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FLOT Regimen for Resectable Gastroesophageal Cancer

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Peter C. Enzinger, MD, Dana-Farber Cancer Institute; Yelena Y. Janjigian, MD, Memorial Sloan Kettering Cancer Center; Kohei Shitara, MD, National Cancer Center Hospital East; Eric Van Cutsem, MD, PhD, University of Leuven
Published: Monday, Jul 30, 2018



Transcript: 

Johanna C. Bendell, MD: These are complicated patients. They are patients who are sicker, they’re nutritionally depleted, there are pain issues. Sometimes you have all different types of effects of the disease. Peter, at the Dana-Farber Cancer Institute at Harvard, how do you approach these patients? Is it just you alone or do you have people helping you out?

Peter C. Enzinger, MD: We obviously have a team, like I’m sure my colleagues here also have. Certainly, we make sure that the patients’ needs are met. Almost all of these patients have problems with nutrition and struggling to maintain their weight. The nutritionist is typically involved in all of our cases. Again, trying to maximize calories, helping patients who really have probably never given much thought to diet in this way, to helping them with ways of maximizing calories and eating right. We often will get a pain and palliative care consult involved, particularly if they have pain that’s refractory to the frontline agents. Then, really social work, psychiatry, are all often employed as well. It’s a team approach, and I think that’s very important. The oncologist needs help; we have so little time now to see our patients that to focus on all of these other issues is really too much. Clearly, if you have various areas of expertise involved, it really leads to better outcomes as has been shown, for instance, in the study from Massachusetts General Hospital.

Johanna C. Bendell, MD: Yes, this is the incorporation of palliative care with medical oncology.

Peter C. Enzinger, MD: Correct.

Johanna C. Bendell, MD: Now we have esophagogastric, or gastroesophageal, whichever one you want to call it. We always used to lump these tumors in together, but now it feels like we’re starting to separate them a little bit more: the esophagus versus the gastroesophageal junction, versus the gastric; proximal versus distal. Yelena, how does this change your approach, and especially in the locally advanced setting, where I think there’re a lot of emerging data about how we should treat these patients?

Yelena Y. Janjigian, MD: We need to make that distinction between locally advanced and metastatic. Locally advanced is all about the location—location, location, location—because the surgical approach is different, and the ability to clear the margin and the type of operation that the patient needs really drive a lot of the goals of therapy.

That being said, the message that I want to put out there, in the metastatic setting: Adenocarcinomas should not be segregated into different studies based on a location. For the gastric and the esophageal TCGA, which is the molecular characterization of these tumors, shows that the fingerprints of esophagus adenocarcinoma and the G-junction adenocarcinoma, are very similar. These are chromosomal unstable P53-mutant, no, RTK-driven tumors.

In a trial, if you arbitrarily exclude esophageal cancers, but then include gastric cardiac tumors, that’s not a good approach. From systemic chemotherapy options, as well. For metastatic disease, we approach these the same.

For localized disease, really the difference is between whether or not the patient will need an esophagectomy or gastrectomy. In the United States, and some parts of Europe, really the dogma is that we need to add radiation. We do that to clear the margin because the R0 resection rate without the radiation in some of the studies can be as low as 60%. If you can’t resect the tumor completely, then you’re really doing the patient a disservice by taking them for that operation.

With the combination strategies and the FLOT regimen, which I’m sure Eric will talk about in a little bit, some of the radiation approaches may have been lessened. Again because the radiation per se has never been shown to improve overall survival in a large study; it’s just mostly to clear the margins.

Johanna C. Bendell, MD: Yes, and then FLOT encompassed esophageal, gastroesophageal, and gastric tumors, is that right?

Eric Van Cutsem, MD, PhD: There were different visions in the neoadjuvant setting. I’m not talking of metastatic disease, but in the neoadjuvant setting. In my center, as well as in many other centers, we have the strategy of perioperative chemotherapy for the real gastric cancer. When it’s the GE-junction tumor, with the major bulk in the esophagus, just the real transition, we usually go for chemoradiotherapy. Although there are no randomized studies until now, larger studies to tell what is the best strategy, one of the challenges is that if you look in many of the neoadjuvant or adjuvant studies, GE-junction is sometimes included in the studies of the esophagus, looking from up high to low or from low to high. In some of the stomach studies, it’s also included. Then that’s a little bit different and difficult. The approach is not the same everywhere. In the UK, for me, there is a bit of strategy; also for the GE-junction tumors to go for perioperative chemotherapy. On the continent, not everywhere in Europe, but especially in my center and in many other centers also, we take the more differential approach like what is being done in Memorial Sloan also for the GE-junction and for chemotherapy in the preoperative setting.

One of the important arguments there is, although there is a relative survival benefit of the strategy of perioperative chemotherapy and preoperative chemoradiotherapy, the relative survival benefit in the trial is quite identical. You achieve a bit more R0 resections, and the impact on R0 resections is higher with chemoradiotherapy in locally advanced disease. In real stomach cancer, that’s not such a big issue for the surgeon, but in the GE-junctions, and especially those extending a bit more to the esophagus, that’s crucial. If the R0 resections become lower, it could be worse. That’s important in the direct argument to defend the study.

Yelena Y. Janjigian, MD: Exactly, and since it’s a positive margin, it’s usually pretty high up in the neck, and that’s not a good place to have a positive margin.

Johanna C. Bendell, MD: Kohei, Japan has led a lot of these studies and trials. Do you agree with that same approach?

Kohei Shitara, MD: Yes. First of all, esophageal is still a very common type in Japan, so very few adenocarcinoma or GE-junction. So, for that type, we usually start with chemotherapy as a neoadjuvant therapy, even for localized disease. Chemoradiotherapy is also used, but this is a more common and definitive treatment for patients who cannot tolerate it for surgery. Currently, we conducted therapy in a phase III trial to compare chemotherapy as a doublet, as standard neoadjuvant, and compared the chemoradiotherapy followed by surgery and treated that chemotherapy up front followed by surgery. This is the study for esophageal cancer. The GE-junction tumor and gastric cancer are usually treated by an abdominal surgeon, and the gastrectomy is still standard for the neoadjuvant. The Japanese study, it suggested that the GE-junction tumor has a slightly worse outcome compared to the disease of stomach cancer. More patients received neoadjuvant chemotherapy in the localized disease in Japan.

Transcript Edited for Clarity 

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Transcript: 

Johanna C. Bendell, MD: These are complicated patients. They are patients who are sicker, they’re nutritionally depleted, there are pain issues. Sometimes you have all different types of effects of the disease. Peter, at the Dana-Farber Cancer Institute at Harvard, how do you approach these patients? Is it just you alone or do you have people helping you out?

Peter C. Enzinger, MD: We obviously have a team, like I’m sure my colleagues here also have. Certainly, we make sure that the patients’ needs are met. Almost all of these patients have problems with nutrition and struggling to maintain their weight. The nutritionist is typically involved in all of our cases. Again, trying to maximize calories, helping patients who really have probably never given much thought to diet in this way, to helping them with ways of maximizing calories and eating right. We often will get a pain and palliative care consult involved, particularly if they have pain that’s refractory to the frontline agents. Then, really social work, psychiatry, are all often employed as well. It’s a team approach, and I think that’s very important. The oncologist needs help; we have so little time now to see our patients that to focus on all of these other issues is really too much. Clearly, if you have various areas of expertise involved, it really leads to better outcomes as has been shown, for instance, in the study from Massachusetts General Hospital.

Johanna C. Bendell, MD: Yes, this is the incorporation of palliative care with medical oncology.

Peter C. Enzinger, MD: Correct.

Johanna C. Bendell, MD: Now we have esophagogastric, or gastroesophageal, whichever one you want to call it. We always used to lump these tumors in together, but now it feels like we’re starting to separate them a little bit more: the esophagus versus the gastroesophageal junction, versus the gastric; proximal versus distal. Yelena, how does this change your approach, and especially in the locally advanced setting, where I think there’re a lot of emerging data about how we should treat these patients?

Yelena Y. Janjigian, MD: We need to make that distinction between locally advanced and metastatic. Locally advanced is all about the location—location, location, location—because the surgical approach is different, and the ability to clear the margin and the type of operation that the patient needs really drive a lot of the goals of therapy.

That being said, the message that I want to put out there, in the metastatic setting: Adenocarcinomas should not be segregated into different studies based on a location. For the gastric and the esophageal TCGA, which is the molecular characterization of these tumors, shows that the fingerprints of esophagus adenocarcinoma and the G-junction adenocarcinoma, are very similar. These are chromosomal unstable P53-mutant, no, RTK-driven tumors.

In a trial, if you arbitrarily exclude esophageal cancers, but then include gastric cardiac tumors, that’s not a good approach. From systemic chemotherapy options, as well. For metastatic disease, we approach these the same.

For localized disease, really the difference is between whether or not the patient will need an esophagectomy or gastrectomy. In the United States, and some parts of Europe, really the dogma is that we need to add radiation. We do that to clear the margin because the R0 resection rate without the radiation in some of the studies can be as low as 60%. If you can’t resect the tumor completely, then you’re really doing the patient a disservice by taking them for that operation.

With the combination strategies and the FLOT regimen, which I’m sure Eric will talk about in a little bit, some of the radiation approaches may have been lessened. Again because the radiation per se has never been shown to improve overall survival in a large study; it’s just mostly to clear the margins.

Johanna C. Bendell, MD: Yes, and then FLOT encompassed esophageal, gastroesophageal, and gastric tumors, is that right?

Eric Van Cutsem, MD, PhD: There were different visions in the neoadjuvant setting. I’m not talking of metastatic disease, but in the neoadjuvant setting. In my center, as well as in many other centers, we have the strategy of perioperative chemotherapy for the real gastric cancer. When it’s the GE-junction tumor, with the major bulk in the esophagus, just the real transition, we usually go for chemoradiotherapy. Although there are no randomized studies until now, larger studies to tell what is the best strategy, one of the challenges is that if you look in many of the neoadjuvant or adjuvant studies, GE-junction is sometimes included in the studies of the esophagus, looking from up high to low or from low to high. In some of the stomach studies, it’s also included. Then that’s a little bit different and difficult. The approach is not the same everywhere. In the UK, for me, there is a bit of strategy; also for the GE-junction tumors to go for perioperative chemotherapy. On the continent, not everywhere in Europe, but especially in my center and in many other centers also, we take the more differential approach like what is being done in Memorial Sloan also for the GE-junction and for chemotherapy in the preoperative setting.

One of the important arguments there is, although there is a relative survival benefit of the strategy of perioperative chemotherapy and preoperative chemoradiotherapy, the relative survival benefit in the trial is quite identical. You achieve a bit more R0 resections, and the impact on R0 resections is higher with chemoradiotherapy in locally advanced disease. In real stomach cancer, that’s not such a big issue for the surgeon, but in the GE-junctions, and especially those extending a bit more to the esophagus, that’s crucial. If the R0 resections become lower, it could be worse. That’s important in the direct argument to defend the study.

Yelena Y. Janjigian, MD: Exactly, and since it’s a positive margin, it’s usually pretty high up in the neck, and that’s not a good place to have a positive margin.

Johanna C. Bendell, MD: Kohei, Japan has led a lot of these studies and trials. Do you agree with that same approach?

Kohei Shitara, MD: Yes. First of all, esophageal is still a very common type in Japan, so very few adenocarcinoma or GE-junction. So, for that type, we usually start with chemotherapy as a neoadjuvant therapy, even for localized disease. Chemoradiotherapy is also used, but this is a more common and definitive treatment for patients who cannot tolerate it for surgery. Currently, we conducted therapy in a phase III trial to compare chemotherapy as a doublet, as standard neoadjuvant, and compared the chemoradiotherapy followed by surgery and treated that chemotherapy up front followed by surgery. This is the study for esophageal cancer. The GE-junction tumor and gastric cancer are usually treated by an abdominal surgeon, and the gastrectomy is still standard for the neoadjuvant. The Japanese study, it suggested that the GE-junction tumor has a slightly worse outcome compared to the disease of stomach cancer. More patients received neoadjuvant chemotherapy in the localized disease in Japan.

Transcript Edited for Clarity 
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