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FLOT4: Perioperative Strategies in Gastroesophageal Cancer

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Ian Chau, MD, Royal Marsden Hospital; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Manish A. Shah, MD, Weill Cornell Medicine, New York-Presbyterian Hospital; Kohei Shitara, MD, National Cancer Center Hospital East, Japan
Published: Wednesday, Jul 05, 2017



Transcript:

Johanna C. Bendell, MD:
Here at ASCO this year, we have heard recent data. It was fun because before we walked in here to do this filming, we were having quite an animated discussion—which I’m hoping we can replicate and we didn’t lose all the fun—about some data we saw here on a regimen called FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel). How do we use that and does this change our treatment paradigm for patients with esophageal, GE junctional, and gastric cancer? And, as we’ve heard, they are very different diseases, so what is our treatment paradigm? And we’ve also heard—and I’m so glad we have this, like, UN board here—that depending on what part of the world you’re in, you may also get different treatment in general.

Ian Chau, MD: This is a study that was conducted in Germany and involves many centers, but is done in 1 country. So, perioperative chemotherapy has become one of the standard treatment options for patients if you have localized gastric cancer or locally advanced gastric cancer. And one of the main data that drove that recommendation is from the original MAGIC study, where we gave 3 cycles of ECF (epirubicin, cisplatin, 5-flourouracil), then I believe it was cisplatin and 5-FU before surgery, and then 3 cycles afterwards. And with the introduction of capecitabine, I think many clinicians are quite comfortable swapping the 5-FU with the capecitabine. So, in this FLOT-4 study, which was reported by Dr. Al-Batran at ASCO this year, they’ve actually done a very large randomized phase III trial where they actually compared what would be deemed as standard: either 3 cycles of ECF or ECX (epirubicin, cisplatin, capecitabine) before and after surgery versus FLOT, which is given as 2-weekly cycle for 4 cycles before and after. FLOT has got 5-FU, leucovorin, oxaliplatin, and docetaxel, and the 5-FU is given over 24 hours.

It is a regimen that has been given in Germany for a while, so I think the clinicians and oncologists are used to using that regimen. And, in that study, they actually have shown a significant improvement, most importantly, in overall survival, but also in relapse-free survival. There are some differences in toxicity, and I think that is something that we probably need to come on to discuss: whether or not this is a regimen that patients in other countries would be able to tolerate in a similar fashion as we have seen in this German study. But, certainly, in all the efficacy outcomes, it was all in favor of FLOT. Even pathologically, there is certainly a significant down-staging compared to the ECX regimen.

Johanna C. Bendell, MD: So, this is like FOLFIRINOX for locally advanced gastric cancer.

Manish A. Shah, MD: With Taxotere.

Johanna C. Bendell, MD: Exactly.

Ian Chau, MD: Well, certainly, this is a practice-changing study, so I think many clinicians in many countries will look at these data and think about whether or not this is something we can implement in our practice. But, as I said, our thought is that most clinicians outside Germany would not have used that regimen, especially in the perioperative setting where you don’t really want to compromise your patients to then undergo surgery. I think it’s something that we now need to go on a very sharp learning curve to make sure that we can deliver this treatment safely to our patients.

Johanna C. Bendell, MD: And so, just to set the stage a little bit, this study included esophageal, gastroesophageal, and gastric cancer patients, all of whom could potentially have different treatment choices. Like in the United States, we use radiation a lot for the esophageal and GE junctional, even possibly gastric cancers. We’ve seen in previous studies that when you include radiation therapy in your adjuvant treatment for gastric cancer, if you try to intensify the chemotherapy part of the regimen, it really doesn’t make any difference. So, now we’re left with a little bit of a conundrum. Manish, New York is the epicenter of gastric cancer. What about radiation, what do you do now with these data?

Manish A. Shah, MD: First, let me say kudos to Dr. Al-Batran and his colleagues. It was a very important randomized phase III study, well done. It took a long time and I think the results are meaningful. And I think, as was said by Dr. Chau and by yourself, there are different disease subtypes, and we should be careful when we lump everything together and apply the same regimen to everybody. The disease burden may be different, the underlying comorbidities may be different, and that may play a role in how patients benefit from treatment. So, that was a long way of not answering your question but, no. And, actually, the other part of this is that the FLOT regimen, 5-FU/oxaliplatin/docetaxel, is actually built from the DCF (docetaxel, cisplatin, 5-fluorouracil) regimen that was developed 10 years ago. Actually, it was published in 2007.

There have been modifications to that regimen to make it more toxic, and so the FLOT regimen really is a modification of that regimen. So, we have evidence in the metastatic setting that a 3-drug regimen like FLOT or DCF is active. I think, again, kudos to the idea that we should test it in a perioperative setting. One of the key drivers of the development of this regimen was that Dr. Al-Batran and colleagues were seeing a number of complete responses. As Ian mentioned, there was down-staging, but, for me, even more importantly, it was actually they did FLOT and then they did surgery and no tumor was seen on the pathologic specimen. It’s actually reported at 20%, and many people in the United States think that’s very high, but that’s similar to what a radiation-based regimen would get for adenocarcinoma. For squamous cell, it’s a little bit different. So, I think that needs to play a role in the decision making as well. Ultimately though, I agree with Ian that in a perioperative setting where patients are curative, we don’t want to do any harm. We need to have comfort with using the FLOT regimen. But I do think that actually the data are compelling, and I think more and more people will be using it for this indication.

Transcript Edited for Clarity

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Transcript:

Johanna C. Bendell, MD:
Here at ASCO this year, we have heard recent data. It was fun because before we walked in here to do this filming, we were having quite an animated discussion—which I’m hoping we can replicate and we didn’t lose all the fun—about some data we saw here on a regimen called FLOT (fluorouracil, leucovorin, oxaliplatin, and docetaxel). How do we use that and does this change our treatment paradigm for patients with esophageal, GE junctional, and gastric cancer? And, as we’ve heard, they are very different diseases, so what is our treatment paradigm? And we’ve also heard—and I’m so glad we have this, like, UN board here—that depending on what part of the world you’re in, you may also get different treatment in general.

Ian Chau, MD: This is a study that was conducted in Germany and involves many centers, but is done in 1 country. So, perioperative chemotherapy has become one of the standard treatment options for patients if you have localized gastric cancer or locally advanced gastric cancer. And one of the main data that drove that recommendation is from the original MAGIC study, where we gave 3 cycles of ECF (epirubicin, cisplatin, 5-flourouracil), then I believe it was cisplatin and 5-FU before surgery, and then 3 cycles afterwards. And with the introduction of capecitabine, I think many clinicians are quite comfortable swapping the 5-FU with the capecitabine. So, in this FLOT-4 study, which was reported by Dr. Al-Batran at ASCO this year, they’ve actually done a very large randomized phase III trial where they actually compared what would be deemed as standard: either 3 cycles of ECF or ECX (epirubicin, cisplatin, capecitabine) before and after surgery versus FLOT, which is given as 2-weekly cycle for 4 cycles before and after. FLOT has got 5-FU, leucovorin, oxaliplatin, and docetaxel, and the 5-FU is given over 24 hours.

It is a regimen that has been given in Germany for a while, so I think the clinicians and oncologists are used to using that regimen. And, in that study, they actually have shown a significant improvement, most importantly, in overall survival, but also in relapse-free survival. There are some differences in toxicity, and I think that is something that we probably need to come on to discuss: whether or not this is a regimen that patients in other countries would be able to tolerate in a similar fashion as we have seen in this German study. But, certainly, in all the efficacy outcomes, it was all in favor of FLOT. Even pathologically, there is certainly a significant down-staging compared to the ECX regimen.

Johanna C. Bendell, MD: So, this is like FOLFIRINOX for locally advanced gastric cancer.

Manish A. Shah, MD: With Taxotere.

Johanna C. Bendell, MD: Exactly.

Ian Chau, MD: Well, certainly, this is a practice-changing study, so I think many clinicians in many countries will look at these data and think about whether or not this is something we can implement in our practice. But, as I said, our thought is that most clinicians outside Germany would not have used that regimen, especially in the perioperative setting where you don’t really want to compromise your patients to then undergo surgery. I think it’s something that we now need to go on a very sharp learning curve to make sure that we can deliver this treatment safely to our patients.

Johanna C. Bendell, MD: And so, just to set the stage a little bit, this study included esophageal, gastroesophageal, and gastric cancer patients, all of whom could potentially have different treatment choices. Like in the United States, we use radiation a lot for the esophageal and GE junctional, even possibly gastric cancers. We’ve seen in previous studies that when you include radiation therapy in your adjuvant treatment for gastric cancer, if you try to intensify the chemotherapy part of the regimen, it really doesn’t make any difference. So, now we’re left with a little bit of a conundrum. Manish, New York is the epicenter of gastric cancer. What about radiation, what do you do now with these data?

Manish A. Shah, MD: First, let me say kudos to Dr. Al-Batran and his colleagues. It was a very important randomized phase III study, well done. It took a long time and I think the results are meaningful. And I think, as was said by Dr. Chau and by yourself, there are different disease subtypes, and we should be careful when we lump everything together and apply the same regimen to everybody. The disease burden may be different, the underlying comorbidities may be different, and that may play a role in how patients benefit from treatment. So, that was a long way of not answering your question but, no. And, actually, the other part of this is that the FLOT regimen, 5-FU/oxaliplatin/docetaxel, is actually built from the DCF (docetaxel, cisplatin, 5-fluorouracil) regimen that was developed 10 years ago. Actually, it was published in 2007.

There have been modifications to that regimen to make it more toxic, and so the FLOT regimen really is a modification of that regimen. So, we have evidence in the metastatic setting that a 3-drug regimen like FLOT or DCF is active. I think, again, kudos to the idea that we should test it in a perioperative setting. One of the key drivers of the development of this regimen was that Dr. Al-Batran and colleagues were seeing a number of complete responses. As Ian mentioned, there was down-staging, but, for me, even more importantly, it was actually they did FLOT and then they did surgery and no tumor was seen on the pathologic specimen. It’s actually reported at 20%, and many people in the United States think that’s very high, but that’s similar to what a radiation-based regimen would get for adenocarcinoma. For squamous cell, it’s a little bit different. So, I think that needs to play a role in the decision making as well. Ultimately though, I agree with Ian that in a perioperative setting where patients are curative, we don’t want to do any harm. We need to have comfort with using the FLOT regimen. But I do think that actually the data are compelling, and I think more and more people will be using it for this indication.

Transcript Edited for Clarity
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