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TKI Therapy for Advanced Thyroid Cancer

Panelists:Marcia S. Brose, MD, PhD, University of Pennsylvania; Naifa Busaidy, MD, FACP, FACE, University of Texas MD Anderson Cancer Center; Eric J. Sherman, MD, Memorial Sloan Kettering Cancer Center; R. Michael tuttle, MD, Memorial Sloan Kettering Cancer Center; Francis Paul Worden, MD, University of Michigan Comprehensive Cancer Center
Published Online: Monday, May 23, 2016



Transcript:

R. Michael Tuttle, MD:
When I was a fellow, we didn’t have systemic therapies for these patients, and oncologists were not interested in it. Give us a little bit of that historical perspective, how we came from Adriamycin not that long ago, to multiple ‘ibs’ these days. How did we get here?

Frank Worden, MD: Right. I think I started my faculty position the year 2000, and these patients came to my clinic and I was like, oh my God. It was really sad because I had nothing to offer them. The endocrinologist would send them to me and I felt so bad, like what can I really do for you? Then came Adriamycin. And with Adriamycin, the response rates weren’t that great, the toxicity, the cardiac toxicity, and the myelosuppression, for what little benefit.

Naifa Busaidy, MD, FACP, FACE: Short-lived.

Frank Worden, MD: Yes, exactly. I’ll be honest, I didn’t really use a lot of Adriamycin in my career. There were some other cytotoxic chemotherapy agents, and I know Marten will talk about sometimes. He does use them, like gemcitabine, for example. We gave that in combination with docetaxel. But then came the targeted therapies, and so those became more en vogue for things like gastrointestinal stromal tumors (GISTs) and the renal cell carcinomas. I think once people were kind of realizing that these cancers were very similar to thyroid cancer, there was exploration looking at these oncoproteins—VEGF, and RET, and MAP, any of those other targets—that are linked to the aberrant tyrosine kinase. And so, with that, we have these drugs now that inhibit tyrosine kinase and VEGF, the angiogenesis that provide actually a sustained and durable response to treatment. That’s kind of where we’ve come from and where we’re at today.

R. Michael Tuttle, MD: So, now the difficult part is we’ve got a couple of FDA-approved drugs. When do I watch and when do I start? Eric, help me. Don’t give me theoretical. I want to know when do I really think about starting somebody on one of these drugs or when do I definitely not? How do you sort them out when you see these guys in clinic?

Eric Sherman, MD: I think that the criteria that was put in the clinical studies for when patients should be put on this is not the time to start. So, the idea that tumor progression over 14 months—well, I think there has to be something that was in these clinical studies—for a lot of the patients it’s too early. I think it’s difficult to figure out exactly when the right time is, and I think it depends on a lot of different factors. Symptoms is an easy one. If they’re symptomatic, you start, in general.

R. Michael Tuttle, MD: What kind of symptoms do they have? Because you guys always talk about symptoms. We never see symptoms in our thyroid cancer patients. What kind of symptoms do they have?

Eric Sherman, MD: It depends on the location. Most often, it’s breathing problems if it’s in the lung, or if it’s right in the Hilar lymph node or mediastinal lymph node area. In bones, there’s going to be pain. Now, some of those you can just radiate. So, sometimes if you can do a local treatment to take care of the problem. It does make more sense.

R. Michael Tuttle, MD: But if they have the symptoms that local treatment can’t do, that would be an indication.

Eric Sherman, MD: Then it’s an indication to go ahead and do something. And a lot of times when they’re not symptomatic, it’s location that’s going to make a difference. So, if you have someone that has a peripheral nodule that’s growing, that’s doubling size in a year from 1 cm to 2 cm, I’m not going to be that worried about it. While, if you’ve got a paratracheal node or a paraesophageal lymph node nodule that’s growing even 20% in a year, that’s going to worry me more when that can’t radiate or was already radiated, and starting to grow in that area.

R. Michael Tuttle, MD: Its structure, its rate of change, its local. How do you decide, Frank?

Frank Worden, MD: I heard Marten talk about this once and Marcia at an advisory board. It was really interesting about making a box, and those people who have large burden of disease that’s progressing very quickly, those are the automatic kind of kneejerk you treat. And those on the flip side that are, like Eric said, you have 1 or 2 nodules that are really just not changing much. It’s the disease that’s more smoldering. You just continue to observe them and maybe even with yearly scans at that point. It’s the people who are kind of in the middle, the large tumor that may not be growing very quickly, but then you may want to treat depending on the location, or if it’s previously treated with radiation, for example. And the same thing, those small disease burden that really isn’t changing that much, more like the miliary disease. That’s why we have these lengthy discussions and meaningful discussions with patients. So, often times, we move CT scans up. There’s some new preliminary data, which informs the oncologist about doubling time with thyroglobulin, like we use in medullary thyroid cancer, to follow those more closely. Those are the people I see back more regularly. And when I’m ready to start treatment, we’ll sit down and say, ‘Okay, look, you were really asymptomatic here, now you’re a little bit more short of breath when you’re walking up the steps. I think it’s time for treatment.’

R. Michael Tuttle, MD: Marcia, same sort of ball park there in terms of when you start.

Marcia S. Brose, MD, PhD: I have a little bit of a different approach. So, I think all of the things that are said are probably where I come out, but the one thing I always like to point out is we actually have data. It seems like a lot of people like to just really say, ‘Oh, I feel this way or I feel that way.’ And Eric pointed out that if you do apply the eligibility criteria that were used in either the SELECT or DECISION study, some patients will not necessarily need to be tested. But let’s talk about the numbers. The numbers say that if you look at the placebo arms for both of those, even using 14 months for progression as a criteria, we know that people tend to progress a little bit quicker, and quicker, and quicker. If you use progressive disease—RAI refractory disease as your criteria—on average, your patients will now have progression-free survival in the three-and-a-half to five-and-a-half months. That’s a pretty aggressive disease.

Now, that’s true that in both of those trials there’s a tail and there’s 10%. But we’re talking 10% of the patients, not 90%. So 90% of the patients, that’s a pretty good criteria. What that says to me, is it absolute? No. But, now, in order to not act on that criteria, I have to have a reason. What are the reasons? Well, the reason might be that it’s a solitary nodule, it’s one peripheral spot. Those patients can be often observed for a very long time because, as Eric said, it’s a peripheral spot. It’s not going to hurt them for a long time. So, I try to figure out who were those 10%, but I think that lots of times people argue that 90% of the people have those 10% characteristics. I just think that’s not true, and I think we have to remember we do have data, that those criteria have given us data, and now you have to have a reason why it is that you feel that that patient is going to be in that 10%. But I find that people many times will take 90% of the patients and say that they would be those 10%. We have to be a little bit cautious about not following the data.

Transcript Edited for Clarity

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Transcript:

R. Michael Tuttle, MD:
When I was a fellow, we didn’t have systemic therapies for these patients, and oncologists were not interested in it. Give us a little bit of that historical perspective, how we came from Adriamycin not that long ago, to multiple ‘ibs’ these days. How did we get here?

Frank Worden, MD: Right. I think I started my faculty position the year 2000, and these patients came to my clinic and I was like, oh my God. It was really sad because I had nothing to offer them. The endocrinologist would send them to me and I felt so bad, like what can I really do for you? Then came Adriamycin. And with Adriamycin, the response rates weren’t that great, the toxicity, the cardiac toxicity, and the myelosuppression, for what little benefit.

Naifa Busaidy, MD, FACP, FACE: Short-lived.

Frank Worden, MD: Yes, exactly. I’ll be honest, I didn’t really use a lot of Adriamycin in my career. There were some other cytotoxic chemotherapy agents, and I know Marten will talk about sometimes. He does use them, like gemcitabine, for example. We gave that in combination with docetaxel. But then came the targeted therapies, and so those became more en vogue for things like gastrointestinal stromal tumors (GISTs) and the renal cell carcinomas. I think once people were kind of realizing that these cancers were very similar to thyroid cancer, there was exploration looking at these oncoproteins—VEGF, and RET, and MAP, any of those other targets—that are linked to the aberrant tyrosine kinase. And so, with that, we have these drugs now that inhibit tyrosine kinase and VEGF, the angiogenesis that provide actually a sustained and durable response to treatment. That’s kind of where we’ve come from and where we’re at today.

R. Michael Tuttle, MD: So, now the difficult part is we’ve got a couple of FDA-approved drugs. When do I watch and when do I start? Eric, help me. Don’t give me theoretical. I want to know when do I really think about starting somebody on one of these drugs or when do I definitely not? How do you sort them out when you see these guys in clinic?

Eric Sherman, MD: I think that the criteria that was put in the clinical studies for when patients should be put on this is not the time to start. So, the idea that tumor progression over 14 months—well, I think there has to be something that was in these clinical studies—for a lot of the patients it’s too early. I think it’s difficult to figure out exactly when the right time is, and I think it depends on a lot of different factors. Symptoms is an easy one. If they’re symptomatic, you start, in general.

R. Michael Tuttle, MD: What kind of symptoms do they have? Because you guys always talk about symptoms. We never see symptoms in our thyroid cancer patients. What kind of symptoms do they have?

Eric Sherman, MD: It depends on the location. Most often, it’s breathing problems if it’s in the lung, or if it’s right in the Hilar lymph node or mediastinal lymph node area. In bones, there’s going to be pain. Now, some of those you can just radiate. So, sometimes if you can do a local treatment to take care of the problem. It does make more sense.

R. Michael Tuttle, MD: But if they have the symptoms that local treatment can’t do, that would be an indication.

Eric Sherman, MD: Then it’s an indication to go ahead and do something. And a lot of times when they’re not symptomatic, it’s location that’s going to make a difference. So, if you have someone that has a peripheral nodule that’s growing, that’s doubling size in a year from 1 cm to 2 cm, I’m not going to be that worried about it. While, if you’ve got a paratracheal node or a paraesophageal lymph node nodule that’s growing even 20% in a year, that’s going to worry me more when that can’t radiate or was already radiated, and starting to grow in that area.

R. Michael Tuttle, MD: Its structure, its rate of change, its local. How do you decide, Frank?

Frank Worden, MD: I heard Marten talk about this once and Marcia at an advisory board. It was really interesting about making a box, and those people who have large burden of disease that’s progressing very quickly, those are the automatic kind of kneejerk you treat. And those on the flip side that are, like Eric said, you have 1 or 2 nodules that are really just not changing much. It’s the disease that’s more smoldering. You just continue to observe them and maybe even with yearly scans at that point. It’s the people who are kind of in the middle, the large tumor that may not be growing very quickly, but then you may want to treat depending on the location, or if it’s previously treated with radiation, for example. And the same thing, those small disease burden that really isn’t changing that much, more like the miliary disease. That’s why we have these lengthy discussions and meaningful discussions with patients. So, often times, we move CT scans up. There’s some new preliminary data, which informs the oncologist about doubling time with thyroglobulin, like we use in medullary thyroid cancer, to follow those more closely. Those are the people I see back more regularly. And when I’m ready to start treatment, we’ll sit down and say, ‘Okay, look, you were really asymptomatic here, now you’re a little bit more short of breath when you’re walking up the steps. I think it’s time for treatment.’

R. Michael Tuttle, MD: Marcia, same sort of ball park there in terms of when you start.

Marcia S. Brose, MD, PhD: I have a little bit of a different approach. So, I think all of the things that are said are probably where I come out, but the one thing I always like to point out is we actually have data. It seems like a lot of people like to just really say, ‘Oh, I feel this way or I feel that way.’ And Eric pointed out that if you do apply the eligibility criteria that were used in either the SELECT or DECISION study, some patients will not necessarily need to be tested. But let’s talk about the numbers. The numbers say that if you look at the placebo arms for both of those, even using 14 months for progression as a criteria, we know that people tend to progress a little bit quicker, and quicker, and quicker. If you use progressive disease—RAI refractory disease as your criteria—on average, your patients will now have progression-free survival in the three-and-a-half to five-and-a-half months. That’s a pretty aggressive disease.

Now, that’s true that in both of those trials there’s a tail and there’s 10%. But we’re talking 10% of the patients, not 90%. So 90% of the patients, that’s a pretty good criteria. What that says to me, is it absolute? No. But, now, in order to not act on that criteria, I have to have a reason. What are the reasons? Well, the reason might be that it’s a solitary nodule, it’s one peripheral spot. Those patients can be often observed for a very long time because, as Eric said, it’s a peripheral spot. It’s not going to hurt them for a long time. So, I try to figure out who were those 10%, but I think that lots of times people argue that 90% of the people have those 10% characteristics. I just think that’s not true, and I think we have to remember we do have data, that those criteria have given us data, and now you have to have a reason why it is that you feel that that patient is going to be in that 10%. But I find that people many times will take 90% of the patients and say that they would be those 10%. We have to be a little bit cautious about not following the data.

Transcript Edited for Clarity
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