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Chemotherapy Options in Neuroendocrine Tumors

Insights From:Jennifer Eads, MD, Case Western Reserve University; Matthew H. Kulke, MD, Harvard Medical School; Diane Reidy Lagunes, MD, Memorial Sloan-Kettering Cancer Center; Eric H. Liu, MD, FACS, Rocky Mountain Cancer Center; James C. Yao, MD, The University of Texas MD Anderson Cancer Center
Published: Wednesday, Apr 13, 2016


Transcript:

Matthew H. Kulke, MD:
James, there’s been a tremendous number of developments with the targeted therapies over the past few years. One thing that sometimes gets forgotten is that there are some situations where chemotherapy really can be effective. I want to turn to Jennifer. One of those areas is the poorly-differentiated neuroendocrine carcinomas that we talked about. How do you use chemotherapy in that setting?

Jennifer Eads, MD: Poorly-differentiated neuroendocrine tumors are a distinct class aside from the well-differentiated tumors, and it has not been extensively studied. It’s a rare subgroup of all neuroendocrine tumors accounting for somewhere around 10% of tumors. So, it’s very difficult to do clinical trials in this population. And historically, because the histology under the microscope has been similar to that seen in small-cell lung cancer, we’ve just extrapolated data from the small cell lung cancer literature to guide our treatments for the poorly-differentiated population.

In the frontline setting, our go-to regimen is a combination of platinum therapy and etoposide, so that tends to be what we are using in the frontline setting for poorly-differentiated tumors. We don’t know the answer as to whether or not that’s correct. The biology of these tumors, we’re learning more about it, and there are histologic similarities, but also some differences seen between the well-differentiated and poorly-differentiated tumors. But also within the poorly-differentiated tumors themselves, some differences between small cell and large cell. So, we’re learning a lot about that, and we’re not sure if the platinum and etoposide is really the most appropriate for all of those patients, but it does remain our go-to option at this point.

Eric H. Liu, MD, FACS: Can I ask a question? As the nonmedical oncologist in the room, can we borrow some of our GI chemotherapy regimens and possibly apply them to neuroendocrine? Just some thoughts about that?

Matthew H. Kulke, MD: Like FOLFOX?

Eric H. Liu, MD, FACS: Yeah, for example.

Matthew H. Kulke, MD: Yeah, sure. Do you ever use it?

Diane Reidy-Lagunes, MD: We can and we do. Interestingly, one could question the role of next-generation sequencing in 2016 and how beneficial it is. But what we’re learning on the experimental side is a lot of the mutations we’re identifying—for example, on a high-grade neuroendocrine carcinoma—are very similar to traditional adenocarcinoma, APC, KRAS, BRAF. We have often used 5-FU, oxaliplatin, irinotecan-based therapies with good responses. They’re not, unfortunately, durable. So, as is typical of these high-grade, poorly-differentiated neuroendocrine adenocarcinomas, they can often very quickly progress. But that point is very well taken, in that the idea of lumping all these poorly-differentiated neuroendocrine carcinomas together is probably not the right thing to do, and that, genetically, their stem cell of origin per se is probably from an adenocarcinoma as opposed to a well-differentiated neuroendocrine tumor.

Matthew H. Kulke, MD: There’s a common wisdom, which is probably incorrect, that the high-grade aggressive tumors, because they’re highly proliferative, respond to chemotherapy and that the slower-growing, low-grade tumors don’t respond to chemotherapy. That is not always correct, and, in fact, we do use, in some situations, temozolomide for neuroendocrine tumors.

Jennifer Eads, MD: Right. Specifically within the pancreatic neuroendocrine tumor population, temozolomide has become our go-to regimen for a lot of patients. And it’s one of the options that we definitely consider in patients who have a large degree of tumor burden and we’re trying to shrink their tumor down to a more manageable size. It’s something that’s not been definitively determined as of yet. We don’t know what the exact numbers are. The study so far that’s been reported is looking at temozolomide therapy; you had participated and conducted two small phase II temozolomide-based studies that showed an initial response to temozolomide in 25% to 45% of patients, and that prompted some further investigation.

What we largely have based our treatment on, at this point, is actually a small retrospective study of 30 patients who had received a combination of temozolomide and capecitabine for pancreatic neuroendocrine tumors, where a pretty impressive rate of 70% was seen and a progression-free survival of 18 months. Amongst all of the options that we have, that’s definitely a very promising one. And, as a community, we have adopted temozolomide or temozolomide-based regimens as a go-to regimen. Fortunately, we are looking at that in a prospective fashion now, in an ongoing Cooperative Group trial looking at temozolomide versus temozolomide and capecitabine. Hopefully, that will give us some guidance as to what’s really the more favored regimen.

James C. Yao, MD: Jennifer, I just want to chime in that I’m always a little bit leery of high response rates from retrospective series.

Jennifer Eads, MD: Oh, absolutely.

James C. Yao, MD: I have no doubt temozolomide is active in pancreatic neuroendocrine tumors, but the exact response rate and whether it should be used in combination or as single agent? We still have to wait for the ECOG study to review its results. And we, as a field, really need to discourage treatment decisions being made on small retrospective series at this time point because the field has moved beyond that now. I also want to get back to an earlier point of discussion, which is the poorly-differentiated regimens. We talked about a number of different chemotherapy regimens to be considered, but I just wanted to mention that this group of tumors occasionally you can cure with cytotoxic chemotherapy—a small percentage, 5% to 10%, of patients even in the setting of distant metastatic disease. Until we have more data back from the prospective study, platinum-based chemotherapy is still probably the frontline rather than going to targeted agents or other types of treatment.

Diane Reidy-Lagunes, MD: And I would highlight that I’m sure you mean curative intent because of the platinum-based therapy as opposed to surgery.

James C. Yao, MD: Yes.

Diane Reidy-Lagunes, MD: Because, generally, these poorly-differentiated neuroendocrine carcinomas should not be taken to surgery even in what would be considered a locally or locally advanced situation. Certainly, if you’re worried about obstruction, that’s different. For palliative reasons then, it could be indicated. But, generally speaking, even when we think it’s local, we will always consider platinum/etoposide-based therapy first before proceeding to a surgical intent because we know that the risk of metastatic disease is so high.

Transcript Edited for Clarity
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Transcript:

Matthew H. Kulke, MD:
James, there’s been a tremendous number of developments with the targeted therapies over the past few years. One thing that sometimes gets forgotten is that there are some situations where chemotherapy really can be effective. I want to turn to Jennifer. One of those areas is the poorly-differentiated neuroendocrine carcinomas that we talked about. How do you use chemotherapy in that setting?

Jennifer Eads, MD: Poorly-differentiated neuroendocrine tumors are a distinct class aside from the well-differentiated tumors, and it has not been extensively studied. It’s a rare subgroup of all neuroendocrine tumors accounting for somewhere around 10% of tumors. So, it’s very difficult to do clinical trials in this population. And historically, because the histology under the microscope has been similar to that seen in small-cell lung cancer, we’ve just extrapolated data from the small cell lung cancer literature to guide our treatments for the poorly-differentiated population.

In the frontline setting, our go-to regimen is a combination of platinum therapy and etoposide, so that tends to be what we are using in the frontline setting for poorly-differentiated tumors. We don’t know the answer as to whether or not that’s correct. The biology of these tumors, we’re learning more about it, and there are histologic similarities, but also some differences seen between the well-differentiated and poorly-differentiated tumors. But also within the poorly-differentiated tumors themselves, some differences between small cell and large cell. So, we’re learning a lot about that, and we’re not sure if the platinum and etoposide is really the most appropriate for all of those patients, but it does remain our go-to option at this point.

Eric H. Liu, MD, FACS: Can I ask a question? As the nonmedical oncologist in the room, can we borrow some of our GI chemotherapy regimens and possibly apply them to neuroendocrine? Just some thoughts about that?

Matthew H. Kulke, MD: Like FOLFOX?

Eric H. Liu, MD, FACS: Yeah, for example.

Matthew H. Kulke, MD: Yeah, sure. Do you ever use it?

Diane Reidy-Lagunes, MD: We can and we do. Interestingly, one could question the role of next-generation sequencing in 2016 and how beneficial it is. But what we’re learning on the experimental side is a lot of the mutations we’re identifying—for example, on a high-grade neuroendocrine carcinoma—are very similar to traditional adenocarcinoma, APC, KRAS, BRAF. We have often used 5-FU, oxaliplatin, irinotecan-based therapies with good responses. They’re not, unfortunately, durable. So, as is typical of these high-grade, poorly-differentiated neuroendocrine adenocarcinomas, they can often very quickly progress. But that point is very well taken, in that the idea of lumping all these poorly-differentiated neuroendocrine carcinomas together is probably not the right thing to do, and that, genetically, their stem cell of origin per se is probably from an adenocarcinoma as opposed to a well-differentiated neuroendocrine tumor.

Matthew H. Kulke, MD: There’s a common wisdom, which is probably incorrect, that the high-grade aggressive tumors, because they’re highly proliferative, respond to chemotherapy and that the slower-growing, low-grade tumors don’t respond to chemotherapy. That is not always correct, and, in fact, we do use, in some situations, temozolomide for neuroendocrine tumors.

Jennifer Eads, MD: Right. Specifically within the pancreatic neuroendocrine tumor population, temozolomide has become our go-to regimen for a lot of patients. And it’s one of the options that we definitely consider in patients who have a large degree of tumor burden and we’re trying to shrink their tumor down to a more manageable size. It’s something that’s not been definitively determined as of yet. We don’t know what the exact numbers are. The study so far that’s been reported is looking at temozolomide therapy; you had participated and conducted two small phase II temozolomide-based studies that showed an initial response to temozolomide in 25% to 45% of patients, and that prompted some further investigation.

What we largely have based our treatment on, at this point, is actually a small retrospective study of 30 patients who had received a combination of temozolomide and capecitabine for pancreatic neuroendocrine tumors, where a pretty impressive rate of 70% was seen and a progression-free survival of 18 months. Amongst all of the options that we have, that’s definitely a very promising one. And, as a community, we have adopted temozolomide or temozolomide-based regimens as a go-to regimen. Fortunately, we are looking at that in a prospective fashion now, in an ongoing Cooperative Group trial looking at temozolomide versus temozolomide and capecitabine. Hopefully, that will give us some guidance as to what’s really the more favored regimen.

James C. Yao, MD: Jennifer, I just want to chime in that I’m always a little bit leery of high response rates from retrospective series.

Jennifer Eads, MD: Oh, absolutely.

James C. Yao, MD: I have no doubt temozolomide is active in pancreatic neuroendocrine tumors, but the exact response rate and whether it should be used in combination or as single agent? We still have to wait for the ECOG study to review its results. And we, as a field, really need to discourage treatment decisions being made on small retrospective series at this time point because the field has moved beyond that now. I also want to get back to an earlier point of discussion, which is the poorly-differentiated regimens. We talked about a number of different chemotherapy regimens to be considered, but I just wanted to mention that this group of tumors occasionally you can cure with cytotoxic chemotherapy—a small percentage, 5% to 10%, of patients even in the setting of distant metastatic disease. Until we have more data back from the prospective study, platinum-based chemotherapy is still probably the frontline rather than going to targeted agents or other types of treatment.

Diane Reidy-Lagunes, MD: And I would highlight that I’m sure you mean curative intent because of the platinum-based therapy as opposed to surgery.

James C. Yao, MD: Yes.

Diane Reidy-Lagunes, MD: Because, generally, these poorly-differentiated neuroendocrine carcinomas should not be taken to surgery even in what would be considered a locally or locally advanced situation. Certainly, if you’re worried about obstruction, that’s different. For palliative reasons then, it could be indicated. But, generally speaking, even when we think it’s local, we will always consider platinum/etoposide-based therapy first before proceeding to a surgical intent because we know that the risk of metastatic disease is so high.

Transcript Edited for Clarity
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