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Optimizing Treatment of Metastatic Gastric/GEJ Cancer

Insights From: David Ilson, MD PhD, Memorial Sloan Kettering Cancer Center; Minaxi Jhawer, MD, Englewood Hospital and Medical Center
Published: Monday, Jul 30, 2018



Transcript: 

David Ilson, MD, PhD: Metastatic esophagogastric disease is not curable. This is a disease where complete responses are very rare. Most patients, if they benefit from chemotherapy, have partial responses or control of the cancer. The survival times of metastatic disease range around 12 months with currently available chemotherapy. For the vast majority of patients, 2-drug regimens would be preferable. Fluorinated pyrimidine is the cornerstone of chemotherapy in combination with a platinum agent, and there’s pretty much a global consensus that it’s standard first-line treatment. We typically model the dose and schedule on colorectal cancer chemotherapy, so we would give a 24-hour, 48-hour infusion of 5-FU [fluorouracil] every 2 weeks, typically in combination with oxaliplatin. Oxaliplatin is as good as or better than cisplatin.

There are randomized trials, particularly a salient one from Germany that compared 5-FU/oxaliplatin versus 5-FU/cisplatin. In all endpoints, the 5-FU/oxaliplatin trended better in response rate, PFS [progression-free survival], and overall survival. Particularly in patients over the age of 65, there was a significant survival benefit. We consider infusional 5-FU/oxaliplatin as a standard regimen. Capecitabine can be considered, but if a patient is going to be on treatment for months and months and months, the issue of hand-foot syndrome is significant, so we typically prefer the IV [intravenous] 5-FU over the oral 5-FU.

Other agents that could be considered for adding to first-line treatment would be a taxane or irinotecan. We do have the randomized trial of DCF [docetaxel/cisplatin/5-fluorouracil] versus platinum/5-FU, which showed modest survival and response advantages for DCF over 2-drug platinum/5-FU but at the cost of substantial toxicity. Typically, we would reserve a triplet regimen for a highly symptomatic patient, where you need that extra percentage point. You need to see a response quickly, where they’re also well enough to tolerate 3-drug therapy. The alternative regimen is the FLOT [docetaxel/oxaliplatin/fluorouracil/leucovorin] regimen, which is also used for metastatic disease in Germany.

The same issues come up. It’s a more toxic regimen. The Germans actually did a randomized trial in patients over the age of 65 comparing FLOT versus 5-FU/oxaliplatin and did not demonstrate a survival difference. Typically, the vast majority of patients are going to be best served with 2-drug therapy, 5-FU platinum-based therapy, where we reserve the addition of the taxane for the highly symptomatic, young, and good performance status patient. Certainly, there’s not clear evidence that older patients are getting any survival benefit from this treatment. The other argument not to use the taxane up front, which we’ll talk about, is now the availability of combining ramucirumab with paclitaxel second-line, which is quite an effective salvage option.

Minaxi Jhawer, MD: In gastric cancer, we have a significant number of drugs that are very active. For example, there are 5-fluorouracil and capecitabine; there are platinum drugs like cisplatin and oxaliplatin; there are taxanes like paclitaxel and docetaxel; and then there are more targeted therapies. These target specific receptors. HER2-targeted therapy is trastuzumab. Patients who have PD-L1 overexpressing tumors or MSI [microsatellite instability]-high tumors do well with pembrolizumab, and then there’s a VEGF-targeted drug, which is ramucirumab.

Combinations of these drugs, or even single-agent drugs, essentially give us the opportunity to use them in the palliative care setting for patients in different sequences. Out of preference, I tend to like FOLFOX, which is 5-FU/oxaliplatin and folinic acid, given just the way it would be as the modified FOLFOX6 for colon cancer. That tends to be a preferred regimen. It’s generally well tolerated. You have expected toxicity, and it’s well managed. I tend to move from FOLFOX to paclitaxel/ramucirumab in the second line, which is approved as well. If the patients have a HER2-overexpressing tumor, you would put in Herceptin, trastuzumab, through the treatment. At that point, if they failed these prior lines of therapy and are known to be MSI-high or PD-L1 overexpressing, pembrolizumab becomes the next standard of care to consider.

Transcript Edited for Clarity 
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Transcript: 

David Ilson, MD, PhD: Metastatic esophagogastric disease is not curable. This is a disease where complete responses are very rare. Most patients, if they benefit from chemotherapy, have partial responses or control of the cancer. The survival times of metastatic disease range around 12 months with currently available chemotherapy. For the vast majority of patients, 2-drug regimens would be preferable. Fluorinated pyrimidine is the cornerstone of chemotherapy in combination with a platinum agent, and there’s pretty much a global consensus that it’s standard first-line treatment. We typically model the dose and schedule on colorectal cancer chemotherapy, so we would give a 24-hour, 48-hour infusion of 5-FU [fluorouracil] every 2 weeks, typically in combination with oxaliplatin. Oxaliplatin is as good as or better than cisplatin.

There are randomized trials, particularly a salient one from Germany that compared 5-FU/oxaliplatin versus 5-FU/cisplatin. In all endpoints, the 5-FU/oxaliplatin trended better in response rate, PFS [progression-free survival], and overall survival. Particularly in patients over the age of 65, there was a significant survival benefit. We consider infusional 5-FU/oxaliplatin as a standard regimen. Capecitabine can be considered, but if a patient is going to be on treatment for months and months and months, the issue of hand-foot syndrome is significant, so we typically prefer the IV [intravenous] 5-FU over the oral 5-FU.

Other agents that could be considered for adding to first-line treatment would be a taxane or irinotecan. We do have the randomized trial of DCF [docetaxel/cisplatin/5-fluorouracil] versus platinum/5-FU, which showed modest survival and response advantages for DCF over 2-drug platinum/5-FU but at the cost of substantial toxicity. Typically, we would reserve a triplet regimen for a highly symptomatic patient, where you need that extra percentage point. You need to see a response quickly, where they’re also well enough to tolerate 3-drug therapy. The alternative regimen is the FLOT [docetaxel/oxaliplatin/fluorouracil/leucovorin] regimen, which is also used for metastatic disease in Germany.

The same issues come up. It’s a more toxic regimen. The Germans actually did a randomized trial in patients over the age of 65 comparing FLOT versus 5-FU/oxaliplatin and did not demonstrate a survival difference. Typically, the vast majority of patients are going to be best served with 2-drug therapy, 5-FU platinum-based therapy, where we reserve the addition of the taxane for the highly symptomatic, young, and good performance status patient. Certainly, there’s not clear evidence that older patients are getting any survival benefit from this treatment. The other argument not to use the taxane up front, which we’ll talk about, is now the availability of combining ramucirumab with paclitaxel second-line, which is quite an effective salvage option.

Minaxi Jhawer, MD: In gastric cancer, we have a significant number of drugs that are very active. For example, there are 5-fluorouracil and capecitabine; there are platinum drugs like cisplatin and oxaliplatin; there are taxanes like paclitaxel and docetaxel; and then there are more targeted therapies. These target specific receptors. HER2-targeted therapy is trastuzumab. Patients who have PD-L1 overexpressing tumors or MSI [microsatellite instability]-high tumors do well with pembrolizumab, and then there’s a VEGF-targeted drug, which is ramucirumab.

Combinations of these drugs, or even single-agent drugs, essentially give us the opportunity to use them in the palliative care setting for patients in different sequences. Out of preference, I tend to like FOLFOX, which is 5-FU/oxaliplatin and folinic acid, given just the way it would be as the modified FOLFOX6 for colon cancer. That tends to be a preferred regimen. It’s generally well tolerated. You have expected toxicity, and it’s well managed. I tend to move from FOLFOX to paclitaxel/ramucirumab in the second line, which is approved as well. If the patients have a HER2-overexpressing tumor, you would put in Herceptin, trastuzumab, through the treatment. At that point, if they failed these prior lines of therapy and are known to be MSI-high or PD-L1 overexpressing, pembrolizumab becomes the next standard of care to consider.

Transcript Edited for Clarity 
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