do as well. Those patients have a median overall survival (OS) that is quite poor and usually die in less than 1 year. However, patients who are in the well-differentiated category and have Ki-67 on the lower end of the G3 range often have a better median OS outcome of several years.

Are there difficulties in detecting that specific diagnosis?

There is also a difference in their response to therapies, such as platinum-based therapy. Platinum-based therapy is the standard for G3 NECs, but is probably not appropriate for patients who have well-differentiated tumors or who may have Ki-67 in the lower end of the G3 pathology category. It requires a lot of pathologic knowledge. You rely heavily on the pathologist to make the correct diagnosis. Pathologists who do this often are able to make these very detailed subtle distinctions, whereas pathologists who do not see as many neuroendocrine neoplasms may be unsure.

Are there differences in how you might approach treatments for these patients?

Are there any ongoing clinical trials in either of those areas that are important to mention?

There is a lot of heterogeneity across pathologists who all look at the same specimens, probably based on their level of experience. Neuroendocrine pathologists know all of the refined details. That is not to say that the general pathologist is not capable of doing these assessments, but oftentimes we have to additionally ask them to give us all the little features of the pathology so that we know we are giving the patient the best treatment. Patients who have a well-differentiated tumor, even though they might be in the high-grade category, should not receive platinum-based chemotherapy. It may be more appropriate for them to be treated along the lines of the less aggressive tumor type, such as a G2 lesion. However, patients who have a G3 aggressive, poorly differentiated, high Ki-67 tumor should be receiving platinum-based chemotherapy. There is an ongoing national clinical trial called EA2142. It's an ECOG study that is available through the National Clinical Trials Network. It is a randomized phase II trial of platinum therapy and etoposide versus temozolomide and capecitabine in patients with a G3 NEC of a non—small cell histology. The primary endpoint for that study is PFS and we are looking to determine if one of those regimens is better than the other. Even though platinum and etoposide is the current standard of care for high-grade NECs, it has never been prospectively evaluated in the high-grade population. This is the first opportunity that we have had to evaluate it.

How long does it take to determine if a patient has a G3 tumor?

Is there anything else you would like to add?

Along with achieving the primary endpoint, we are hoping to gain some insightful information about pathology, imaging characteristics, and genetics that are going to help us further distinguish which patients within this trial population should benefit the most from either the platinum-based therapy or the temozolomide-based therapy. These are not the typical NETs that we often talk about. When you think about NETs, you often think of those more indolent patients. G3 tumors are usually not seen in the indolent type of patient. The median OS for a poorly differentiated aggressive tumor is under 1 year. If you do not diagnosis it quickly then they succumb to their disease. Usually, you know that in the beginning. That is why it is important for the pathology report to specify the differentiation status. The physician needs to know what they are dealing with since it makes a huge prognostic difference.In the lung, the pathologist uses a different set of components to make their classification as opposed to the GI tumors. There are many thoughts among the neuroendocrine community that it would be helpful to change the lung classification to incorporate Ki-67 because it may affect how the lung NETs should be treated. It is important to remember there is a big difference between lung and GI from the community physician standpoint. Additionally, it is also important to ensure that you have all of the components of the pathology report before you make a decision about treating patients. You need to know the primary tumor site, the differentiation, the Ki-67 [value], and the mitotic index to determine the right treatment choice.