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Metastatic Pancreatic Cancer: Dosing Strategies in the Frontline Setting

Panelists: Johanna Bendell, MD, Sarah Cannon Research Institute; Eileen O’Reilly, MD, Memorial Sloan-Kettering Cancer Center; John Marshall, MD, Ruesch Cancer Center at the Lombardi Comprehensive Cancer Center; George Kim, MD, University of Florida Health Oncology; Caio Max S. Rocha Lima, MD, Gibbs Cancer Center
Published Online: Tuesday, Feb 21, 2017



Transcript:

Johanna Bendell, MD:
Now, outside of clinical trials, let’s take our clinic day: you have a brand new patient where you see somebody just diagnosed with metastatic pancreatic cancer. So, Eileen, we have some treatment options that are available for these patients. How do you approach this and what do you think?

Eileen O’Reilly, MD: Meeting a new untreated patient, putting aside clinical trial options, presents the 2 current standards of care for good performance status patients: FOLFIRINOX or gemcitabine and nab-paclitaxel. I have relative equipoise with these. I think we’re excited to have options and excited to have choices for patients, and I think depending on the person, the individual and their setting, one may prove to be a better fit.

So, for example, some patients may have concerns about having a port and having an infusional treatment with FOLFIRINOX. Other patients may have concerns about alopecia with nab-paclitaxel–based therapy and that may help decide. I say to patients, “We don’t know, but we know from other diseases, it doesn’t matter which order you get the drugs, but hopefully you’ll have the opportunity to be exposed to all of the active drugs in this disease.” I suspect that principle holds true in pancreas cancer. I encourage people to make sure they’re comfortable with their choices and discuss the issues of growth factors, discuss the schedule issues in terms of weekly versus every other week. And it may depend a little bit where they live. Some will have come in with a very strong opinion in terms of what’s right for them. And I think in the absence of definitive data to suggest otherwise, that’s reasonable.

Johanna Bendell, MD: Certainly, some people will make a choice on first-line treatment options based on toxicity profile. You alluded to, with the gemcitabine and nab-paclitaxel, the issues with thrombocytopenia and neutropenia. You can see, with FOLFIRINOX, the issues with nausea, vomiting, and diarrhea. And I think a lot of us self-modify these regimens to try to make these regimens more tolerable, yet not lose out on efficacy. John, I think there have been some recent publications that have looked at modification of both of these regimens and what kind of impact these have had on treatment of the patients.

John Marshall, MD: Yes. So, I don’t actually think I’ve ever given classic FOLFIRINOX. I’m thinking if I even did it once. Most of us adopt to drop the bolus 5-FU quickly because we rationalize, if they’re getting plenty of 5-FU, that’s only adding toxicity. And then, I almost always will cut the irinotecan down, usually just to 150 mg/m2—but there are lots of different strategies. What’s nice about that is that, as you referred to, there are now some studies that actually looked at whether it’s response rate or progression-free survival in single-arm studies with dose modifications. In essence, in some cases, they’re performing better than the phase III randomized trial. So, at least we’re reassured that we’re not too far off from what the published data are in a controlled randomized trial.

And I don’t really think I could give the standard regimen regularly to people. Even with the current modifications, I almost always give a growth factor. It’s the only time I ever order a growth factor as a GI oncologist. And it’s still hard to manage. It’s intensive antiemetics, which is what we’ll start with, and then often the fatigue element. So, even with modifications, we all buckle in for what might be a rough 1 to 2 cycles until we get the dosing right.

Johanna Bendell, MD: And, certainly, even with gemcitabine and nab-paclitaxel, there are some folks that are doing modifications for that regimen as well. Eileen, tell us a little bit about this every-other-week concept.

Eileen O’Reilly, MD: So, the group in Ohio State looked at this a couple of years ago. Their data have been recently reported looking at people with untreated newly diagnosed pancreas cancer, giving the full dose every other week, and supporting favorable outcomes, comparatively speaking—with the potential advantages of less cumulative toxicity in terms of neuropathy, maybe less issues with myelosuppression growth factor requirements, perhaps an economic gain. And I think we don’t know whether that’s the right fit for all patients, and it’s certainly not the FDA-approved regimen. But I think it’s heartening, if one is running into toxicity, that there are nice data to suggest that this is may be a very reasonable strategy to consider.

George Kim, MD: So, are you going to go up on the dose then? Are you going to go from 125 mg/m2 to 150 mg/m2? There are some data out there that say that going to 150 mg/m2may be more beneficial. And if you did the math, it’s really not that different; it’s about 10%. But yes, those data are out there, including the Hochster data from Brown using 150 mg/m2. And then the folks down in Houston do the 150 mg/m2 every 2 weeks also, but they also give it with a fixed–dose rate gemcitabine.

Johanna Bendell, MD: So, people are modifying the other way around.

George Kim, MD: If you are going to do that, my point is you can dial up the Abraxane or nab-paclitaxel.

Eileen O’Reilly, MD: You struggle a little bit with that.

George Kim, MD: Well, we’re 2-week physicians, right? We treat people every 2 weeks, so we don’t know how to treat people every week.

Eileen O’Reilly, MD: I think it’s reassuring, and as John says, I think a lot of us use modified FOLFIRINOX and are comfortable with that and are confident by not seeing adverse outcomes in terms of nonrandomized data. But you could think of the argument the same way. So, what’s there to gain in terms of going up? It’s probably toxicity.

John Marshall, MD: I think of this as I’ve got so many milligrams to give before I get into some cumulative neurotoxicity, too. So, if I can get that benefit with a lower dose, then maybe I can go a little longer than playing harder and up front. But I think all of these things are supported and you make your decision based on the person sitting in front of you.

Caio Max S. Rocha Lima, MD: If you don’t mind, I interject, but I’m old enough to tell that the phase I trial of gemcitabine given every other week, the maximum tolerated dose, was not reached. It’s 4.9 g/m2 given every other week, and the investigator just got tired of escalating the dose and said, “Enough is enough.” There was basically no myelosuppression. So, every time you run into myelosuppression in comparing gemcitabine with any other cytotoxic drug, there’s a way to overcome that. You just give gemcitabine every other week. And I think that starting nab-paclitaxel on the every-other-week schedule is a little bit uncomfortable, just because we have phase II efficacy instead of phase III. But I think it will be a good way to adjust the dose if you cannot deliver the weekly schedule. That’s my position.

Transcript Edited for Clarity

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Transcript:

Johanna Bendell, MD:
Now, outside of clinical trials, let’s take our clinic day: you have a brand new patient where you see somebody just diagnosed with metastatic pancreatic cancer. So, Eileen, we have some treatment options that are available for these patients. How do you approach this and what do you think?

Eileen O’Reilly, MD: Meeting a new untreated patient, putting aside clinical trial options, presents the 2 current standards of care for good performance status patients: FOLFIRINOX or gemcitabine and nab-paclitaxel. I have relative equipoise with these. I think we’re excited to have options and excited to have choices for patients, and I think depending on the person, the individual and their setting, one may prove to be a better fit.

So, for example, some patients may have concerns about having a port and having an infusional treatment with FOLFIRINOX. Other patients may have concerns about alopecia with nab-paclitaxel–based therapy and that may help decide. I say to patients, “We don’t know, but we know from other diseases, it doesn’t matter which order you get the drugs, but hopefully you’ll have the opportunity to be exposed to all of the active drugs in this disease.” I suspect that principle holds true in pancreas cancer. I encourage people to make sure they’re comfortable with their choices and discuss the issues of growth factors, discuss the schedule issues in terms of weekly versus every other week. And it may depend a little bit where they live. Some will have come in with a very strong opinion in terms of what’s right for them. And I think in the absence of definitive data to suggest otherwise, that’s reasonable.

Johanna Bendell, MD: Certainly, some people will make a choice on first-line treatment options based on toxicity profile. You alluded to, with the gemcitabine and nab-paclitaxel, the issues with thrombocytopenia and neutropenia. You can see, with FOLFIRINOX, the issues with nausea, vomiting, and diarrhea. And I think a lot of us self-modify these regimens to try to make these regimens more tolerable, yet not lose out on efficacy. John, I think there have been some recent publications that have looked at modification of both of these regimens and what kind of impact these have had on treatment of the patients.

John Marshall, MD: Yes. So, I don’t actually think I’ve ever given classic FOLFIRINOX. I’m thinking if I even did it once. Most of us adopt to drop the bolus 5-FU quickly because we rationalize, if they’re getting plenty of 5-FU, that’s only adding toxicity. And then, I almost always will cut the irinotecan down, usually just to 150 mg/m2—but there are lots of different strategies. What’s nice about that is that, as you referred to, there are now some studies that actually looked at whether it’s response rate or progression-free survival in single-arm studies with dose modifications. In essence, in some cases, they’re performing better than the phase III randomized trial. So, at least we’re reassured that we’re not too far off from what the published data are in a controlled randomized trial.

And I don’t really think I could give the standard regimen regularly to people. Even with the current modifications, I almost always give a growth factor. It’s the only time I ever order a growth factor as a GI oncologist. And it’s still hard to manage. It’s intensive antiemetics, which is what we’ll start with, and then often the fatigue element. So, even with modifications, we all buckle in for what might be a rough 1 to 2 cycles until we get the dosing right.

Johanna Bendell, MD: And, certainly, even with gemcitabine and nab-paclitaxel, there are some folks that are doing modifications for that regimen as well. Eileen, tell us a little bit about this every-other-week concept.

Eileen O’Reilly, MD: So, the group in Ohio State looked at this a couple of years ago. Their data have been recently reported looking at people with untreated newly diagnosed pancreas cancer, giving the full dose every other week, and supporting favorable outcomes, comparatively speaking—with the potential advantages of less cumulative toxicity in terms of neuropathy, maybe less issues with myelosuppression growth factor requirements, perhaps an economic gain. And I think we don’t know whether that’s the right fit for all patients, and it’s certainly not the FDA-approved regimen. But I think it’s heartening, if one is running into toxicity, that there are nice data to suggest that this is may be a very reasonable strategy to consider.

George Kim, MD: So, are you going to go up on the dose then? Are you going to go from 125 mg/m2 to 150 mg/m2? There are some data out there that say that going to 150 mg/m2may be more beneficial. And if you did the math, it’s really not that different; it’s about 10%. But yes, those data are out there, including the Hochster data from Brown using 150 mg/m2. And then the folks down in Houston do the 150 mg/m2 every 2 weeks also, but they also give it with a fixed–dose rate gemcitabine.

Johanna Bendell, MD: So, people are modifying the other way around.

George Kim, MD: If you are going to do that, my point is you can dial up the Abraxane or nab-paclitaxel.

Eileen O’Reilly, MD: You struggle a little bit with that.

George Kim, MD: Well, we’re 2-week physicians, right? We treat people every 2 weeks, so we don’t know how to treat people every week.

Eileen O’Reilly, MD: I think it’s reassuring, and as John says, I think a lot of us use modified FOLFIRINOX and are comfortable with that and are confident by not seeing adverse outcomes in terms of nonrandomized data. But you could think of the argument the same way. So, what’s there to gain in terms of going up? It’s probably toxicity.

John Marshall, MD: I think of this as I’ve got so many milligrams to give before I get into some cumulative neurotoxicity, too. So, if I can get that benefit with a lower dose, then maybe I can go a little longer than playing harder and up front. But I think all of these things are supported and you make your decision based on the person sitting in front of you.

Caio Max S. Rocha Lima, MD: If you don’t mind, I interject, but I’m old enough to tell that the phase I trial of gemcitabine given every other week, the maximum tolerated dose, was not reached. It’s 4.9 g/m2 given every other week, and the investigator just got tired of escalating the dose and said, “Enough is enough.” There was basically no myelosuppression. So, every time you run into myelosuppression in comparing gemcitabine with any other cytotoxic drug, there’s a way to overcome that. You just give gemcitabine every other week. And I think that starting nab-paclitaxel on the every-other-week schedule is a little bit uncomfortable, just because we have phase II efficacy instead of phase III. But I think it will be a good way to adjust the dose if you cannot deliver the weekly schedule. That’s my position.

Transcript Edited for Clarity
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