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IDEA Collaboration; Impact on Adjuvant Therapy

Panelists: John Marshall, MD, Georgetown University; Cathy Eng, MD, Vanderbilt University; Tanios Bekaii-Saab, MD, Mayo Clinic; Dustin Deming, MD, University of Wisconsin; Michael Morse, MD, Duke Cancer Institute
Published: Tuesday, Jul 16, 2019



Transcript: 

John Marshall, MD: I see a lot of nodding going on. Are we comfortable there? Dustin, what’s your strategy on this?

Dustin Deming, MD: My strategy is actually a little bit different.

John Marshall, MD: Good.

Dustin Deming, MD: I am not convinced about the superiority of CAPOX [capecitabine/oxaliplatin] over FOLFOX [folinic acid/fluorouracil/oxaliplatin]. The nonrandomization really bothers me in interpreting this data this way. When you think about, if you are a primary folinic acid/fluorouracil/oxaliplatin prescriber and you’re now switching to capecitabine/oxaliplatin for a particular patient, it’s probably going to be the more active patient who wants to come less frequently, etcetera, and probably a better performance status patient. If you are a capecitabine/oxaliplatin person and you’re switching a quarter of your patients to folinic acid/fluorouracil/oxaliplatin, there’s got to be some reason why you did that. I worry that it’s because folinic acid/fluorouracil/oxaliplatin is better tolerated and those patients have a worse performance status. When we look at the presentations that have been made related to the IDEA collaboration, they’re not diving into that particular data. It’s not being presented—the performance status,[folinic acid/fluorouracil/oxaliplatin versus capecitabine/oxaliplatin, etcetera, and a lot of the comorbidities that these patients have. I actually am not a proponent for capecitabine/oxaliplatin in this setting. I give folinic acid/fluorouracil/oxaliplatin really well. I have a lot of experience with folinic acid/fluorouracil/oxaliplatin, so I stick with folinic acid/fluorouracil/oxaliplatin.

John Marshall, MD: Have you ever taken a pump home and tied it around your neck for 46 hours? It’s not easy.

Dustin Deming, MD: Well, the answer is yes, I have.

John Marshall, MD: You have?

Dustin Deming, MD: I actually had stage III rectal cancer.

John Marshall, MD: Ahh, so you have. You’re the first person ever like, “Psych! Yes, I have.” How is it? Did it upset your cat or anything? I keep worrying about the pets at home when you bring the pump home.

Dustin Deming, MD: I don’t have a cat so that wasn’t an issue. It didn’t bother my dog, either. Yes, it is inconvenient to bring a pump home. That’s a reality of the folinic acid/fluorouracil/oxaliplatin regimen, but it’s also concerning to me, when you’re having a patient take a couple weeks of chemotherapy pills, whether or not they’re going to take all those pills.

John Marshall, MD: Comply with it.

Dustin Deming, MD: At least with the folinic acid/fluorouracil/oxaliplatin regimen, if it’s gone in through the IV [intravenous infusion], I know they’ve had it. A lot of the patients who didn’t receive adjuvant therapy the way that I would have wanted them to have were patients who were receiving capecitabine, usually when I was doing it, it was as a monotherapy.

John Marshall, MD: Great additional perspective. Yes, Tony?

Tanios Bekaii-Saab, MD: Let me put a point on this. I don’t disagree. The capecitabine/oxaliplatin data are very clear, although there are limitations. Those curves sit on top of each other and there may be different reasons why. Perhaps it’s how you select your patients, but then that’s how you need to select your patients. You can’t discount capecitabine/oxaliplatin as, perhaps, a better fit for some patients. Now, that said, I don’t disagree on that with the higher-risk patients. With the lower-risk patients, I don’t believe we need more than 3 months. With the high-risk patients, I think it’s fair to consider 6 months. However, I don’t believe that there’s much benefit from an additional 3 months of oxaliplatin, for a lot of reasons.

First of all, when we look at the clinical relevance of the data, not the statistical piece that gets quite complicated, you’re really still measuring disease-free survival. Yes, it does correlate with overall survival, but you lose about half of the benefit when it translates into survival. That 1 patient out of 100 that you may be hurting in the disease-free survival—essentially, cut that by half when you get to the survival. You talk about close, but 1 in 1000 patients, perhaps, may be harmed by the 3 versus 6.

Now, when you look historically at the primary driver of benefit in colon cancer, it’s surgery at 50%. The other 15% that you add comes from fluoropyrimidines. Then you can argue that the data with CAPE [capecitabine] versus 5-FU [fluorouracil] gave a little edge to capecitabine, but again, that was barely significant, or not significant statistically, at least. Then, oxaliplatin adds about 3% to 4% on the survival, and a little bit more on the disease-free survival. Then you look at the grade 3 and 4 toxicity with your 6 months of oxaliplatin, and it’s about a 3% to 4% of grade 3 to 4 toxicity, which is horrendous, frankly. It washes out. I think a missing arm there was 3 months of capecitabine/oxaliplatin or folinic acid/fluorouracil/oxaliplatin, followed by 3 months of 5-FU or capecitabine.

John Marshall, MD: In some way, that arm was there, because a lot of people stopped their OX [oxaliplatin], right? That really is the arm.

Tanios Bekaii-Saab, MD: It wasn’t the intent.

John Marshall, MD: It wasn’t the intent, yes.

Cathy Eng, MD: That wasn’t the original study design, but I do want to make sure people understand that although capecitabine/oxaliplatin can be considered for your low-risk patient population for the 3 months, you still have to select the correct patients to provide capecitabine to. You need patients with good creatinine clearance. I don’t want people to be persuaded that all patients should go ahead and receive capecitabine. Also, I agree that we do have to follow up in regard to adherence. Not everyone is a perfect patient for capecitabine.

John Marshall, MD: Mike, I want to close this part of our discussion with a shift to patient selection. In metastatic disease, we’re increasingly doing molecular profiling. We have these new CMS [Centers for Medicare & Medicaid Services] criteria for how to characterize the different cancers in the colon. We did see one abstract, which may or may not be that valuable to us today. Do you see a time when we’re actually doing a better job of stratifying patients and not treating all of them the same?

Michael Morse, MD: Well, I think we already know that, and we didn’t talk much about expression profiling, choosing patients based on that information or circulating DNA, and so on. Circulating DNA metrics for who may have disease and who may not, are coming in the future, but right now, the reality is that other than MSI [microsatellite instability]—and really, for MSI, stage II is where the decision comes—we’re really not using that other information right now.

John Marshall, MD: I hope for it, because with all this discussion about a percent here, a percent there around 3 versus 6, we’re still leaving 25% of the patients who are going to relapse and die. We’re over-treating a very high proportion of patients who are cured by the surgery. Figuring this out, to me, is maybe the highest priority, and I’m hoping we move in that direction.

Transcript Edited for Clarity

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Transcript: 

John Marshall, MD: I see a lot of nodding going on. Are we comfortable there? Dustin, what’s your strategy on this?

Dustin Deming, MD: My strategy is actually a little bit different.

John Marshall, MD: Good.

Dustin Deming, MD: I am not convinced about the superiority of CAPOX [capecitabine/oxaliplatin] over FOLFOX [folinic acid/fluorouracil/oxaliplatin]. The nonrandomization really bothers me in interpreting this data this way. When you think about, if you are a primary folinic acid/fluorouracil/oxaliplatin prescriber and you’re now switching to capecitabine/oxaliplatin for a particular patient, it’s probably going to be the more active patient who wants to come less frequently, etcetera, and probably a better performance status patient. If you are a capecitabine/oxaliplatin person and you’re switching a quarter of your patients to folinic acid/fluorouracil/oxaliplatin, there’s got to be some reason why you did that. I worry that it’s because folinic acid/fluorouracil/oxaliplatin is better tolerated and those patients have a worse performance status. When we look at the presentations that have been made related to the IDEA collaboration, they’re not diving into that particular data. It’s not being presented—the performance status,[folinic acid/fluorouracil/oxaliplatin versus capecitabine/oxaliplatin, etcetera, and a lot of the comorbidities that these patients have. I actually am not a proponent for capecitabine/oxaliplatin in this setting. I give folinic acid/fluorouracil/oxaliplatin really well. I have a lot of experience with folinic acid/fluorouracil/oxaliplatin, so I stick with folinic acid/fluorouracil/oxaliplatin.

John Marshall, MD: Have you ever taken a pump home and tied it around your neck for 46 hours? It’s not easy.

Dustin Deming, MD: Well, the answer is yes, I have.

John Marshall, MD: You have?

Dustin Deming, MD: I actually had stage III rectal cancer.

John Marshall, MD: Ahh, so you have. You’re the first person ever like, “Psych! Yes, I have.” How is it? Did it upset your cat or anything? I keep worrying about the pets at home when you bring the pump home.

Dustin Deming, MD: I don’t have a cat so that wasn’t an issue. It didn’t bother my dog, either. Yes, it is inconvenient to bring a pump home. That’s a reality of the folinic acid/fluorouracil/oxaliplatin regimen, but it’s also concerning to me, when you’re having a patient take a couple weeks of chemotherapy pills, whether or not they’re going to take all those pills.

John Marshall, MD: Comply with it.

Dustin Deming, MD: At least with the folinic acid/fluorouracil/oxaliplatin regimen, if it’s gone in through the IV [intravenous infusion], I know they’ve had it. A lot of the patients who didn’t receive adjuvant therapy the way that I would have wanted them to have were patients who were receiving capecitabine, usually when I was doing it, it was as a monotherapy.

John Marshall, MD: Great additional perspective. Yes, Tony?

Tanios Bekaii-Saab, MD: Let me put a point on this. I don’t disagree. The capecitabine/oxaliplatin data are very clear, although there are limitations. Those curves sit on top of each other and there may be different reasons why. Perhaps it’s how you select your patients, but then that’s how you need to select your patients. You can’t discount capecitabine/oxaliplatin as, perhaps, a better fit for some patients. Now, that said, I don’t disagree on that with the higher-risk patients. With the lower-risk patients, I don’t believe we need more than 3 months. With the high-risk patients, I think it’s fair to consider 6 months. However, I don’t believe that there’s much benefit from an additional 3 months of oxaliplatin, for a lot of reasons.

First of all, when we look at the clinical relevance of the data, not the statistical piece that gets quite complicated, you’re really still measuring disease-free survival. Yes, it does correlate with overall survival, but you lose about half of the benefit when it translates into survival. That 1 patient out of 100 that you may be hurting in the disease-free survival—essentially, cut that by half when you get to the survival. You talk about close, but 1 in 1000 patients, perhaps, may be harmed by the 3 versus 6.

Now, when you look historically at the primary driver of benefit in colon cancer, it’s surgery at 50%. The other 15% that you add comes from fluoropyrimidines. Then you can argue that the data with CAPE [capecitabine] versus 5-FU [fluorouracil] gave a little edge to capecitabine, but again, that was barely significant, or not significant statistically, at least. Then, oxaliplatin adds about 3% to 4% on the survival, and a little bit more on the disease-free survival. Then you look at the grade 3 and 4 toxicity with your 6 months of oxaliplatin, and it’s about a 3% to 4% of grade 3 to 4 toxicity, which is horrendous, frankly. It washes out. I think a missing arm there was 3 months of capecitabine/oxaliplatin or folinic acid/fluorouracil/oxaliplatin, followed by 3 months of 5-FU or capecitabine.

John Marshall, MD: In some way, that arm was there, because a lot of people stopped their OX [oxaliplatin], right? That really is the arm.

Tanios Bekaii-Saab, MD: It wasn’t the intent.

John Marshall, MD: It wasn’t the intent, yes.

Cathy Eng, MD: That wasn’t the original study design, but I do want to make sure people understand that although capecitabine/oxaliplatin can be considered for your low-risk patient population for the 3 months, you still have to select the correct patients to provide capecitabine to. You need patients with good creatinine clearance. I don’t want people to be persuaded that all patients should go ahead and receive capecitabine. Also, I agree that we do have to follow up in regard to adherence. Not everyone is a perfect patient for capecitabine.

John Marshall, MD: Mike, I want to close this part of our discussion with a shift to patient selection. In metastatic disease, we’re increasingly doing molecular profiling. We have these new CMS [Centers for Medicare & Medicaid Services] criteria for how to characterize the different cancers in the colon. We did see one abstract, which may or may not be that valuable to us today. Do you see a time when we’re actually doing a better job of stratifying patients and not treating all of them the same?

Michael Morse, MD: Well, I think we already know that, and we didn’t talk much about expression profiling, choosing patients based on that information or circulating DNA, and so on. Circulating DNA metrics for who may have disease and who may not, are coming in the future, but right now, the reality is that other than MSI [microsatellite instability]—and really, for MSI, stage II is where the decision comes—we’re really not using that other information right now.

John Marshall, MD: I hope for it, because with all this discussion about a percent here, a percent there around 3 versus 6, we’re still leaving 25% of the patients who are going to relapse and die. We’re over-treating a very high proportion of patients who are cured by the surgery. Figuring this out, to me, is maybe the highest priority, and I’m hoping we move in that direction.

Transcript Edited for Clarity
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