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FOLFOX versus FOLFIRI in the MAVERICC Trial in CRC

Panelists:Tanios Bekaii-Saab, MD, Ohio State University – James Cancer Hospital; Johanna Bendell, MD, Sarah Cannon Research Institute; Charles S. Fuchs, MD, Dana-Farber Cancer Institute; Richard Kim, MD, Moffitt Cancer Center; John L. Marshall, MD, Georgetown University Hospital
Published: Monday, Apr 04, 2016


Transcript:

John L. Marshall, MD:
We have some more evidence at this meeting, and we happen to be blessed today with the lead author of some of the studies that are being presented here at the meeting, looking at optimum frontline choices. And I’ll let Johanna describe those studies and walk us through them. But they also bring into play what I always like to call the kitchen sink versus the bathroom sink of a three-drug regimen of FOLFIRINOX, oxaliplatin, irinotecan regimen. So take it away. Tell us about these studies and how you interpret their impact on our practice today.

Johanna Bendell, MD: So, there are two big studies looking at chemotherapy backbones, and I’m going to go to the MAVERICC study first because this is just what we’ve been talking about: oxaliplatin versus irinotecan. Which do you pick? This is a study that looked at FOLFOX plus bevacizumab, plus FOLFIRI plus bevacizumab. It’s almost a 400-patient study. The primary endpoint is progression-free survival. And very interestingly, what they’re reporting out is the progression-free survival in the irinotecan-treated patient seems to be longer than the oxaliplatin-treated patients.

Tony’s over there saying, ‘Yeah, I told you so.’ And when you look at the survival data, it seems to be bordering a little bit more impressive towards the FOLFIRI side. Now, what happened? When you look at the intensity of the dosing of the regimens, you can see very clearly that the folks who got oxaliplatin got six less cycles of chemotherapy with oxaliplatin than the irinotecan. So this is also alluding to Tony’s point of the issue where toxicity plays a part in how people do and what their choices are, and when you drop a treatment versus not drop a treatment.

John L. Marshall, MD: In that study, does anybody remember, was there a forced maintenance or you could do whatever you wanted it?

Johanna Bendell, MD: And so that’s the rub, is that if you had a forced maintenance, would you see something a little bit different? I also think with the maintenance approaches, it really points out that very often with the oxaliplatin-based therapies, nobody goes back to the oxaliplatin again or until much later. And so, how does that play a role? And do we really need to squeeze the juice totally out of the lemon to say that they got all that therapy? So, I think the MAVERICC study is saying, is FOLFIRI something that we should be considering as first-line because people stay on it longer and are able to get that dosing that will take them until progression?

John L. Marshall, MD: Go ahead, Charlie.

Charles S. Fuchs, MD, MPH: I think this is really interesting, because several of us remember a decade ago when this debate was going on: which chemotherapy is a better partner for biologics? And a bunch of us were involved in the BICC-C study when there were a variety of studies going on. And, at that time, FOLFIRI and bevacizumab offered the longest survival of any of the combinations across trials. I think many people ignored that. But it’s interesting to hear that in a head-to-head comparison, maybe it is better.

Tanios Bekaii-Saab, MD: I did not ignore it. I would agree. And actually, if you look at CALGB 80405, although there were somewhat different patient populations—and, again, not that there were these comparisons between the FOLFIRI and FOLFOX group—but that is very consistent with Johanna’s study and with the BICC-C. You continued to see that slight trend. And, again, it’s not a four- or five-month difference. It’s a small, but I think meaningful, difference for those patients who have metastatic colorectal cancer.

John L. Marshall, MD: I just want to interpret this as, if you keep your foot on the pedal longer, you have better, longer control. But I could also imagine you get a tired patient, a little bit more bone marrow, all those things. But you then say, OS looks a little better, too, which means they’re getting subsequent lines of therapy. So they’re okay to do this.

Tanios Bekaii-Saab, MD: Just remember, with FOLFOX, it’s not just the lingering neurotoxicity that can limit, sometimes, access to second-line. It’s also, in 5% of the patients, grade 3-plus thrombocytopenia because of hypersplenism, which also limits access to other trials or other intense regimens. So there are certain nuances of the long-term therapy that may affect not just the progression-free, but the overall survival as well.

John L. Marshall, MD: Very good. Well, let’s go to the second study. Kitchen versus bathroom sink. We have two different sinks.

Johanna Bendell, MD: What this did was play off the TRIBE study. So the TRIBE study, it was an Italian study that looked at FOLFOXIRI. Now, this is not FOLFIRINOX, right, because we’re used to giving FOLFIRINOX for pancreatic cancer patients now. But FOLFOXIRI, it’s a different regimen where you use a little higher dose of the infusional 5-FU, a little lower dose of the irinotecan. So this was FOLFOXIRI plus bevacizumab.

John L. Marshall, MD: Do you think that matters?

Johanna Bendell, MD: I don’t know.

John L. Marshall, MD: You think it matters what recipe you use in the soup?

Charles S. Fuchs, MD, MPH: The lower dose of irinotecan, it makes it easier.

John L. Marshall, MD: Whichever recipe, I always come down to 150 mg/m2. It is what I’ll tend to start with.

Charles S. Fuchs, MD, MPH: And sometimes 120 mg/m2.

John L. Marshall, MD: What do you do?

Johanna Bendell, MD: I actually give full dose FOLFOXIRI but not FOLFIRINOX.

John L. Marshall, MD: I see. Richard?

Richard Kim, MD: Same thing. I dose irinotecan at 150 mg/m2.

John L. Marshall, MD: Bolus 5-FU, anybody?

Richard Kim, MD: No.

John L. Marshall, MD: Dropped? Dropped?

Tanios Bekaii-Saab, MD: No.

Charles S. Fuchs, MD, MPH: I delete it.

Johanna Bendell, MD: No, it’s not in FOLFOXIRI.

John L. Marshall, MD: Right. And not there in the first place.

Johanna Bendell, MD: And I don’t do it in FOLFOX.

Richard Kim, MD: I take it out.

John L. Marshall, MD: And drop it. So we’re all modifying that comfortable regimen.

Tanios Bekaii-Saab, MD: And the leucovorin.

John L. Marshall, MD: You drop your leucovorin.

Tanios Bekaii-Saab, MD: If I’m going to give bolus 5-FU, I wouldn’t give leucovorin.

John L. Marshall, MD: A debated point?

Charles S. Fuchs, MD, MPH: I still give leucovorin.

John L. Marshall, MD: I do, too.

Tanios Bekaii-Saab, MD: Infusional 5-FU that goes over two days, and you’re giving leucovorin just for a fraction of the time, is really questionable. But, really, it’s not wrong to give it.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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Transcript:

John L. Marshall, MD:
We have some more evidence at this meeting, and we happen to be blessed today with the lead author of some of the studies that are being presented here at the meeting, looking at optimum frontline choices. And I’ll let Johanna describe those studies and walk us through them. But they also bring into play what I always like to call the kitchen sink versus the bathroom sink of a three-drug regimen of FOLFIRINOX, oxaliplatin, irinotecan regimen. So take it away. Tell us about these studies and how you interpret their impact on our practice today.

Johanna Bendell, MD: So, there are two big studies looking at chemotherapy backbones, and I’m going to go to the MAVERICC study first because this is just what we’ve been talking about: oxaliplatin versus irinotecan. Which do you pick? This is a study that looked at FOLFOX plus bevacizumab, plus FOLFIRI plus bevacizumab. It’s almost a 400-patient study. The primary endpoint is progression-free survival. And very interestingly, what they’re reporting out is the progression-free survival in the irinotecan-treated patient seems to be longer than the oxaliplatin-treated patients.

Tony’s over there saying, ‘Yeah, I told you so.’ And when you look at the survival data, it seems to be bordering a little bit more impressive towards the FOLFIRI side. Now, what happened? When you look at the intensity of the dosing of the regimens, you can see very clearly that the folks who got oxaliplatin got six less cycles of chemotherapy with oxaliplatin than the irinotecan. So this is also alluding to Tony’s point of the issue where toxicity plays a part in how people do and what their choices are, and when you drop a treatment versus not drop a treatment.

John L. Marshall, MD: In that study, does anybody remember, was there a forced maintenance or you could do whatever you wanted it?

Johanna Bendell, MD: And so that’s the rub, is that if you had a forced maintenance, would you see something a little bit different? I also think with the maintenance approaches, it really points out that very often with the oxaliplatin-based therapies, nobody goes back to the oxaliplatin again or until much later. And so, how does that play a role? And do we really need to squeeze the juice totally out of the lemon to say that they got all that therapy? So, I think the MAVERICC study is saying, is FOLFIRI something that we should be considering as first-line because people stay on it longer and are able to get that dosing that will take them until progression?

John L. Marshall, MD: Go ahead, Charlie.

Charles S. Fuchs, MD, MPH: I think this is really interesting, because several of us remember a decade ago when this debate was going on: which chemotherapy is a better partner for biologics? And a bunch of us were involved in the BICC-C study when there were a variety of studies going on. And, at that time, FOLFIRI and bevacizumab offered the longest survival of any of the combinations across trials. I think many people ignored that. But it’s interesting to hear that in a head-to-head comparison, maybe it is better.

Tanios Bekaii-Saab, MD: I did not ignore it. I would agree. And actually, if you look at CALGB 80405, although there were somewhat different patient populations—and, again, not that there were these comparisons between the FOLFIRI and FOLFOX group—but that is very consistent with Johanna’s study and with the BICC-C. You continued to see that slight trend. And, again, it’s not a four- or five-month difference. It’s a small, but I think meaningful, difference for those patients who have metastatic colorectal cancer.

John L. Marshall, MD: I just want to interpret this as, if you keep your foot on the pedal longer, you have better, longer control. But I could also imagine you get a tired patient, a little bit more bone marrow, all those things. But you then say, OS looks a little better, too, which means they’re getting subsequent lines of therapy. So they’re okay to do this.

Tanios Bekaii-Saab, MD: Just remember, with FOLFOX, it’s not just the lingering neurotoxicity that can limit, sometimes, access to second-line. It’s also, in 5% of the patients, grade 3-plus thrombocytopenia because of hypersplenism, which also limits access to other trials or other intense regimens. So there are certain nuances of the long-term therapy that may affect not just the progression-free, but the overall survival as well.

John L. Marshall, MD: Very good. Well, let’s go to the second study. Kitchen versus bathroom sink. We have two different sinks.

Johanna Bendell, MD: What this did was play off the TRIBE study. So the TRIBE study, it was an Italian study that looked at FOLFOXIRI. Now, this is not FOLFIRINOX, right, because we’re used to giving FOLFIRINOX for pancreatic cancer patients now. But FOLFOXIRI, it’s a different regimen where you use a little higher dose of the infusional 5-FU, a little lower dose of the irinotecan. So this was FOLFOXIRI plus bevacizumab.

John L. Marshall, MD: Do you think that matters?

Johanna Bendell, MD: I don’t know.

John L. Marshall, MD: You think it matters what recipe you use in the soup?

Charles S. Fuchs, MD, MPH: The lower dose of irinotecan, it makes it easier.

John L. Marshall, MD: Whichever recipe, I always come down to 150 mg/m2. It is what I’ll tend to start with.

Charles S. Fuchs, MD, MPH: And sometimes 120 mg/m2.

John L. Marshall, MD: What do you do?

Johanna Bendell, MD: I actually give full dose FOLFOXIRI but not FOLFIRINOX.

John L. Marshall, MD: I see. Richard?

Richard Kim, MD: Same thing. I dose irinotecan at 150 mg/m2.

John L. Marshall, MD: Bolus 5-FU, anybody?

Richard Kim, MD: No.

John L. Marshall, MD: Dropped? Dropped?

Tanios Bekaii-Saab, MD: No.

Charles S. Fuchs, MD, MPH: I delete it.

Johanna Bendell, MD: No, it’s not in FOLFOXIRI.

John L. Marshall, MD: Right. And not there in the first place.

Johanna Bendell, MD: And I don’t do it in FOLFOX.

Richard Kim, MD: I take it out.

John L. Marshall, MD: And drop it. So we’re all modifying that comfortable regimen.

Tanios Bekaii-Saab, MD: And the leucovorin.

John L. Marshall, MD: You drop your leucovorin.

Tanios Bekaii-Saab, MD: If I’m going to give bolus 5-FU, I wouldn’t give leucovorin.

John L. Marshall, MD: A debated point?

Charles S. Fuchs, MD, MPH: I still give leucovorin.

John L. Marshall, MD: I do, too.

Tanios Bekaii-Saab, MD: Infusional 5-FU that goes over two days, and you’re giving leucovorin just for a fraction of the time, is really questionable. But, really, it’s not wrong to give it.
                                                                                                                                                                                                                                                                                                                
Transcript Edited for Clarity
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