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Neoadjuvant Therapy in Resectable Pancreatic Cancer

Insights From:Thomas A. Abrams, MD, Harvard Medical School; Johanna Bendell, MD, Sarah Cannon Research Institute; George P. Kim, MD, 21st Century Oncology; Caio Rocha Lima, MD, Gibbs Cancer Center and Research Institute; Philip A. Philip, MD, PhD, FRCP, Wayne State University
Published: Wednesday, Apr 13, 2016


Transcript:

Johanna Bendell, MD:
I find it’s very institution-dependent. There seem to be institutions that are believers in the neoadjuvant approach, even in a resectable patient versus not. How do you do it at your institution, Philip?

Philip A. Philip, MD, PhD, FRCP: I can tell you that in patients who have resectable disease, the standard of care continues to be surgery up front. And in institutions that have been doing as they’ve done for a long time, like MD Anderson, I haven’t seen any major conclusions from it. Unfortunately, this continues to be institution-dependent. Every institution did their own study.

At this time, there is a national trial which is led by Dr. Sohal from the Cleveland Clinic, and SWOG is involved with it. It’s a study of combination chemotherapy prior to doing surgery. That treatment, which is given prior to surgery, is a comparison between nab-paclitaxel/gemcitabine and FOLFIRINOX. It’s not so much a comparison. You’re trying to pick the winner, so at the next generation of trials, using neoadjuvant treatment will be done. But the point to make is that it’s not a standard of care. Now we’re moving into it.

What about radiation treatment? That trial does not include radiation therapy up front. The reason for that is we’re making a little distinction between resectable disease, where the surgeon is almost confident they can go in and do an R0 resection, versus borderline resectable. Remember, borderline resectable is still resectable, but the surgeon is saying, I can resect it, but I’m just a little bit concerned I’m going to leave a positive margin. In the borderline resectable disease, the clinical trial, which is now being developed, will include radiotherapy.

So, that’s one point. The second point is that in borderline resectable disease, measurement of response is not really that important, because even if you don’t see a response, it may affect the margin. When you clear margins as clear as possible, the measurement of response isn’t that much of importance, and we don’t care as much about it at this point in time. Now, my dream is that in resectable and borderline resectable disease, we end up doing something like we do, for example, in esophageal cancer. We give all the treatment up front, chemotherapy systemic. We may do the radiation treatment, and then we go to surgery. Some patients may not benefit from surgery. We know that. But also that wait of 4 to 6 months, which now surgeons are less concerned about, might also tell us the biology of the disease. If someone develops liver metastases during that time, then you know your surgery won’t make sense, or radiation treatment. So the paradigm shift may come bringing systemic treatment earlier.

Why is it important? Because from our experience, even in patients who have resectable disease and they look fine, giving even single-agent gemcitabine after surgery can be a struggle in a lot of patients. In fact, only 40% or less than 50% get going on good systemic therapy out of surgery. So how are we going to give combination therapy? If you do it before surgery in this disease where nutrition is a problem, complicated surgery is a problem, it makes more sense. That’s where the future is moving. But still, the standard of care is surgery for resectable disease, and neoadjuvant chemotherapy and chemoradiotherapy for the borderline resectable disease.

Johanna Bendell, MD: So, certainly, Tom, it’s all over the place, right? You’ve got people using the new chemotherapy regimens. You had some MD Anderson data that came out at ASCO last year using FOLFIRINOX plus chemoradiation therapy for surgery. What’s grand old Farber doing?

Thomas A. Abrams MD: For borderline resectable disease, which in and of itself is not the easiest thing to pin down, we are typically using FOLFIRINOX, based on the fact that the response rates in the metastatic setting are higher than gemcitabine/nab-paclitaxel, not tremendously higher, but enough to make it a more attractive regimen and then hoping for the best. Dr. Philip presented a very cogent discussion of what we’re thinking. Ultimately, with giving the treatment up front, the benefits are that you might be able to assess a response. You’re going to have a period of time where you can observe the biology of the disease, which is critical. And, if ultimately, you can’t operate, then you were giving effective therapy for metastatic disease anyway. So the potential role for neoadjuvant therapy is it’s not potential. We’re using it and we’re using it often. It’s not a standard of care for absolutely resectable disease, but it’s not inconceivable that it will become one, just because of the rates of recurrence are so high. Most people believe that gemcitabine adjuvantly is weak therapy, maybe not very helpful, maybe delaying recurrences but not really curing patients. Trying to give more aggressive therapy up front, hopefully will lead to more cures, and these trials are underway. So we’re bound to get data at least sometime in the next few years.

Johanna Bendell, MD: For your borderline resectable patients, your locally advanced patients in your own hands, just anecdotally, are you converting more people?

Thomas A. Abrams MD: Maybe. It is really hard to tell what kind of response a patient has gotten from CT scans and MRIs. Ultimately, if your plan was to take a patient to the OR and there hasn’t been any substantial change, it should still be the plan to do so, and then really make the decision intraoperatively. Because there are certainly anecdotes of patients who were thought not to have been downstaged, and then were taken to the operating room, and ultimately were found to have very good responses and were able to be operated on. Whether it resulted in long-term disease-free survival or not, I don’t think we know. But the very fact that patients were able to be taken to the operating room, when their radiology was still very ambiguous, speaks to the fact that this is at least effective at downstaging.

Transcript Edited for Clarity
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Transcript:

Johanna Bendell, MD:
I find it’s very institution-dependent. There seem to be institutions that are believers in the neoadjuvant approach, even in a resectable patient versus not. How do you do it at your institution, Philip?

Philip A. Philip, MD, PhD, FRCP: I can tell you that in patients who have resectable disease, the standard of care continues to be surgery up front. And in institutions that have been doing as they’ve done for a long time, like MD Anderson, I haven’t seen any major conclusions from it. Unfortunately, this continues to be institution-dependent. Every institution did their own study.

At this time, there is a national trial which is led by Dr. Sohal from the Cleveland Clinic, and SWOG is involved with it. It’s a study of combination chemotherapy prior to doing surgery. That treatment, which is given prior to surgery, is a comparison between nab-paclitaxel/gemcitabine and FOLFIRINOX. It’s not so much a comparison. You’re trying to pick the winner, so at the next generation of trials, using neoadjuvant treatment will be done. But the point to make is that it’s not a standard of care. Now we’re moving into it.

What about radiation treatment? That trial does not include radiation therapy up front. The reason for that is we’re making a little distinction between resectable disease, where the surgeon is almost confident they can go in and do an R0 resection, versus borderline resectable. Remember, borderline resectable is still resectable, but the surgeon is saying, I can resect it, but I’m just a little bit concerned I’m going to leave a positive margin. In the borderline resectable disease, the clinical trial, which is now being developed, will include radiotherapy.

So, that’s one point. The second point is that in borderline resectable disease, measurement of response is not really that important, because even if you don’t see a response, it may affect the margin. When you clear margins as clear as possible, the measurement of response isn’t that much of importance, and we don’t care as much about it at this point in time. Now, my dream is that in resectable and borderline resectable disease, we end up doing something like we do, for example, in esophageal cancer. We give all the treatment up front, chemotherapy systemic. We may do the radiation treatment, and then we go to surgery. Some patients may not benefit from surgery. We know that. But also that wait of 4 to 6 months, which now surgeons are less concerned about, might also tell us the biology of the disease. If someone develops liver metastases during that time, then you know your surgery won’t make sense, or radiation treatment. So the paradigm shift may come bringing systemic treatment earlier.

Why is it important? Because from our experience, even in patients who have resectable disease and they look fine, giving even single-agent gemcitabine after surgery can be a struggle in a lot of patients. In fact, only 40% or less than 50% get going on good systemic therapy out of surgery. So how are we going to give combination therapy? If you do it before surgery in this disease where nutrition is a problem, complicated surgery is a problem, it makes more sense. That’s where the future is moving. But still, the standard of care is surgery for resectable disease, and neoadjuvant chemotherapy and chemoradiotherapy for the borderline resectable disease.

Johanna Bendell, MD: So, certainly, Tom, it’s all over the place, right? You’ve got people using the new chemotherapy regimens. You had some MD Anderson data that came out at ASCO last year using FOLFIRINOX plus chemoradiation therapy for surgery. What’s grand old Farber doing?

Thomas A. Abrams MD: For borderline resectable disease, which in and of itself is not the easiest thing to pin down, we are typically using FOLFIRINOX, based on the fact that the response rates in the metastatic setting are higher than gemcitabine/nab-paclitaxel, not tremendously higher, but enough to make it a more attractive regimen and then hoping for the best. Dr. Philip presented a very cogent discussion of what we’re thinking. Ultimately, with giving the treatment up front, the benefits are that you might be able to assess a response. You’re going to have a period of time where you can observe the biology of the disease, which is critical. And, if ultimately, you can’t operate, then you were giving effective therapy for metastatic disease anyway. So the potential role for neoadjuvant therapy is it’s not potential. We’re using it and we’re using it often. It’s not a standard of care for absolutely resectable disease, but it’s not inconceivable that it will become one, just because of the rates of recurrence are so high. Most people believe that gemcitabine adjuvantly is weak therapy, maybe not very helpful, maybe delaying recurrences but not really curing patients. Trying to give more aggressive therapy up front, hopefully will lead to more cures, and these trials are underway. So we’re bound to get data at least sometime in the next few years.

Johanna Bendell, MD: For your borderline resectable patients, your locally advanced patients in your own hands, just anecdotally, are you converting more people?

Thomas A. Abrams MD: Maybe. It is really hard to tell what kind of response a patient has gotten from CT scans and MRIs. Ultimately, if your plan was to take a patient to the OR and there hasn’t been any substantial change, it should still be the plan to do so, and then really make the decision intraoperatively. Because there are certainly anecdotes of patients who were thought not to have been downstaged, and then were taken to the operating room, and ultimately were found to have very good responses and were able to be operated on. Whether it resulted in long-term disease-free survival or not, I don’t think we know. But the very fact that patients were able to be taken to the operating room, when their radiology was still very ambiguous, speaks to the fact that this is at least effective at downstaging.

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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