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Risk Stratification and Management of NETs

Insights From: Heloisa P. Soares, MD, UNM Comprehensive Cancer Center; Jonathan R. Strosberg, MD, Moffitt Cancer Center; Timothy J. Hobday, MD, Mayo Clinic College of Medicine and Science
Published: Friday, Mar 02, 2018



Transcript: 

Heloisa P. Soares, MD: The classification of neuroendocrine tumors is very complex, and that’s one of the things I try to explain to patients. We classify NETs as well differentiated, moderately differentiated, and poorly differentiated. But on the top of that, we also classify by grade. Grade 1 patients are typically those who have a Ki-67 index between 0% and 2% in the cells. In grade 2, the Ki-67 is between 3% and 20%. And in grade 3, the Ki-67 percentage is more than 20%. This is important because this defines how you treat the patient. Patients who have a grade 1 tumor are certainly treated very differently from patients who have a grade 3 or high-grade tumor. So, it’s very important, from the beginning, to have very good communication with your pathologist. It’s important to identify exactly what type or subtype of neuroendocrine tumor we are dealing with. That will really impact treatment decisions.

In terms of primary site, we also try to identify the origin—foregut, midgut, and hindgut. Patients who have a midgut tumor or a small bowel tumor typically behave in one way. Patients with a foregut or tumor from the pancreas behave a little bit differently. And the options will be different. There are a few more options for patients with pancreatic neuroendocrine tumors than for those with small bowel neuroendocrine tumors. So, it is also very important, when you’re thinking about the patient and how you’re going to treat him or her, to take into account where the primary tumor is.

Jonathan R. Strosberg, MD: Neuroendocrine tumors are extremely diverse. It’s not really 1 cancer. It’s a family of cancers and is about as heterogenous as we see for a group of cancers. They range from the very slowest growing tumors to the fastest growing. The small cell histology is technically a form of neuroendocrine carcinoma.

There are a lot of different ways of distinguishing prognostic groups. We look at differentiation in grade—grade referring to the proliferative activity of the tumors. We look at the primary site. Each primary site has its own, distinct biology, we’re learning, which explains why the clinical behavior is so different. We look at whether tumors express somatostatin receptors or not and whether they’re hormonally functioning or not. All these things influence both treatment and prognosis. So, for example, the poorly differentiated neuroendocrine carcinomas are treated with platinum-based chemotherapy. This is completely different from what is done with well-differentiated neuroendocrine tumors, which are initially treated with somatostatin analogs. It gets very complicated. The bottom line is, it’s a very diverse group of tumors.

Timothy J. Hobday, MD: A fairly significant number of patients who come to us with their disease are almost incidentally detected. They may have had brief abdominal pain and may have ended up in the emergency department. They may have undergone some imaging that found several small liver metastases and, perhaps, a primary tumor in their abdomen somewhere. These patients are otherwise asymptomatic. They’re quite concerned, obviously, about the diagnosis of a metastatic cancer. Often the biopsy will show a very well differentiated neuroendocrine tumor without a very high mitotic index, or Ki 67. We know that these patients often can have stable disease with very, very slow growth, for long periods of time. Yet we also know that the disease is not curable. So, the question is, if we’re hopeful that somebody may live 5, 10, 15 years with their disease, do we need to aggressively treat them up front?

I think many of these patients are candidates for observation without therapy. If we look at a number of clinical trials in the recent decade that randomized patients to an active therapy—such as a somatostatin receptor antagonist, everolimus, sunitinib—they were always compared with a group that received placebo. The placebo group generally got treatment later on, and there isn’t a trial that shows even a hint of a long-term overall survival advantage. This would suggest that patients can receive the benefit from these same therapies further down the road, in the course of their disease, and be spared the costs, the toxicities, and the hassle of receiving therapy, as long as they’re being followed closely in an expert center. So, I think there are many patients in whom initial observation is a quite reasonable treatment strategy.

Transcript Edited for Clarity
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Transcript: 

Heloisa P. Soares, MD: The classification of neuroendocrine tumors is very complex, and that’s one of the things I try to explain to patients. We classify NETs as well differentiated, moderately differentiated, and poorly differentiated. But on the top of that, we also classify by grade. Grade 1 patients are typically those who have a Ki-67 index between 0% and 2% in the cells. In grade 2, the Ki-67 is between 3% and 20%. And in grade 3, the Ki-67 percentage is more than 20%. This is important because this defines how you treat the patient. Patients who have a grade 1 tumor are certainly treated very differently from patients who have a grade 3 or high-grade tumor. So, it’s very important, from the beginning, to have very good communication with your pathologist. It’s important to identify exactly what type or subtype of neuroendocrine tumor we are dealing with. That will really impact treatment decisions.

In terms of primary site, we also try to identify the origin—foregut, midgut, and hindgut. Patients who have a midgut tumor or a small bowel tumor typically behave in one way. Patients with a foregut or tumor from the pancreas behave a little bit differently. And the options will be different. There are a few more options for patients with pancreatic neuroendocrine tumors than for those with small bowel neuroendocrine tumors. So, it is also very important, when you’re thinking about the patient and how you’re going to treat him or her, to take into account where the primary tumor is.

Jonathan R. Strosberg, MD: Neuroendocrine tumors are extremely diverse. It’s not really 1 cancer. It’s a family of cancers and is about as heterogenous as we see for a group of cancers. They range from the very slowest growing tumors to the fastest growing. The small cell histology is technically a form of neuroendocrine carcinoma.

There are a lot of different ways of distinguishing prognostic groups. We look at differentiation in grade—grade referring to the proliferative activity of the tumors. We look at the primary site. Each primary site has its own, distinct biology, we’re learning, which explains why the clinical behavior is so different. We look at whether tumors express somatostatin receptors or not and whether they’re hormonally functioning or not. All these things influence both treatment and prognosis. So, for example, the poorly differentiated neuroendocrine carcinomas are treated with platinum-based chemotherapy. This is completely different from what is done with well-differentiated neuroendocrine tumors, which are initially treated with somatostatin analogs. It gets very complicated. The bottom line is, it’s a very diverse group of tumors.

Timothy J. Hobday, MD: A fairly significant number of patients who come to us with their disease are almost incidentally detected. They may have had brief abdominal pain and may have ended up in the emergency department. They may have undergone some imaging that found several small liver metastases and, perhaps, a primary tumor in their abdomen somewhere. These patients are otherwise asymptomatic. They’re quite concerned, obviously, about the diagnosis of a metastatic cancer. Often the biopsy will show a very well differentiated neuroendocrine tumor without a very high mitotic index, or Ki 67. We know that these patients often can have stable disease with very, very slow growth, for long periods of time. Yet we also know that the disease is not curable. So, the question is, if we’re hopeful that somebody may live 5, 10, 15 years with their disease, do we need to aggressively treat them up front?

I think many of these patients are candidates for observation without therapy. If we look at a number of clinical trials in the recent decade that randomized patients to an active therapy—such as a somatostatin receptor antagonist, everolimus, sunitinib—they were always compared with a group that received placebo. The placebo group generally got treatment later on, and there isn’t a trial that shows even a hint of a long-term overall survival advantage. This would suggest that patients can receive the benefit from these same therapies further down the road, in the course of their disease, and be spared the costs, the toxicities, and the hassle of receiving therapy, as long as they’re being followed closely in an expert center. So, I think there are many patients in whom initial observation is a quite reasonable treatment strategy.

Transcript Edited for Clarity
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