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Locally Advanced Pancreas Cancer: Phase II LAPACT Trial

Panelists: John L. Marshall, MD, Georgetown University; George Kim, MD, 21st Century Oncology; Kabir Mody, MD, Mayo Clinic Cancer Center; Eileen M. O
Published: Friday, Aug 03, 2018



Transcript: 

John L. Marshall, MD: Eileen, let’s talk a little bit about borderline. Resectability is in the eye of the beholder, so we’ve gotten a lot of folks getting a preoperative approach. Can you talk a little bit about that in theory? We’ll talk a little bit about the data to support that.

Eileen M. O’Reilly, MD: This is a very topical area in pancreas cancer— borderline resectable and where the limits are in terms of the definitions. I think we all realize there are very nice prints on paper of where these actually fall. But, in truth, it’s a spectrum. Increasingly I would say, and my colleagues may disagree with me here, but I think a pragmatic approach for resectable or borderline, we’re going to be giving all these patients upfront neoadjuvant therapy. We may not necessarily be, because we know we’re not very good at this, predicting who’s going to go on and get surgery at the end of the day. I think things that are encouraging are when patients’ symptoms improve; when their CA 19-9 goes down. But we know radiographically; and this goes to Toni’s point a minute ago about novel imaging approaches to be able to understand who’s responding; this may help select and increase the potential for identifying patients who are going to benefit from an operation.

John L. Marshall, MD: I’m always surprised that we don’t see a lot of change on imaging after a few cycles or a few months, but the marker is down. We explore those patients anyway and find the tumor pops out of there. Is that a modality, even if the imaging is not supporting a regression? Do you explore them anyway and hope that you’re going to be one of those resectable patients?

Kabir Mody, MD: To Toni’s point, I think it’s a combination of factors that play into this. Obviously, CA 19-9 response is important. As you say, imaging is not everything. I think The University of Texas MD Anderson Cancer Center group showed nicely that a large percentage of the patients who did not have a response on imaging; borderline resectable; were able to go on to resection. Again, it speaks a little bit to the experience of the surgeon; how comfortable they are in that area of the abdomen.

John L. Marshall, MD: But, back to your point, you need to be in a center where they’re doing this, right?

Kabir Mody, MD: Right, right. Exploration is fine, as long as that surgeon is willing and able to say no when it’s appropriate, and to say yes when it’s appropriate.

John L. Marshall, MD: That’s a really good point. George, let’s take it one step a little further, and that is, what if it’s a locally advanced and everybody is agreeing that this is not a resectable candidate. There’s some new data; it’s about 6 months old out of GI ASCO, of giving some frontline “neoadjuvant” chemotherapy. You want to review the LAPACT trial?

George P. Kim, MD: What’s going on right now; we are still trying to decide what chemotherapy to use; is it FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin), or is it gemcitabine/nab-paclitaxel (Gemzar/Abraxane)? There’s a lot of discussion, and I think some work out of the Alliance, has shown that FOLFIRINOX may be good in that setting. But this trial actually helps understand what the value of nab-paclitaxel and gemcitabine are. This is a 100-patient trial of locally advanced, unresectable patients. They received conventional treatment with Abraxane; nab-paclitaxel and gemcitabine. About 50% of patients were able to tolerate 6 cycles of treatment. They subsequently went on to additional therapy; 12% continued on chemotherapy, 16% went on to radiation, and 15% went on to surgery, of which half of the patients had R0 resections. Side effects obviously were neutropenia, but otherwise well tolerated. It really helps us bring nab-paclitaxel/gemcitabine into the discussion that it could be used in the neoadjuvant setting; so very helpful.

John L. Marshall, MD: This was unheard of in some way. These were patients that we were never going to operate on in our traditional algorithms, and now we’re seeing the chemotherapy; although not a huge number, but 15% is not inconsequential; is worth approaching. Are you bold enough to tell a patient that you’re thinking this way?

Kabir Mody, MD: I definitely tell a patient up front with locally advanced disease that, “Hey, there’s a very good chance that we’re not going to be able to get this tumor out. But it’s a matter of time and with observation, we’ll take it one step at a time”. I think that the neoadjuvant realm is also a great area for us to explore the activity of new agents. We’ve seen at this conference also, the use of an anti-CTGF agent targeting the stroma, increasing that resection rate. I think there’s a lot of room for improvement certainly.

John L. Marshall, MD: In the unresectable patient, Eileen, there is some frontline chemotherapy that doesn’t enjoy this benefit to surgery; is there a role for radiation in this patient?

Eileen M. O’Reilly, MD: Yes, I think that’s an open question, and you can argue to continue chemotherapy, to stop chemotherapy, or you may choose to include radiation. The LAP07 study suggested there wasn’t a huge advantage; although it may help in terms of delaying when people need to go back on therapy. And those that are symptomatic, there may be a benefit.

John L. Marshall, MD: The local control pain relief, future pain relief, that kind of thing.

Eileen M. O’Reilly, MD: Yes. So, I think it’s an open question.

John L. Marshall, MD: I’ve always tended to do it based on not much; but just a hunch that it’s the right thing. I saw, George, you were shaking your head a little bit there, too.

George P. Kim, MD: I was nodding my head. Yeah, I agree that radiation has a value.

John L. Marshall, MD: In this setting? Chemotherapy first; unresectable; still maybe radiated at that point.

George P. Kim, MD: Let’s stir the pot here. What do you do? You give a couple months of chemotherapy. It’s very hard to measure response in the primary tumor as it is. So, then what do you do, so you don’t get a response. Do you give more chemotherapy? Do you go on to radiation? I’m a believer that maybe more chemotherapy, and then maybe radiation. Radiation still causes about 30% response rate, so it’s still a value. Then the other benefit is that you do get pain control. They showed that a long time ago. Mike Haddock showed that you do get pain relief.

John L. Marshall, MD: Stereotactic radiation, traditional 5 weeks?

George P. Kim, MD: Stereotactic because you don’t want to tie the patient up. Get in there 5 days. You don’t want to give 5-and-a-half weeks of radiation.

John L. Marshall, MD: I don’t know. So we have a debate here?

Eileen M. O’Reilly, MD: The field has dragged their feet, in terms of moving away from the more traditional 5-and-a-half weeks of chemoradiation. It’s hard for patients; it’s tiring. Probably the side effects overall, are worse. But we certainly don’t have randomized data to tell us that SBRT (stereotactic body radiation therapy) is a better way to go. If you speak to some of our radiation colleagues, some have very, very strong opinions about what radiation strategy we should have.

Tanios S. Bekaii-Saab, MD: We have to be careful. I think the data overall, does not support the role of radiation. I don’t think 30% is realistic from radiation in this disease as a response rate. In fact, I don’t think radiation adds much of a response to this. What I hear from my surgeons when we have the discussion about SBRT versus traditional chemoradiation is as follows: If the patient is considered resectable, I don’t need a pinpoint or a smaller field radiation. I can do that and clean it up surgically. What I need is the bed, the whole bed, including the lymph nodes, to be radiated because I want an R0 resection, because that’s the best way we’re going to actually get those patients through survival. Remember, this is only 10 to 15% of the patients, so it’s really limited. And I want to coin a term though and I give credit to 1 of my surgeons. We see that there’s a lot of gray zones between the borderline, and locally advanced, and pretty much treat them the same. Although we may differ, this should be called advanced nonmetastatic pancreatic cancers, and they can fit different shades of gray.

John L. Marshall, MD: I blame ourselves, at some level, for our lack of progress because we, as a group; maybe out of desperation; we move new technologies forward without a lot of organized study. I think our breast cancer colleagues or lung cancer colleagues have been more methodical in their clinical research. I do wonder on some level, if our trying to incorporate and make leaps, has in some way impaired our outcome.

Transcript Edited for Clarity 

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Transcript: 

John L. Marshall, MD: Eileen, let’s talk a little bit about borderline. Resectability is in the eye of the beholder, so we’ve gotten a lot of folks getting a preoperative approach. Can you talk a little bit about that in theory? We’ll talk a little bit about the data to support that.

Eileen M. O’Reilly, MD: This is a very topical area in pancreas cancer— borderline resectable and where the limits are in terms of the definitions. I think we all realize there are very nice prints on paper of where these actually fall. But, in truth, it’s a spectrum. Increasingly I would say, and my colleagues may disagree with me here, but I think a pragmatic approach for resectable or borderline, we’re going to be giving all these patients upfront neoadjuvant therapy. We may not necessarily be, because we know we’re not very good at this, predicting who’s going to go on and get surgery at the end of the day. I think things that are encouraging are when patients’ symptoms improve; when their CA 19-9 goes down. But we know radiographically; and this goes to Toni’s point a minute ago about novel imaging approaches to be able to understand who’s responding; this may help select and increase the potential for identifying patients who are going to benefit from an operation.

John L. Marshall, MD: I’m always surprised that we don’t see a lot of change on imaging after a few cycles or a few months, but the marker is down. We explore those patients anyway and find the tumor pops out of there. Is that a modality, even if the imaging is not supporting a regression? Do you explore them anyway and hope that you’re going to be one of those resectable patients?

Kabir Mody, MD: To Toni’s point, I think it’s a combination of factors that play into this. Obviously, CA 19-9 response is important. As you say, imaging is not everything. I think The University of Texas MD Anderson Cancer Center group showed nicely that a large percentage of the patients who did not have a response on imaging; borderline resectable; were able to go on to resection. Again, it speaks a little bit to the experience of the surgeon; how comfortable they are in that area of the abdomen.

John L. Marshall, MD: But, back to your point, you need to be in a center where they’re doing this, right?

Kabir Mody, MD: Right, right. Exploration is fine, as long as that surgeon is willing and able to say no when it’s appropriate, and to say yes when it’s appropriate.

John L. Marshall, MD: That’s a really good point. George, let’s take it one step a little further, and that is, what if it’s a locally advanced and everybody is agreeing that this is not a resectable candidate. There’s some new data; it’s about 6 months old out of GI ASCO, of giving some frontline “neoadjuvant” chemotherapy. You want to review the LAPACT trial?

George P. Kim, MD: What’s going on right now; we are still trying to decide what chemotherapy to use; is it FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin), or is it gemcitabine/nab-paclitaxel (Gemzar/Abraxane)? There’s a lot of discussion, and I think some work out of the Alliance, has shown that FOLFIRINOX may be good in that setting. But this trial actually helps understand what the value of nab-paclitaxel and gemcitabine are. This is a 100-patient trial of locally advanced, unresectable patients. They received conventional treatment with Abraxane; nab-paclitaxel and gemcitabine. About 50% of patients were able to tolerate 6 cycles of treatment. They subsequently went on to additional therapy; 12% continued on chemotherapy, 16% went on to radiation, and 15% went on to surgery, of which half of the patients had R0 resections. Side effects obviously were neutropenia, but otherwise well tolerated. It really helps us bring nab-paclitaxel/gemcitabine into the discussion that it could be used in the neoadjuvant setting; so very helpful.

John L. Marshall, MD: This was unheard of in some way. These were patients that we were never going to operate on in our traditional algorithms, and now we’re seeing the chemotherapy; although not a huge number, but 15% is not inconsequential; is worth approaching. Are you bold enough to tell a patient that you’re thinking this way?

Kabir Mody, MD: I definitely tell a patient up front with locally advanced disease that, “Hey, there’s a very good chance that we’re not going to be able to get this tumor out. But it’s a matter of time and with observation, we’ll take it one step at a time”. I think that the neoadjuvant realm is also a great area for us to explore the activity of new agents. We’ve seen at this conference also, the use of an anti-CTGF agent targeting the stroma, increasing that resection rate. I think there’s a lot of room for improvement certainly.

John L. Marshall, MD: In the unresectable patient, Eileen, there is some frontline chemotherapy that doesn’t enjoy this benefit to surgery; is there a role for radiation in this patient?

Eileen M. O’Reilly, MD: Yes, I think that’s an open question, and you can argue to continue chemotherapy, to stop chemotherapy, or you may choose to include radiation. The LAP07 study suggested there wasn’t a huge advantage; although it may help in terms of delaying when people need to go back on therapy. And those that are symptomatic, there may be a benefit.

John L. Marshall, MD: The local control pain relief, future pain relief, that kind of thing.

Eileen M. O’Reilly, MD: Yes. So, I think it’s an open question.

John L. Marshall, MD: I’ve always tended to do it based on not much; but just a hunch that it’s the right thing. I saw, George, you were shaking your head a little bit there, too.

George P. Kim, MD: I was nodding my head. Yeah, I agree that radiation has a value.

John L. Marshall, MD: In this setting? Chemotherapy first; unresectable; still maybe radiated at that point.

George P. Kim, MD: Let’s stir the pot here. What do you do? You give a couple months of chemotherapy. It’s very hard to measure response in the primary tumor as it is. So, then what do you do, so you don’t get a response. Do you give more chemotherapy? Do you go on to radiation? I’m a believer that maybe more chemotherapy, and then maybe radiation. Radiation still causes about 30% response rate, so it’s still a value. Then the other benefit is that you do get pain control. They showed that a long time ago. Mike Haddock showed that you do get pain relief.

John L. Marshall, MD: Stereotactic radiation, traditional 5 weeks?

George P. Kim, MD: Stereotactic because you don’t want to tie the patient up. Get in there 5 days. You don’t want to give 5-and-a-half weeks of radiation.

John L. Marshall, MD: I don’t know. So we have a debate here?

Eileen M. O’Reilly, MD: The field has dragged their feet, in terms of moving away from the more traditional 5-and-a-half weeks of chemoradiation. It’s hard for patients; it’s tiring. Probably the side effects overall, are worse. But we certainly don’t have randomized data to tell us that SBRT (stereotactic body radiation therapy) is a better way to go. If you speak to some of our radiation colleagues, some have very, very strong opinions about what radiation strategy we should have.

Tanios S. Bekaii-Saab, MD: We have to be careful. I think the data overall, does not support the role of radiation. I don’t think 30% is realistic from radiation in this disease as a response rate. In fact, I don’t think radiation adds much of a response to this. What I hear from my surgeons when we have the discussion about SBRT versus traditional chemoradiation is as follows: If the patient is considered resectable, I don’t need a pinpoint or a smaller field radiation. I can do that and clean it up surgically. What I need is the bed, the whole bed, including the lymph nodes, to be radiated because I want an R0 resection, because that’s the best way we’re going to actually get those patients through survival. Remember, this is only 10 to 15% of the patients, so it’s really limited. And I want to coin a term though and I give credit to 1 of my surgeons. We see that there’s a lot of gray zones between the borderline, and locally advanced, and pretty much treat them the same. Although we may differ, this should be called advanced nonmetastatic pancreatic cancers, and they can fit different shades of gray.

John L. Marshall, MD: I blame ourselves, at some level, for our lack of progress because we, as a group; maybe out of desperation; we move new technologies forward without a lot of organized study. I think our breast cancer colleagues or lung cancer colleagues have been more methodical in their clinical research. I do wonder on some level, if our trying to incorporate and make leaps, has in some way impaired our outcome.

Transcript Edited for Clarity 
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Oncology Briefings™: Integrating Novel Targeted Treatment Strategies to Advance Pancreatic Cancer CareNov 30, 20181.0
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