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Management of Borderline Resectable Pancreas Cancer

Panelists: Johanna C. Bendell, MD, Sarah Cannon Research Institute; Winson Y. Cheung, MD, MPH, University of Calgary and CancerControl Alberta; Manuel Hidalgo, MD, PhD, Harvard Medical School and Beth Israel Deaconess Medical Center; Ramesh K. Ramanathan, MD, Mayo Clinic; Tanios Bekaii-Saab, MD, FACP, Mayo Clinic; Thomas Seufferlein, MD, University of Ulm
Published Online: Thursday, Nov 09, 2017



Transcript: 

Johanna C. Bendell, MD: Tony, the Mayo Clinic has some very, very interesting data on looking at outcomes once these patients have been taken to surgery, and there may be predictors of people who will do better or worse. Can you tell us a little bit about that?

Tanios Bekaii-Saab, MD, FACP: Yes. This is interesting. We’re actually, I think, lucky that we have some surgeons who are happy not to do surgery on the patients that shouldn’t get surgery. Some still want to do surgery on every patient, but it’s always good to work with a surgeon who’s willing to say, “Give it a shot,” if that patient declares himself or herself as unresectable. “I don’t want to do that surgery. I’m happy that I haven’t done it on the patient.” This sets a good stage.

We’ve tried to standardize, a little bit more. But, with a particular practice, we’ve been finding out that, first of all, we’ve moved for some—either to clinical trials or what we call “total neoadjuvant therapy,” to borrow the term from rectal cancer. And this is where you move the whole treatment to prior to surgery.

And with this particular practice, what we’ve been finding, from the way it structures (perhaps similar to how you’re doing your FOLFIRINOX followed by gemcitabine/Abraxane) is if you use 1 regimen and it doesn’t seem to essentially induce shrinkage and doesn’t drop the CA 19-9 to a certain level—less than 100 is desirable— then those patients are essentially the ones that will not do good with resection. Those patients are switched to the other regimen. So, if you start with the oxaliplatin, you go to nab-paclitaxel. If you start with nab-paclitaxel, you go to the IROX (irinotecan/oxaliplatin). So, F-NOX (FOLFIRINOX), gemcitabine/Abraxane; gemcitabine/Abraxane, F-NOX. And actually, it was interesting to see the data once we looked back at it. For most patients, you are able to consolidate the advantage by doing the switch. And the outcomes of some of these patients are just short of astounding.

So, if you select those patients who are most likely to be local and those that are most likely to respond to local therapy, and you’ve tested their biology, those patients are the ones that actually end up benefitting the most from surgery, to the point of at least 20%, or maybe more than 20%. But, we know that 20% of the patients should never get surgery, even when it’s clearly resectable. Those are the patients, in fact, that would do better not having surgery and going through the complications, or not getting any exposure to systemic therapy when they should. And those are the patients that may have worse survival by going to surgery than not. And so, if you select those patients out by doing different types of maneuvering, then I think we can optimize the outcome of these patients who go to resection.

Johanna C. Bendell, MD: Using CA 19-9 as a guide is very interesting. We’ve seen neoadjuvant approaches in small trials with FOLFIRINOX, FOLFIRINOX with radiation, gemcitabine/nab-paclitaxel, and gemcitabine/nab-paclitaxel with radiation. What ongoing studies do we have, right now, that are looking at patients? Ramesh, can you tell us about a few of them?

Ramesh K. Ramanathan, MD: For borderline to potentially resectable?

Johanna C. Bendell, MD: Yes.

Ramesh K. Ramanathan, MD: One problem is there is a proliferation of single institution studies across the United States and Europe, which makes it difficult to come to a consensus of what’s best. It’s chemotherapy followed by SBRT (stereotactic body radiation therapy) of various doses, and external beam for 4 to 5 weeks. There’s obviously some selection bias, but I think it’s increasingly important to have some randomized studies. And that’s starting in Europe. I think we have a randomized study of pre- versus post-chemotherapy and radiation. I think that’s an important study.

In the United States, there is an intergroup study—there’s a pilot study for borderline resectable cancers with FOLFIRINOX, showing that in a multicenter setting, it was feasible. The R0 resection rate was about 60% in about 35 patients. So, that showed the feasibility. There is also another SWOG study looking at FOLFIRINOX with gemcitabine/nab-paclitaxel in potentially resectable patients. That’s ongoing. The challenges in a multi-center study include staging because within borderline and resectable patients, there is often no concurrence.

Johanna C. Bendell, MD: And Thomas, predicting who is going to recur, after we go through all of this, there is some neat data on circulating tumor DNA. Can you tell us a little bit about what we’ve seen there?

Thomas Seufferlein, MD: There is one issue to mention. When we do neoadjuvant treatment, the main advantage is—and this is the unique chance in a trial—you get the tissue after neoadjuvant treatment, when the patients get operated on. You can differentiate between those responding and those not. And this may really help us in stratifying and selecting, in future times, the identifying biomarkers that really will give us a cue as to who should be treated and who should not be treated preoperatively.

For the postoperative setting, there is also the circulating tumor DNA if you can detect it preoperatively. It disappears postoperatively. And, you can detect RAS mutations. Essentially, it’s a bit more complex than just 1 mutation. It’s a panel of mutations. It’s highly sophisticated, but what they can show is if you cannot detect it, it’s a good prognosis. If circulating tumor DNA reoccurs and you can find it in blood, that’s bad news. That indicates micrometastases or early metastases. Those patients have a high chance of recurrence, early. So, there might be a chance. We talked about adjuvant combination treatment, even in the absence of the evidence. But, sometimes we’re not treating adjuvant cases. We’re treating earlier palliative cases. Maybe those patients will benefit from a more aggressive adjuvant approach, straightaway? So, this might be useful, also, for setting up trials and stratifying patient selection in the adjuvant setting, when we can detect tumor DNA.

Transcript Edited for Clarity 

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Transcript: 

Johanna C. Bendell, MD: Tony, the Mayo Clinic has some very, very interesting data on looking at outcomes once these patients have been taken to surgery, and there may be predictors of people who will do better or worse. Can you tell us a little bit about that?

Tanios Bekaii-Saab, MD, FACP: Yes. This is interesting. We’re actually, I think, lucky that we have some surgeons who are happy not to do surgery on the patients that shouldn’t get surgery. Some still want to do surgery on every patient, but it’s always good to work with a surgeon who’s willing to say, “Give it a shot,” if that patient declares himself or herself as unresectable. “I don’t want to do that surgery. I’m happy that I haven’t done it on the patient.” This sets a good stage.

We’ve tried to standardize, a little bit more. But, with a particular practice, we’ve been finding out that, first of all, we’ve moved for some—either to clinical trials or what we call “total neoadjuvant therapy,” to borrow the term from rectal cancer. And this is where you move the whole treatment to prior to surgery.

And with this particular practice, what we’ve been finding, from the way it structures (perhaps similar to how you’re doing your FOLFIRINOX followed by gemcitabine/Abraxane) is if you use 1 regimen and it doesn’t seem to essentially induce shrinkage and doesn’t drop the CA 19-9 to a certain level—less than 100 is desirable— then those patients are essentially the ones that will not do good with resection. Those patients are switched to the other regimen. So, if you start with the oxaliplatin, you go to nab-paclitaxel. If you start with nab-paclitaxel, you go to the IROX (irinotecan/oxaliplatin). So, F-NOX (FOLFIRINOX), gemcitabine/Abraxane; gemcitabine/Abraxane, F-NOX. And actually, it was interesting to see the data once we looked back at it. For most patients, you are able to consolidate the advantage by doing the switch. And the outcomes of some of these patients are just short of astounding.

So, if you select those patients who are most likely to be local and those that are most likely to respond to local therapy, and you’ve tested their biology, those patients are the ones that actually end up benefitting the most from surgery, to the point of at least 20%, or maybe more than 20%. But, we know that 20% of the patients should never get surgery, even when it’s clearly resectable. Those are the patients, in fact, that would do better not having surgery and going through the complications, or not getting any exposure to systemic therapy when they should. And those are the patients that may have worse survival by going to surgery than not. And so, if you select those patients out by doing different types of maneuvering, then I think we can optimize the outcome of these patients who go to resection.

Johanna C. Bendell, MD: Using CA 19-9 as a guide is very interesting. We’ve seen neoadjuvant approaches in small trials with FOLFIRINOX, FOLFIRINOX with radiation, gemcitabine/nab-paclitaxel, and gemcitabine/nab-paclitaxel with radiation. What ongoing studies do we have, right now, that are looking at patients? Ramesh, can you tell us about a few of them?

Ramesh K. Ramanathan, MD: For borderline to potentially resectable?

Johanna C. Bendell, MD: Yes.

Ramesh K. Ramanathan, MD: One problem is there is a proliferation of single institution studies across the United States and Europe, which makes it difficult to come to a consensus of what’s best. It’s chemotherapy followed by SBRT (stereotactic body radiation therapy) of various doses, and external beam for 4 to 5 weeks. There’s obviously some selection bias, but I think it’s increasingly important to have some randomized studies. And that’s starting in Europe. I think we have a randomized study of pre- versus post-chemotherapy and radiation. I think that’s an important study.

In the United States, there is an intergroup study—there’s a pilot study for borderline resectable cancers with FOLFIRINOX, showing that in a multicenter setting, it was feasible. The R0 resection rate was about 60% in about 35 patients. So, that showed the feasibility. There is also another SWOG study looking at FOLFIRINOX with gemcitabine/nab-paclitaxel in potentially resectable patients. That’s ongoing. The challenges in a multi-center study include staging because within borderline and resectable patients, there is often no concurrence.

Johanna C. Bendell, MD: And Thomas, predicting who is going to recur, after we go through all of this, there is some neat data on circulating tumor DNA. Can you tell us a little bit about what we’ve seen there?

Thomas Seufferlein, MD: There is one issue to mention. When we do neoadjuvant treatment, the main advantage is—and this is the unique chance in a trial—you get the tissue after neoadjuvant treatment, when the patients get operated on. You can differentiate between those responding and those not. And this may really help us in stratifying and selecting, in future times, the identifying biomarkers that really will give us a cue as to who should be treated and who should not be treated preoperatively.

For the postoperative setting, there is also the circulating tumor DNA if you can detect it preoperatively. It disappears postoperatively. And, you can detect RAS mutations. Essentially, it’s a bit more complex than just 1 mutation. It’s a panel of mutations. It’s highly sophisticated, but what they can show is if you cannot detect it, it’s a good prognosis. If circulating tumor DNA reoccurs and you can find it in blood, that’s bad news. That indicates micrometastases or early metastases. Those patients have a high chance of recurrence, early. So, there might be a chance. We talked about adjuvant combination treatment, even in the absence of the evidence. But, sometimes we’re not treating adjuvant cases. We’re treating earlier palliative cases. Maybe those patients will benefit from a more aggressive adjuvant approach, straightaway? So, this might be useful, also, for setting up trials and stratifying patient selection in the adjuvant setting, when we can detect tumor DNA.

Transcript Edited for Clarity 
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