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Dosing and Side Effect Management in Metastatic CRC

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Cathy Eng, MD, FACP, The University of Texas MD Anderson Cancer Center; John L. Marshall, MD, The Ruesch Center for the Cure of GI Cancers ; Michael A. Morse, MD, Duke Cancer Institute; Dale R. Shepard, MD, PhD, FACP, Taussig Cancer Institute, Cleveland Clinic
Published: Thursday, Apr 26, 2018



Transcript: 

John L. Marshall, MD: What’s the right dose of regorafenib?

Johanna C. Bendell, MD: According to data that looks at dosing regorafenib the regular way—160 mg, right from the start.

John L. Marshall, MD: Four pills? Three weeks on? One week off?

Johanna C. Bendell, MD: Or, do a rapid acceleration titration. So, you start at 80 mg, weekly.

John L. Marshall, MD: Two pills?

Johanna C. Bendell, MD: Two pills, and then weekly bumps, as tolerated. From the study, it looks like most people come out at about a 120-mg tolerated dose. But, very interestingly, the purpose and the main endpoint of the study was to see how many people got to the next cycle. And, certainly, we see that more people get to the next cycle with the titration. It also seems to be that people who did the titration live longer, too. And so, that might be a better way to give regorafenib, versus full on.

John L. Marshall, MD: This is a big deal, right? We’ve been frustrated with the current standard dosing. This gives us the option to do what we’ve been doing anyway. Is that fair?

Cathy Eng, MD, FACP: That’s very fair. I’ve always been starting at 120 mg, and maybe lowering it to 80 mg, as needed. But I mostly give 120 mg.

John L. Marshall, MD: On first- and second-line treatment, we were seeing patients maybe every 2 weeks. We were seeing some people every 4 weeks. Now you’re telling me that I’ve got to see them every week?

Johanna C. Bendell, MD: With regorafenib, I tend to do that, unless I have a completely reliable patient that’s going to call me if there’s an issue. The worst thing that you can do with regorafenib is let the toxicities get too bad. When they happen, they happen quickly. They go from 0 to 60 pretty fast. And so, you want to catch them before they get there, so you can stop that toxicity.

John L. Marshall, MD: Yes. When they stopped going to the infusion unit, I thought that was going to be good. I thought that was going to be like a break. But, in fact, they love the infusion unit. There’s Ativan there, and stuff.

Dale R. Shepard, MD, PhD, FACP: I love that because I get to see them. Otherwise, patients may not call with significant problems. It’s a population. Sometimes, they’re like, “Oh, we don’t want to bother you.” But, they can’t walk because of the rash.

John L. Marshall, MD: In most of our experiences, is it true that after you’ve got them on a dose, you don’t need to see them quite as often?

Johanna C. Bendell, MD: Yes. Once you get them on a dose, usually the first 4 weeks, or so.

John L. Marshall, MD: How often are you seeing them? Weekly?

Michael A. Morse, MD: If they will come in.

Cathy Eng, MD, FACP: We do every 2 weeks, at our place. Then, we’ll move to every month, depending on how they’re doing.

John L. Marshall, MD: It depends on how they’re doing. Let’s talk about trifluridine/tipiracil (TAS-102). These are the 2 drugs. They’re very similar in benefit. You talked a little bit about choosing between them.

Dale R. Shepard, MD, PhD, FACP: Just around the fatigue thing, just to follow up with the regorafenib issue, I think another thing to discuss is the fact that the toxicity profile is much, much different. They’re taking a daily pill for 3 weeks. Often, they’ve come off of intravenous therapies. They feel OK. A couple of days later, they feel a little punky. This may last for 2 or 3 days. Then, they get better. They may not have the profound fatigue, but it’s every day. So, we need to make sure that everybody is onboard with the fact that this has a totally different toxicity profile.

Michael A. Morse, MD: I feel a little bit more comfortable giving it to people, partly because the main side effect is neutropenia, and it’s rarely that severe. And, even if people develop it, they usually rebound. If you give them an extra week—beyond the 2 weeks— if they haven’t rebounded, they often will. In that scenario, people are also accustomed to that. They’ve gotten chemotherapy before, so they know what the drill is, in terms of getting their labs. They may not be able to start for another week, but they’re OK with that. It’s something that most patients, I think, take to a lot easier, compared with a side effect profile that’s very different—unless they’ve had capecitabine and have experienced what hand-foot syndrome is. But, in general, it’s a known quantity to them.

John L. Marshall, MD: Johanna, TAS-102—full dose? Two pill sizes? The whole thing?

Johanna C. Bendell, MD: Yes, I’ll go with the full dose. I try to train them to do Monday through Friday, because it’s a little easier to remember that. Then, we’ve certainly seen that the neutropenia might actually be correlated with response to therapy.

John L. Marshall, MD: So, maintaining the treatment?

Johanna C. Bendell, MD: Don’t treat to neutropenia. But, if you’ve got it, you might feel a little better.

John L. Marshall, MD: Week on, week off?

Cathy Eng, MD, FACP: I have done that.

John L. Marshall, MD: Yes? Who’s guilty of this?

Michael A. Morse, MD: No.

John L. Marshall, MD: Really?

Dale R. Shepard, MD, PhD, FACP: I have not.

Cathy Eng, MD, FACP: I’ve done it, and have had less issues with the blood counts. It’s tolerated extremely well. It is still very effective.

John L. Marshall, MD: I realize that’s kind of off-label, but, in the end, they end up with the same amount. The question is, does it matter? I don’t know what the right answer is. We fiddle with all these things, right?

Cathy Eng, MD, FACP: I’ve talked to them about it before, and they’re not opposed to it.

John L. Marshall, MD: Do you give VEGF beyond progression, if you use TAS-102? You just told me that it was the right thing to do.

Cathy Eng, MD, FACP: That is tricky.

John L. Marshall, MD: Should I keep a little bevacizumab going in with my TAS-102?

Michael A. Morse, MD: It’s being studied. I think you’ll want to see what the results are.

John L. Marshall, MD: Is there any right order, if you are MSI-high, between checkpoint inhibitors, TAS-102, and regorafenib? Do you have a bias, if you were MSI-high?

Michael A. Morse, MD: An interesting abstract attempted to look at the financial implications of it. And, not surprisingly, it’s actually very expensive to go with a checkpoint blockade, even though it is really more efficacious. Interestingly, it’s so much more expensive to give the checkpoint blockade.

Transcript Edited for Clarity 

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Transcript: 

John L. Marshall, MD: What’s the right dose of regorafenib?

Johanna C. Bendell, MD: According to data that looks at dosing regorafenib the regular way—160 mg, right from the start.

John L. Marshall, MD: Four pills? Three weeks on? One week off?

Johanna C. Bendell, MD: Or, do a rapid acceleration titration. So, you start at 80 mg, weekly.

John L. Marshall, MD: Two pills?

Johanna C. Bendell, MD: Two pills, and then weekly bumps, as tolerated. From the study, it looks like most people come out at about a 120-mg tolerated dose. But, very interestingly, the purpose and the main endpoint of the study was to see how many people got to the next cycle. And, certainly, we see that more people get to the next cycle with the titration. It also seems to be that people who did the titration live longer, too. And so, that might be a better way to give regorafenib, versus full on.

John L. Marshall, MD: This is a big deal, right? We’ve been frustrated with the current standard dosing. This gives us the option to do what we’ve been doing anyway. Is that fair?

Cathy Eng, MD, FACP: That’s very fair. I’ve always been starting at 120 mg, and maybe lowering it to 80 mg, as needed. But I mostly give 120 mg.

John L. Marshall, MD: On first- and second-line treatment, we were seeing patients maybe every 2 weeks. We were seeing some people every 4 weeks. Now you’re telling me that I’ve got to see them every week?

Johanna C. Bendell, MD: With regorafenib, I tend to do that, unless I have a completely reliable patient that’s going to call me if there’s an issue. The worst thing that you can do with regorafenib is let the toxicities get too bad. When they happen, they happen quickly. They go from 0 to 60 pretty fast. And so, you want to catch them before they get there, so you can stop that toxicity.

John L. Marshall, MD: Yes. When they stopped going to the infusion unit, I thought that was going to be good. I thought that was going to be like a break. But, in fact, they love the infusion unit. There’s Ativan there, and stuff.

Dale R. Shepard, MD, PhD, FACP: I love that because I get to see them. Otherwise, patients may not call with significant problems. It’s a population. Sometimes, they’re like, “Oh, we don’t want to bother you.” But, they can’t walk because of the rash.

John L. Marshall, MD: In most of our experiences, is it true that after you’ve got them on a dose, you don’t need to see them quite as often?

Johanna C. Bendell, MD: Yes. Once you get them on a dose, usually the first 4 weeks, or so.

John L. Marshall, MD: How often are you seeing them? Weekly?

Michael A. Morse, MD: If they will come in.

Cathy Eng, MD, FACP: We do every 2 weeks, at our place. Then, we’ll move to every month, depending on how they’re doing.

John L. Marshall, MD: It depends on how they’re doing. Let’s talk about trifluridine/tipiracil (TAS-102). These are the 2 drugs. They’re very similar in benefit. You talked a little bit about choosing between them.

Dale R. Shepard, MD, PhD, FACP: Just around the fatigue thing, just to follow up with the regorafenib issue, I think another thing to discuss is the fact that the toxicity profile is much, much different. They’re taking a daily pill for 3 weeks. Often, they’ve come off of intravenous therapies. They feel OK. A couple of days later, they feel a little punky. This may last for 2 or 3 days. Then, they get better. They may not have the profound fatigue, but it’s every day. So, we need to make sure that everybody is onboard with the fact that this has a totally different toxicity profile.

Michael A. Morse, MD: I feel a little bit more comfortable giving it to people, partly because the main side effect is neutropenia, and it’s rarely that severe. And, even if people develop it, they usually rebound. If you give them an extra week—beyond the 2 weeks— if they haven’t rebounded, they often will. In that scenario, people are also accustomed to that. They’ve gotten chemotherapy before, so they know what the drill is, in terms of getting their labs. They may not be able to start for another week, but they’re OK with that. It’s something that most patients, I think, take to a lot easier, compared with a side effect profile that’s very different—unless they’ve had capecitabine and have experienced what hand-foot syndrome is. But, in general, it’s a known quantity to them.

John L. Marshall, MD: Johanna, TAS-102—full dose? Two pill sizes? The whole thing?

Johanna C. Bendell, MD: Yes, I’ll go with the full dose. I try to train them to do Monday through Friday, because it’s a little easier to remember that. Then, we’ve certainly seen that the neutropenia might actually be correlated with response to therapy.

John L. Marshall, MD: So, maintaining the treatment?

Johanna C. Bendell, MD: Don’t treat to neutropenia. But, if you’ve got it, you might feel a little better.

John L. Marshall, MD: Week on, week off?

Cathy Eng, MD, FACP: I have done that.

John L. Marshall, MD: Yes? Who’s guilty of this?

Michael A. Morse, MD: No.

John L. Marshall, MD: Really?

Dale R. Shepard, MD, PhD, FACP: I have not.

Cathy Eng, MD, FACP: I’ve done it, and have had less issues with the blood counts. It’s tolerated extremely well. It is still very effective.

John L. Marshall, MD: I realize that’s kind of off-label, but, in the end, they end up with the same amount. The question is, does it matter? I don’t know what the right answer is. We fiddle with all these things, right?

Cathy Eng, MD, FACP: I’ve talked to them about it before, and they’re not opposed to it.

John L. Marshall, MD: Do you give VEGF beyond progression, if you use TAS-102? You just told me that it was the right thing to do.

Cathy Eng, MD, FACP: That is tricky.

John L. Marshall, MD: Should I keep a little bevacizumab going in with my TAS-102?

Michael A. Morse, MD: It’s being studied. I think you’ll want to see what the results are.

John L. Marshall, MD: Is there any right order, if you are MSI-high, between checkpoint inhibitors, TAS-102, and regorafenib? Do you have a bias, if you were MSI-high?

Michael A. Morse, MD: An interesting abstract attempted to look at the financial implications of it. And, not surprisingly, it’s actually very expensive to go with a checkpoint blockade, even though it is really more efficacious. Interestingly, it’s so much more expensive to give the checkpoint blockade.

Transcript Edited for Clarity 
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