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Long-term Strategies in Gastric 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 24, 2017



Transcript:
 
Johanna C. Bendell, MD: So, can you tell us a little bit more about how you treat metastatic disease in Japan and how you sequence the treatments?
Kohei Shitara, MD: If I had to name a case, a fluoropyrimidine and a platinum agent as a first-line followed by paclitaxel and ramucirumab is commonly used. And it was the most recommended treatment sequencing in our guidelines. I think this is not so different from other countries. Our guidelines are simpler to recommend and are the most recommended one. But the NCCN guidelines have the more various treatment options. We are currently devising these guidelines, and we will increase evaluation of treatment as an optional treatment. But I think the most recommended treatments seem to go the same.
Johanna C. Bendell, MD: Yes. In the first-line setting, you also have access to S1, where we don’t.
Kohei Shitara, MD: Yes. We commonly use S1 rather than capecitabine, but both can be used, and also we can use FOLFOX.
Regarding the HER2-targeting agent, we surely use trastuzumab in combination with either a fluoropyrimidine or a platinum. And in the second-line, paclitaxel and ramucirumab, we surely must recommend that type of treatment based on the RAINBOW study. We also joined the RAINBOW study, and, in over 140 patients, it showed a clear survival benefit, so we use this regimen if a patient had no contraindications. In the HER2-positive case, we use paclitaxel and ramucirumab. And going back to the previous question about what to do after the triplet regimen, we are not so commonly using a triplet regimen, but there are several clinical trials ongoing to evaluate a triplet regimen. From this experience, we use a lower dose of docetaxel, so a paclitaxel-based regimen seemed to be active even if there was a docetaxel-based regimen. So, paclitaxel/ramucirumab is commonly used after a DCS [docetaxel/cisplatin/S1] or DOS [docetaxel/oxaliplatin/S1] triplet regimen. As a third-line option, we use irinotecan. Clearly, this kind of continuation on treatment might be very important to prolong the survival.
Johanna C. Bendell, MD: Yes. And it sounds like everybody is thinking about a doublet, single plus targeted agents, to try to continue that thought of prolonging survival but not giving so much.
Yelena Y. Janjigian, MD: I always tell my patients that you have to think about it as a long-term plan but also use standard and experimental therapies as stepping stones. So, you’re trying to cross a river. The more stepping stones you have, the better.
Johanna C. Bendell, MD: That’s a great way to look at it. Manish, I’m going to hit you on 2 things. First is, when we’re talking about the stepping stones, do we actually set the size of the stepping stone? So, what am I talking about? Nobody ever knows. The question is for the first-line treatment, there are several different approaches you can take, right? Because we treat people with colon cancer with FOLFOX, and then we do this maintenance-type regimen. We also do this in gastric cancer. And we’ve seen this in several trials: you use chemotherapy for 6 months and you’re out. You’re done. So, what’s your thought on where we should go with this?
Manish A. Shah, MD: I think outside of the United Kingdom, many people would actually not stop chemotherapy entirely. I think that we would do a doublet for most patients, and then drop the more toxic agent, the platinum, and continue the 5-FU of some variety in a maintenance or less intensive therapy. I think with our increasing number of treatments, this is going to be important, because people may actually need to have chemotherapy holidays or breaks, and that’s where single-agent ramucirumab actually may be really wonderful. Because, as Ian mentioned, single-agent activity is equal to single-agent activity with a cytotoxic. But I think the other part of it is that in the next 6 months to a year, we very likely might have a PD-1 inhibitor approved for gastric cancer. And then if we start with a doublet and then we use Taxol/ramucirumab, then we use irinotecan, and then we use the PD-1 inhibitor, people won’t get there. And that’s another reason to think about our first-line strategy in an important way.
The idea of combining a targeted agent with a 3-drug regimen, I think that has been proven actually in large trials for epirubicin-based therapy, with an EGFR antibody inhibitor and epirubicin-based therapy, but not true for a modified DCF [docetaxel/cisplatin/5-fluorouracil] or FLOT regimen. We published a modified DCF with Avastin and actually had a very good outcome and also equal safety aspect. So, I think I wouldn’t lump all 3-drug regimens together.

Transcript Edited for Clarity

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Transcript:
 
Johanna C. Bendell, MD: So, can you tell us a little bit more about how you treat metastatic disease in Japan and how you sequence the treatments?
Kohei Shitara, MD: If I had to name a case, a fluoropyrimidine and a platinum agent as a first-line followed by paclitaxel and ramucirumab is commonly used. And it was the most recommended treatment sequencing in our guidelines. I think this is not so different from other countries. Our guidelines are simpler to recommend and are the most recommended one. But the NCCN guidelines have the more various treatment options. We are currently devising these guidelines, and we will increase evaluation of treatment as an optional treatment. But I think the most recommended treatments seem to go the same.
Johanna C. Bendell, MD: Yes. In the first-line setting, you also have access to S1, where we don’t.
Kohei Shitara, MD: Yes. We commonly use S1 rather than capecitabine, but both can be used, and also we can use FOLFOX.
Regarding the HER2-targeting agent, we surely use trastuzumab in combination with either a fluoropyrimidine or a platinum. And in the second-line, paclitaxel and ramucirumab, we surely must recommend that type of treatment based on the RAINBOW study. We also joined the RAINBOW study, and, in over 140 patients, it showed a clear survival benefit, so we use this regimen if a patient had no contraindications. In the HER2-positive case, we use paclitaxel and ramucirumab. And going back to the previous question about what to do after the triplet regimen, we are not so commonly using a triplet regimen, but there are several clinical trials ongoing to evaluate a triplet regimen. From this experience, we use a lower dose of docetaxel, so a paclitaxel-based regimen seemed to be active even if there was a docetaxel-based regimen. So, paclitaxel/ramucirumab is commonly used after a DCS [docetaxel/cisplatin/S1] or DOS [docetaxel/oxaliplatin/S1] triplet regimen. As a third-line option, we use irinotecan. Clearly, this kind of continuation on treatment might be very important to prolong the survival.
Johanna C. Bendell, MD: Yes. And it sounds like everybody is thinking about a doublet, single plus targeted agents, to try to continue that thought of prolonging survival but not giving so much.
Yelena Y. Janjigian, MD: I always tell my patients that you have to think about it as a long-term plan but also use standard and experimental therapies as stepping stones. So, you’re trying to cross a river. The more stepping stones you have, the better.
Johanna C. Bendell, MD: That’s a great way to look at it. Manish, I’m going to hit you on 2 things. First is, when we’re talking about the stepping stones, do we actually set the size of the stepping stone? So, what am I talking about? Nobody ever knows. The question is for the first-line treatment, there are several different approaches you can take, right? Because we treat people with colon cancer with FOLFOX, and then we do this maintenance-type regimen. We also do this in gastric cancer. And we’ve seen this in several trials: you use chemotherapy for 6 months and you’re out. You’re done. So, what’s your thought on where we should go with this?
Manish A. Shah, MD: I think outside of the United Kingdom, many people would actually not stop chemotherapy entirely. I think that we would do a doublet for most patients, and then drop the more toxic agent, the platinum, and continue the 5-FU of some variety in a maintenance or less intensive therapy. I think with our increasing number of treatments, this is going to be important, because people may actually need to have chemotherapy holidays or breaks, and that’s where single-agent ramucirumab actually may be really wonderful. Because, as Ian mentioned, single-agent activity is equal to single-agent activity with a cytotoxic. But I think the other part of it is that in the next 6 months to a year, we very likely might have a PD-1 inhibitor approved for gastric cancer. And then if we start with a doublet and then we use Taxol/ramucirumab, then we use irinotecan, and then we use the PD-1 inhibitor, people won’t get there. And that’s another reason to think about our first-line strategy in an important way.
The idea of combining a targeted agent with a 3-drug regimen, I think that has been proven actually in large trials for epirubicin-based therapy, with an EGFR antibody inhibitor and epirubicin-based therapy, but not true for a modified DCF [docetaxel/cisplatin/5-fluorouracil] or FLOT regimen. We published a modified DCF with Avastin and actually had a very good outcome and also equal safety aspect. So, I think I wouldn’t lump all 3-drug regimens together.

Transcript Edited for Clarity
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