Minimizing Adverse Events With Dose Modification in Pancreatic Cancer

Evolving ParadigmsPancreatic Cancer

Given the benefits of nab-paclitaxel plus gemcitabine and FOLFIRINOX, efforts have been made to improve the toxicity profiles through dose modifications.


Despite the varying tactics that exist, phase III data are not available to verify which strategy is optimal. A panel discussion was formed to explore the various strategies available for dose modifications. This discussion included insight from Thomas A. Abrams, MD, Dana-Farber Cancer Institute, George P. Kim, MD, Mayo Clinic, Caio Rocha Lima, MD, Gibbs Cancer Center & Research Institute, and Philip A. Philip, MD, PhD, Wayne State University.

Q:What are your dose reduction strategies for FOLFIRINOX?

Lima: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 and gemcitabine plus nab-paclitaxel. You have two regimens at full doses, so it’s very tempting to do a modification—both in the FOLFIRINOX regimen as well as in the nab-paclitaxel/gemcitabine. But, we are not basing modifications on phase III trials or on experience. So I try to shy away from it. I try to modify the doses after starting rather than start low and escalate. Whenever I use them, I start them at full doses.

Abrams:I’m not so brave. I definitely drop the bolus for FOLFIRINOX, 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.

Kim: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.

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/nab-paclitaxel 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.

Q:What strategies do you use for nab-paclitaxel/gemcitabine?

Philip: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.

Abrams: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 nice way to dose modify that regimen.

Kim: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.

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