Dose Modification Rationale in Advanced Pancreatic Cancer

Transcript:Philip A. Philip, MD, PhD, FRCP: Now, we have to keep in mind that the way FOLFIRINOX is being used is not the same as was published.

Johanna Bendell, MD: Right, right. So what are your modifications? Everybody modifies FOLFIRINOX.

Philip A. Philip, MD, PhD, FRCP: Well, I personally drop the bolus 5-FU. In fact, in the trial we have, SWOG, it’s the same. We drop the bolus 5-FU assuming the treatment is not affected, but I also know that other people do different things.

Johanna Bendell, MD: Caio?

Caio Rocha Lima, MD: We all do drug development here, and most of the time when we combine agents, we tend to drop the doses, predominantly in cytotoxic drugs. Now, we have in pancreatic cancer, two regimens that use full doses of all drugs, FOLFIRINOX (85 mg/m2 oxaliplatin; 180 mg/m2 irinotecan; 2400 mg/m2 infusion of 5-FU; 400 mg/m2 leucovorin; full doses); gemcitabine at 1000 mg/m2 weekly times 3, every four week, nab-paclitaxel at 125 mg/m2 also three out of four weeks. You have two regimens at full doses, so it’s very tempting to do a modification. But modification is both in the FOLFIRINOX regimen, as well as in the nab-paclitaxel/gemcitabine. But we are not basing this modification in phase III trials or basing that modification on experience. So I try to shy away from it. I try to modify the doses after starting rather than start low and escalate.

Johanna Bendell, MD: You use the full doses of both.

Caio Rocha Lima, MD: Whenever I use them I start them at full doses.

Johanna Bendell, MD: Tom?

Thomas A. Abrams MD: I’m not so brave. I definitely drop the bolus and even take a dose-level reduction of the irinotecan to 150 mg/m2. It’s the institutional practice. I think most of my colleagues are doing the same thing and we’ve written protocols that have piggy backed on that dose regimen. And I think it is more tolerable. Obviously, you’re right, we don’t have the phase III data to decide whether it’s really as effective, but just as clinical trials tend not to have the same real world toxicities as we see in the clinic, I think we have to account for that and try to dose reduce them just a tad, so that we can at least get them through a few cycles and assess the response. But, I agree with your rationale. I understand it. I found it very difficult to give full dose FOLFIRINOX and full dose gemcitabine/nab-paclitaxel for that matter. I do start them off on full dose, but I tend to have modifications very quickly. It is not that easy a regimen to get through either.

Philip A. Philip, MD, PhD, FRCP: Do you check the UGT1A1 before?

Thomas A. Abrams MD: Never.

Philip A. Philip, MD, PhD, FRCP: Anyone here do?

Johanna Bendell, MD: No.

Philip A. Philip, MD, PhD, FRCP: I do.

Johanna Bendell, MD: You do?

Philip A. Philip, MD, PhD, FRCP: Yeah. Well, like with experiments I’ve seen that if you have a Guillain-Barre syndrome and give them the full dose of irinotecan, I’ve seen toxicity for sure. Although, it’s not very consistent to say that every single patient will get toxicity. But if I can really predict how the patient is going to respond in terms of toxicity, I would like to do that.

Caio Rocha Lima, MD: Can I just make one comment?

Johanna Bendell, MD: Sure.

Caio Rocha Lima, MD: We actually have that as part of the panel. I’m not going to disclose the third party that does our panel, but actually there is a pharmacogenomic component in the panel. It’s a next-generation sequence. We actually get the gene. But Medicare rules say it has to be at least two weeks after they’re discharged from the hospital for us to be able to solicit the test. So by the time the test gets back, I’m already starting the treatment. So, I actually am analyzing that, and actually it is a predictor. But it’s too late when I start the treatment.

Johanna Bendell, MD: George, do you like the boluses? Do you keep the boluses?

George P. Kim, MD: I do, I like boluses. I’m a little bolder.

Johanna Bendell, MD: You do?

George P. Kim, MD: Yeah.

Johanna Bendell, MD: Wow.

George P. Kim, MD: The reality is we don’t know how these drugs interact. We know there’s an interaction between oxaliplatin and irinotecan. We know there’s an interaction between 5-FU and oxaliplatin. Remember oxaliplatin almost got kicked out because by itself it didn’t do anything. So we don’t know what the real interactions are. And there’s this famous story. I was with de Gramont on a bus and I asked him, what is it, is it the bolus, is it the continuous infusion? He says to me, “I don’t know.” And he’s the father of that regimen. So, I take the irinotecan down by about 20%, and I take the bolus down by about 20%, but I don’t throw it out. And you’re right, with gemcitabine/Abraxane, you do have to make dose modifications. Remember, it’s a higher dose, 125 mg/m2, not the lung dose. But I might push that dose and try to lower my gemcitabine like we did in the old days.

Johanna Bendell, MD: So, let’s throw in the use of Neupogen. Do you do it with FOLFIRINOX?

George P. Kim, MD: Not prophylactically, no. I let the patient’s bone marrow express itself, and then move from there. This is another factor. What are the costs of the different regimens? Everybody says Abraxane is expensive, but once you start factoring in Neulasta into FOLFIRINOX, it does get expensive. And then, when you factor in hospitalization, that also gets expensive. So, that’s another factor that I think we have to pay more and more attention to.

Johanna Bendell, MD: And Philip, things that folks don’t talk about as much as modifying the gemcitabine/nab-paclitaxel upfront, is thinking about the use of growth factors there. Certainly the original MPACT study had folks using Neupogen for a few days here, a few days there. And can we make the regimen modified to be kinder to our patients? What data have we seen there?

Philip A. Philip, MD, PhD, FRCP: My good friend, Tony Saab, does it. That’s my evidence. We don’t have any good evidence to support either how to modify or to see the results of the modification in terms of efficacy. And that type of data will never come. I personally do dose modifications for the nab-paclitaxel and gemcitabine combination, and I do that mostly in the older patients and also in patients who are younger who are going on treatment for months and months. Because then they start to have side effects that, even if you use G-CSF, you’re not going to overcome—fatigue, neuropathy, the malaise—which goes with the treatment.

But sometimes, in older patients with performance status that is borderline, I would start with every other week. In fact, I can tell you my personal experience has shown that every other week really makes patients feel better after experiencing a lot of the side effects with the fatigue. Starting off right away with every other week, I would not do it in an average patient. And in the minority of patients who I think that are not going to tolerate it, I do it every other week. But in patients who are continuing for a while, that’s something I will do.

Thomas A. Abrams MD: Yeah, I agree. I think it’s nice to have gemcitabine/nab-paclitaxel, at least some data supporting an every two week dose regimen, because it is so much easier on patients, and it is a really nice way to dose it. And the fact that, even in a single arm sort of setting, that it seems safe and reasonably effective, that’s nice because it is a very way to dose modify that regimen.

George P. Kim, MD: All right, I’ve got to disagree. I still give it weekly. I shorten the cycle day 1, day 8, every 21 if I’m worried about that. But every two weeks? We talk about modifying FOLFIRINOX. We don’t know the outcome when we do it every two weeks. It’s a single institution study, so I think you’ve got to stay close to how that protocol was.

Caio Rocha Lima, MD: I agree with George.

George P. Kim, MD: Thank you.

Philip A. Philip, MD, PhD, FRCP: So we’re divided here, 2 against 2.

Johanna Bendell, MD: See, I love it. I love it, controversy. Should I be the deal breaker?

Philip A. Philip, MD, PhD, FRCP: Exactly right.

Johanna Bendell, MD: Let’s talk about, though, we have these patients with pancreas cancer. They’re in this inflammatory state. They’re anorexic, they’re in pain, they feel poorly. And certainly people have used different methods to assess, what’s clinical benefit response? What’s a response rate? How do we really tell or assess response in a pancreatic cancer patient, George?

George P. Kim, MD: I’m old-fashioned. I still scan the patients. Just CT scans every two months, monitor the tumor markers. Don’t make treatment decisions based on that, but I do monitor them. And, obviously, if the patient is miserable, we’re not going to keep treating them. So, we do institute breaks and try to provide as much support as possible. And Philip said that earlier. We really have got to manage these patients. I think people forget that pancreas cancer is not breast cancer, it’s not colon cancer. You really have got to manage the patients and stay on top of their pain, their nutrition, their diabetes, their blood clot risk, their bile duct function, all those important aspects of pancreas cancer. And that’s why all you guys are experts.

Johanna Bendell, MD: And certainly with the responses that we see with some of these new regimens, what’s really nice that goes along with it is that patients start feeling so much better. And that’s the big thing, right, is that why are we doing all this chemo that has all this toxicity, it’s to make the patients feel better.

George P. Kim, MD: It’s under-appreciated, pain control. And I think even our radiation collogues help with the pain control. So sometimes they can get in there and radiate the primary tumor and help us out. And our gastroenterologists, obviously with endoscopic guided neurolysis of the celiac plexus, so absolutely.

Transcript Edited for Clarity