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Peptide Receptor Radionuclide Therapy in NETs

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 20, 2016


Transcript:

Matthew H. Kulke, MD:
We’ve talked about all kinds of different treatment options. We’ve talked about somatostatin analogues, we’ve talked about mTOR inhibitors, we’ve talked about angiogenesis inhibitors, and we’ve talked about chemotherapy. There is yet another treatment approach that has been used primarily in Europe: peptide receptor radionuclide therapy. Eric, you probably referred a few of your own patients over for that, and there’s recent new data about peptide receptor radionuclide therapy (PRRT) that looks pretty exciting.

Eric H. Liu, MD, FACS: Absolutely. The PRRT is a different technology and approach to what we’re doing. Talk about milking somatostatin for every little bit we can; we have. We treated for symptoms as a cohormone. We use it for imaging. And now we can put a radioactive payload behind it and give internal radiation therapy. So PRRT, which is peptide receptor radionuclide therapy, is essentially fixing the octreotide analogue, a somatostatin analogue, with a chelator, and you can carry a radioactive isotope, either the isotope 177 lutetium or 90 yttrium. In general, we’re starting to use the lutetium 177 because it’s a more gentle, more durable probably, second-generation isotope. It’s an IV injection so there’s a little bit of a catch to it because there’s a companion diagnostic to it, which is either the Octreoscan or the gallium scan. And what that does is, it tells me, is the somatostatin receptor in place? Is there a target for me to send the hormone to? If there is a good signal, then what you can do is, it’s an IV therapy, and it’s systemic as well, so it’s kind of in complement with your systemic therapies. And it essentially binds to the tumor. It absorbs the radiation within the tumor itself, and then it continually radiates the tumors from the inside out. The general regimen is you take a dose of the PRRT, you wait 2 months for your bone marrow to recover, you take another one, you take another one, and you take another one. You take about 4 therapies. What we found is that, especially in Europe, it is quite effective in tumor control, progression-free survival, symptom control, many wonderful outcomes.

Unfortunately, in Europe, it was a cottage industry, so you had small retrospective studies for which we didn’t collect and look carefully enough. But exciting, advanced accelerated applications are now bringing this forward. They just completed the NETTER-1 trial, which is a large PRRT trial, a randomized trial, international, multi-center looking at the effects in metastatic midgut carcinoids in progressive disease. And they found a significant separation in progression-free survival between the patients who were on either high-dose Sandostatin, so a pseudo-therapy of some sort, versus their PRRT. And it’s actually interesting because they’ve been following it out now, and they’re even seeing some separation in overall survival. We’re hopeful that we’ll be able to bring this therapy to the United States, and it will be just yet another tool as the surgery, as hormone, as chemotherapies are in order to treat these patients.

It does open up a lot of questions, though, because the question now is, well, when do I use it? Can I use it before surgery, after surgery, before chemotherapy, after chemotherapy? So, getting back to the whole sequencing. Don’t get me wrong, I’d much rather have more tools in the toolbox than less, but it’s something that’s new and something that’s exciting. And, again, you really need a whole multidisciplinary team to evaluate when to treat these patients and with what.

James C. Yao, MD: Eric, I want to toss a question back to you. You mentioned the gallium 68 as a companion diagnostic. To my knowledge, gallium 68 tied to DOTATATE has not been really demonstrated to be a companion diagnostic for PRRT. NETTER-1 was done based on Octreoscan. In fact, the Krenning scale is based on the least sensitive part of the Octreoscan, which is the planar image. The idea is you don’t want to treat patients who are barely positive. You are using a very sensitive test. You want to treat patients who are super, super positive that you can pick up even with very insensitive tests. How are we going to translate what Krenning scale means in the age of DOTATATE tied to gallium 68 and PET?

Eric H. Liu, MD, FACS: That’s a really good question, James. And part of that comes from the fact that we haven’t had gallium technology here. So just to step back a little bit. The gallium scan is basically a gallium 68 isotope hooked to the octreotide molecule. And instead of therapy or cold therapy, you take pictures of it, so it’s an imaging technology. What’s different from Octreoscan, though, is that it’s PET technology, so you can actually do a lot more things with it. It’s more sensitive. You get better resolution. It’s just a better picture. So maybe you’re just getting better pictures. But actually, the one thing that’s most valuable with it is you can quantitate the amount of radiation that’s taken up by your tumors. As we get more experience with the gallium scan, we can actually get a better quantitation. You’re exactly right, does the Krenning scale, which is essentially just how dark an image looks in Octreoscan on a planar image, does that correlate better with the standardized uptake values from a PET scan? Maybe we can actually correlate that. If you have an SUV of 40, maybe those are going to be the best ones for PRRT. And if it’s 6, maybe those are not the best ones. But, at least, having some quantitation, and that’s an emerging technology as well. Hopefully, we’ll have that approved in the US. As we start to develop more experience, they’ll start to come together.

Transcript Edited for Clarity
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Transcript:

Matthew H. Kulke, MD:
We’ve talked about all kinds of different treatment options. We’ve talked about somatostatin analogues, we’ve talked about mTOR inhibitors, we’ve talked about angiogenesis inhibitors, and we’ve talked about chemotherapy. There is yet another treatment approach that has been used primarily in Europe: peptide receptor radionuclide therapy. Eric, you probably referred a few of your own patients over for that, and there’s recent new data about peptide receptor radionuclide therapy (PRRT) that looks pretty exciting.

Eric H. Liu, MD, FACS: Absolutely. The PRRT is a different technology and approach to what we’re doing. Talk about milking somatostatin for every little bit we can; we have. We treated for symptoms as a cohormone. We use it for imaging. And now we can put a radioactive payload behind it and give internal radiation therapy. So PRRT, which is peptide receptor radionuclide therapy, is essentially fixing the octreotide analogue, a somatostatin analogue, with a chelator, and you can carry a radioactive isotope, either the isotope 177 lutetium or 90 yttrium. In general, we’re starting to use the lutetium 177 because it’s a more gentle, more durable probably, second-generation isotope. It’s an IV injection so there’s a little bit of a catch to it because there’s a companion diagnostic to it, which is either the Octreoscan or the gallium scan. And what that does is, it tells me, is the somatostatin receptor in place? Is there a target for me to send the hormone to? If there is a good signal, then what you can do is, it’s an IV therapy, and it’s systemic as well, so it’s kind of in complement with your systemic therapies. And it essentially binds to the tumor. It absorbs the radiation within the tumor itself, and then it continually radiates the tumors from the inside out. The general regimen is you take a dose of the PRRT, you wait 2 months for your bone marrow to recover, you take another one, you take another one, and you take another one. You take about 4 therapies. What we found is that, especially in Europe, it is quite effective in tumor control, progression-free survival, symptom control, many wonderful outcomes.

Unfortunately, in Europe, it was a cottage industry, so you had small retrospective studies for which we didn’t collect and look carefully enough. But exciting, advanced accelerated applications are now bringing this forward. They just completed the NETTER-1 trial, which is a large PRRT trial, a randomized trial, international, multi-center looking at the effects in metastatic midgut carcinoids in progressive disease. And they found a significant separation in progression-free survival between the patients who were on either high-dose Sandostatin, so a pseudo-therapy of some sort, versus their PRRT. And it’s actually interesting because they’ve been following it out now, and they’re even seeing some separation in overall survival. We’re hopeful that we’ll be able to bring this therapy to the United States, and it will be just yet another tool as the surgery, as hormone, as chemotherapies are in order to treat these patients.

It does open up a lot of questions, though, because the question now is, well, when do I use it? Can I use it before surgery, after surgery, before chemotherapy, after chemotherapy? So, getting back to the whole sequencing. Don’t get me wrong, I’d much rather have more tools in the toolbox than less, but it’s something that’s new and something that’s exciting. And, again, you really need a whole multidisciplinary team to evaluate when to treat these patients and with what.

James C. Yao, MD: Eric, I want to toss a question back to you. You mentioned the gallium 68 as a companion diagnostic. To my knowledge, gallium 68 tied to DOTATATE has not been really demonstrated to be a companion diagnostic for PRRT. NETTER-1 was done based on Octreoscan. In fact, the Krenning scale is based on the least sensitive part of the Octreoscan, which is the planar image. The idea is you don’t want to treat patients who are barely positive. You are using a very sensitive test. You want to treat patients who are super, super positive that you can pick up even with very insensitive tests. How are we going to translate what Krenning scale means in the age of DOTATATE tied to gallium 68 and PET?

Eric H. Liu, MD, FACS: That’s a really good question, James. And part of that comes from the fact that we haven’t had gallium technology here. So just to step back a little bit. The gallium scan is basically a gallium 68 isotope hooked to the octreotide molecule. And instead of therapy or cold therapy, you take pictures of it, so it’s an imaging technology. What’s different from Octreoscan, though, is that it’s PET technology, so you can actually do a lot more things with it. It’s more sensitive. You get better resolution. It’s just a better picture. So maybe you’re just getting better pictures. But actually, the one thing that’s most valuable with it is you can quantitate the amount of radiation that’s taken up by your tumors. As we get more experience with the gallium scan, we can actually get a better quantitation. You’re exactly right, does the Krenning scale, which is essentially just how dark an image looks in Octreoscan on a planar image, does that correlate better with the standardized uptake values from a PET scan? Maybe we can actually correlate that. If you have an SUV of 40, maybe those are going to be the best ones for PRRT. And if it’s 6, maybe those are not the best ones. But, at least, having some quantitation, and that’s an emerging technology as well. Hopefully, we’ll have that approved in the US. As we start to develop more experience, they’ll start to come together.

Transcript Edited for Clarity
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