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The Potential Impact of FLOT4 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: Monday, Jul 10, 2017



Transcript:

Johanna C. Bendell, MD:
So, right now in the United States—tell me if you think I’m wrong—basically for patients with esophageal cancer, in general, it’s chemoradiation therapy neoadjuvantly. For GE junctional, probably chemoradiation neoadjuvantly. Some people may shift a little bit now towards chemotherapy before and after. And then, for the more distal cancers, you could even use radiation there outside of having surgical experts like we have in Japan. The whole thought behind using radiation adjuvantly for gastric in the United States was that they were cleaning up after potentially inadequate surgery.

Manish A. Shah, MD: Right.

Johanna C. Bendell, MD: And so, we now have new surgical standards that when you have the adequate surgery, maybe you don’t need the radiation.

Manish A. Shah, MD: The ARTIST study actually goes against that a little bit, because that was done in Korea where everybody had a D2 dissection. And, in patients with node positive gastric cancer, there was a trend or a suggestion that radiation may have benefit as well. So, although you’re absolutely right, that in the United States study where the majority of patients didn’t have an adequate node dissection, there was a suggestion that maybe radiation was cleaning up perhaps inadequate surgery or identification of microscopic disease. But, with this other study, maybe radiation does have a role, and they’re actually following it up with a specific study for node positive gastric cancer.

Johanna C. Bendell, MD: Excellent. Dr. Janjigian, what do you think in terms of will this be practice changing?

Yelena Y. Janjigian, MD: Absolutely, for a subset of patients. FLOT-4 is an important study for a number of reasons. A study had shown that addition of epirubicin does not do much compared to 5-FU/platinum, and that was presented by Dr. Cunningham. So, we have data to suggest that epirubicin is not important. But, as you alluded to earlier with FOLFIRINOX in pancreas cancer, there is enough literature and body of thought in a lot of these aggressive GI tumors that you do need the impact of multiple 3-drug combination therapies to sterilize micrometastatic disease. And so, when we talk about FLOT-4, it is a more toxic regimen, but the data have shown that it has been used in elderly patients greater than 75 years of age. And, yes, in a selected patient population in Germany, they were able to get them through it, but these patients need to be followed carefully.

And the concern for this patient population is not only the tumor location, but also the ability to clear the margin. If you attempt an operation, it’s not successful, and you leave a microscopic margin behind, the pathologic CR rate, you can’t worry about the wallpaper if the house is on fire, you have to worry about the R0 resection rate. Therefore, in my mind, and at least in the United States—I just came from a similar program with the Netherlands investigators and oncologists—radiation is still an important part of treatment for esophageal and serotype 1 and 2 of GE junction tumors. Because, if you cannot clear the margin, the margin is in the neck, there are positive tumors, and then it’s a symptomatic and metastatic disaster. So, FLOT-4 is practice changing in select fit patients with locally advanced gastric cancer in whom you think you can get safely through in a tertiary, highly specialized center where you can watch neutropenic fever, which there was a high rate of, and other toxicities. Manish alluded to the modified schedules that we’ve co-developed in the metastatic setting, and I think that’s a great idea. There will be different real-world iterations of FLOT-4, maybe FLOT-3.5, and that will be the way that the real-world doctors will start implementing it.

Transcript Edited for Clarity

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Transcript:

Johanna C. Bendell, MD:
So, right now in the United States—tell me if you think I’m wrong—basically for patients with esophageal cancer, in general, it’s chemoradiation therapy neoadjuvantly. For GE junctional, probably chemoradiation neoadjuvantly. Some people may shift a little bit now towards chemotherapy before and after. And then, for the more distal cancers, you could even use radiation there outside of having surgical experts like we have in Japan. The whole thought behind using radiation adjuvantly for gastric in the United States was that they were cleaning up after potentially inadequate surgery.

Manish A. Shah, MD: Right.

Johanna C. Bendell, MD: And so, we now have new surgical standards that when you have the adequate surgery, maybe you don’t need the radiation.

Manish A. Shah, MD: The ARTIST study actually goes against that a little bit, because that was done in Korea where everybody had a D2 dissection. And, in patients with node positive gastric cancer, there was a trend or a suggestion that radiation may have benefit as well. So, although you’re absolutely right, that in the United States study where the majority of patients didn’t have an adequate node dissection, there was a suggestion that maybe radiation was cleaning up perhaps inadequate surgery or identification of microscopic disease. But, with this other study, maybe radiation does have a role, and they’re actually following it up with a specific study for node positive gastric cancer.

Johanna C. Bendell, MD: Excellent. Dr. Janjigian, what do you think in terms of will this be practice changing?

Yelena Y. Janjigian, MD: Absolutely, for a subset of patients. FLOT-4 is an important study for a number of reasons. A study had shown that addition of epirubicin does not do much compared to 5-FU/platinum, and that was presented by Dr. Cunningham. So, we have data to suggest that epirubicin is not important. But, as you alluded to earlier with FOLFIRINOX in pancreas cancer, there is enough literature and body of thought in a lot of these aggressive GI tumors that you do need the impact of multiple 3-drug combination therapies to sterilize micrometastatic disease. And so, when we talk about FLOT-4, it is a more toxic regimen, but the data have shown that it has been used in elderly patients greater than 75 years of age. And, yes, in a selected patient population in Germany, they were able to get them through it, but these patients need to be followed carefully.

And the concern for this patient population is not only the tumor location, but also the ability to clear the margin. If you attempt an operation, it’s not successful, and you leave a microscopic margin behind, the pathologic CR rate, you can’t worry about the wallpaper if the house is on fire, you have to worry about the R0 resection rate. Therefore, in my mind, and at least in the United States—I just came from a similar program with the Netherlands investigators and oncologists—radiation is still an important part of treatment for esophageal and serotype 1 and 2 of GE junction tumors. Because, if you cannot clear the margin, the margin is in the neck, there are positive tumors, and then it’s a symptomatic and metastatic disaster. So, FLOT-4 is practice changing in select fit patients with locally advanced gastric cancer in whom you think you can get safely through in a tertiary, highly specialized center where you can watch neutropenic fever, which there was a high rate of, and other toxicities. Manish alluded to the modified schedules that we’ve co-developed in the metastatic setting, and I think that’s a great idea. There will be different real-world iterations of FLOT-4, maybe FLOT-3.5, and that will be the way that the real-world doctors will start implementing it.

Transcript Edited for Clarity
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