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Third-Line Therapy for Pancreatic Cancer

Insights From:Philip A. Philip, MD, Karmanos Cancer Center; Tanios Bekaii-Saab, MD, Mayo Clinic
Published: Friday, Aug 26, 2016


Transcript:

Tanios Bekaii-Saab, MD:
In pancreas cancer, when you go from first to second line, you lose about 30% to 50% of your patients who will never get to that line, unfortunately, because they progress rapidly, become too fatigued, or they essentially die before making it to second-line treatment. When you get to third-line treatment, you’re talking, again, about fewer patients, unfortunately. We have less than 15%, 20% of the patients who will ever make it to the third line. In fact, that may be optimistic. I think it probably is less than that. When you consider the goals of treatment in the second line versus the third line, in the second line, we do understand that we have a regimen that’s active and that helps us essentially prolong survival further. In the third-line setting, when patients would fail gemcitabine/nab-paclitaxel, let’s say, and 5-FU/MM-398, you really don’t have any options with proven benefit. Those patients, preferentially, will not cross any line. They should preferentially go to clinical trial, but this definitely is a setting where they should go on a clinical trial. Outside of a clinical trial, it’s a little bit more tricky. Certain oncologists would consider FOLFOX. I actually would be reluctant, given the negative data from PANCREOX, and I think the jury is still out on oxaliplatin. Overall, your goals end up being a little different, because there are lesser options. So, it’s either a clinical trial, in my patients, or essentially consider palliative care.

Philip A. Philip, MD: I wish we can talk about multiple lines in this disease, pancreatic cancer, where we don’t have the luxury of going into multiple lines. However, we have to be careful in one thing. The good thing is that we can treat patients who have received frontline treatment, then they go to second-line treatment, and then there will be a small percentage of patients who will go to third-line treatment. But, we have to also keep in mind that patients who go to second-line treatment and go to third-line treatment, they are undergoing some natural selection of the fitter patients who are staying and being able to get second- or third-line treatment. But, having said that, trying to give chemotherapy to someone who’s been exposed to prior chemotherapies, and being able to deliver it without much toxicity and without apparent major decline in their performance status, is certainly something which is welcome. And this is why this regimen becomes an important one.

There’s another reason why it’s an important regimen, because we have been using, over the last few years, a combination of oxaliplatin plus 5-FU. Some call it FOLFOX, which is what we do in this country, and the Europeans did a study in which the combination was called OFF, which was still a combination of 5-fluorouracil and oxaliplatin. The European trial showed some improvement over 5-FU/leucovorin given as a control arm. However, a subsequent trial by the Canadians, in fact, questioned the benefit of the combination. They used FOLFOX. And in that trial, they showed that FOLFOX did worse than the 5-FU/leucovorin, which was really very concerning. So, at this point in time, we know that 5-FU-based treatment, fluoropyrimidine-based treatment, including the use of oxaliplatin plus that drug, can be an option in the second-line setting. But, we also, at the same time, are very concerned that that combination is not necessarily or consistently showing activity. However, the NAPOLI-1 trial was a well conducted prospective trial, and, in this study, we definitely are seeing a benefit for the combination. That makes it a bit easier on us to start thinking of second-line therapy and sequencing treatment when we have a combination that has been prospectively tested in a rigorous trial. Not only that, but it’s an FDA approved combination, whereas the other combination with oxaliplatin is not an FDA approved combination.

We always talk about nowadays second-line treatment, and many of my colleagues are so excited about patients who go on third-line therapy. But, we have to be careful, because those patients who go into third-line treatment are further selected from those who are going to second-line treatment from the frontline. And when it comes to numbers, they are the real minority. We work in academic situations. We get a lot of patients referred to us, so that might give us higher numbers of patients who are in the category, third line. But, in the real world, these are a very, very small number of patients. But, they exist; they come to us and they need treatment, and we have to respond to that. And in those patients, there are not many options, or I can say that there aren’t any options sometimes if we think about it. Patients who have started with gemcitabine/nab-paclitaxel, they can go on liposomal irinotecan plus 5-FU/leucovorin, and then they can maybe go on, subsequent to that, 5-FU/leucovorin and oxaliplatin, FOLFOX. That’s one possibility. But, we have to be careful, because as the lines of treatment advance, how much left of life is also getting shorter. At the same time, patients have to be considered in the light of good quality of life, and not lose the quality of life for treatments that we know are not going to be that effective.

Transcript Edited for Clarity
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Transcript:

Tanios Bekaii-Saab, MD:
In pancreas cancer, when you go from first to second line, you lose about 30% to 50% of your patients who will never get to that line, unfortunately, because they progress rapidly, become too fatigued, or they essentially die before making it to second-line treatment. When you get to third-line treatment, you’re talking, again, about fewer patients, unfortunately. We have less than 15%, 20% of the patients who will ever make it to the third line. In fact, that may be optimistic. I think it probably is less than that. When you consider the goals of treatment in the second line versus the third line, in the second line, we do understand that we have a regimen that’s active and that helps us essentially prolong survival further. In the third-line setting, when patients would fail gemcitabine/nab-paclitaxel, let’s say, and 5-FU/MM-398, you really don’t have any options with proven benefit. Those patients, preferentially, will not cross any line. They should preferentially go to clinical trial, but this definitely is a setting where they should go on a clinical trial. Outside of a clinical trial, it’s a little bit more tricky. Certain oncologists would consider FOLFOX. I actually would be reluctant, given the negative data from PANCREOX, and I think the jury is still out on oxaliplatin. Overall, your goals end up being a little different, because there are lesser options. So, it’s either a clinical trial, in my patients, or essentially consider palliative care.

Philip A. Philip, MD: I wish we can talk about multiple lines in this disease, pancreatic cancer, where we don’t have the luxury of going into multiple lines. However, we have to be careful in one thing. The good thing is that we can treat patients who have received frontline treatment, then they go to second-line treatment, and then there will be a small percentage of patients who will go to third-line treatment. But, we have to also keep in mind that patients who go to second-line treatment and go to third-line treatment, they are undergoing some natural selection of the fitter patients who are staying and being able to get second- or third-line treatment. But, having said that, trying to give chemotherapy to someone who’s been exposed to prior chemotherapies, and being able to deliver it without much toxicity and without apparent major decline in their performance status, is certainly something which is welcome. And this is why this regimen becomes an important one.

There’s another reason why it’s an important regimen, because we have been using, over the last few years, a combination of oxaliplatin plus 5-FU. Some call it FOLFOX, which is what we do in this country, and the Europeans did a study in which the combination was called OFF, which was still a combination of 5-fluorouracil and oxaliplatin. The European trial showed some improvement over 5-FU/leucovorin given as a control arm. However, a subsequent trial by the Canadians, in fact, questioned the benefit of the combination. They used FOLFOX. And in that trial, they showed that FOLFOX did worse than the 5-FU/leucovorin, which was really very concerning. So, at this point in time, we know that 5-FU-based treatment, fluoropyrimidine-based treatment, including the use of oxaliplatin plus that drug, can be an option in the second-line setting. But, we also, at the same time, are very concerned that that combination is not necessarily or consistently showing activity. However, the NAPOLI-1 trial was a well conducted prospective trial, and, in this study, we definitely are seeing a benefit for the combination. That makes it a bit easier on us to start thinking of second-line therapy and sequencing treatment when we have a combination that has been prospectively tested in a rigorous trial. Not only that, but it’s an FDA approved combination, whereas the other combination with oxaliplatin is not an FDA approved combination.

We always talk about nowadays second-line treatment, and many of my colleagues are so excited about patients who go on third-line therapy. But, we have to be careful, because those patients who go into third-line treatment are further selected from those who are going to second-line treatment from the frontline. And when it comes to numbers, they are the real minority. We work in academic situations. We get a lot of patients referred to us, so that might give us higher numbers of patients who are in the category, third line. But, in the real world, these are a very, very small number of patients. But, they exist; they come to us and they need treatment, and we have to respond to that. And in those patients, there are not many options, or I can say that there aren’t any options sometimes if we think about it. Patients who have started with gemcitabine/nab-paclitaxel, they can go on liposomal irinotecan plus 5-FU/leucovorin, and then they can maybe go on, subsequent to that, 5-FU/leucovorin and oxaliplatin, FOLFOX. That’s one possibility. But, we have to be careful, because as the lines of treatment advance, how much left of life is also getting shorter. At the same time, patients have to be considered in the light of good quality of life, and not lose the quality of life for treatments that we know are not going to be that effective.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Oncology Briefings™: Integrating Novel Targeted Treatment Strategies to Advance Pancreatic Cancer CareNov 30, 20181.0
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