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The Role of Neoadjuvant Therapy in Pancreatic Cancer

Insights From: Tony Saab, MD, Mayo Clinic; Davendra Sohal, MD, MPH, Cleveland Clinic
Published: Tuesday, Feb 19, 2019



Transcript:

Davendra Sohal, MD, MPH:
So preoperative chemo is, of course, what we are moving toward. The rationale behind this approach is that we use early aggressive chemotherapy regimens—FOLFIRINOX, gem [gemcitabine], nab-paclitaxel, etc—to control systemic disease early. We hit the patient hard, as I mentioned, that in the adjuvant setting we, it is difficult to deliver these chemotherapies after significant surgery. And probably in the neoadjuvant setting they are better tolerated. However, the risk is that patients might fail to get to surgery, but that seems to be a small proportion. In our SWOG S1505 study being presented at ASCO GI [Gastrointestinal Cancers Symposium], for example, we have shown that there is certainly feasibility and safety of this approach of using preoperative chemotherapy. So that’s what we’re moving toward. It also allows us to study the biology of the disease and the response in an in vivo setting, by giving chemotherapy before resection to allow radiologic and other responses assessments.

So for SWOG 1505, the results are being presented, the initial results, for the first time at ASCO GI this year. We are presenting results on the feasibility, eligibility, and safety. We enrolled 147 patients on this study nationwide. It accrued rapidly. The results show, however, that on central radiology review, about 29% of cases were found to be ineligible for resectability criteria under the Intergroup definition. And this ineligibility is based on central retrospective scanned reviews, some involvement in a third of the cases, arterial involvement in half the cases. And in fact, suspicion of metastatic disease in almost 70% of the cases. These are non-mutually exclusive reasons for ineligibility.

Furthermore, however, chemotherapy was well tolerated in 102 patients where we started. A significant proportion were able to achieve, to complete preoperative chemotherapy for 3 months, and 77% of patients went on to surgical resection that was planned. The reasons for not going to surgical resection: a third of the cases were because of progression of disease. Another third are because of toxicity from preoperative chemotherapy and then a smattering of other reasons. But this is in line with prior data from single-agent chemotherapy studies or even with multiagent chemotherapy, for which we did not see an increase in the rate of patients falling out and not being able to get to surgery.

The gemcitabine plus S-1 adjuvant trial in Japan was a very well conducted study, asked an important question of the role of doublet chemotherapy in the neoadjuvant setting. It enrolled about 360 patients, and they treated these patients with gemcitabine plus S-1 for 4 weeks in fact, which is not a long neoadjuvant course. But even that 4-week treatment with gemcitabine plus S-1 prior to resection improved median overall survival from 26 months approximately to 36 months approximately. Both arms, whether up-front surgery or with preoperative chemotherapy, achieved surgical resection rates and R0 resection rates equally. And in both arms patients received adjuvant S-1 for about 6 months, so it is interesting to note that even with 1 month of preoperative chemotherapy there was a significant improvement in overall survival that lends itself to the idea further supporting the use of neoadjuvant therapy.

Tanios Bekaii-Saab, MD: You know, for the longest time we really just wanted to move this therapy up front. There were a lot of studies that looked at before and after, so neoadjuvant versus adjuvant; perioperative split here, split there. But it was mostly smaller studies that were almost introspective analyses. And we had our bias. I always thought that we really need to move the treatment ahead because, again, those patients get so beat after surgery. I mean, you’ve got to salvage them appropriately. And part of the deal is that before surgery they are more capable to get more aggressive treatment. And we know from other cancers that you can do that, and you do it, and in fact in some cancers you essentially even produce better response and better outcomes.

So this PREOPANC study tried to answer this question. Now the problem, of course, with the design of the study is that it was a question of chemotherapy followed by chemotherapy and gemcitabine, which is not our standard today. But at least it’s a proof of concept followed by gemcitabine and radiation, followed by more gemcitabine, versus surgery followed by gemcitabine. So there are some limitations to how you interpret the study. One, does it apply to the world we live in today. The answer is no, except it gives the headline; it doesn’t give the juice. The second question is, of course, the role of radiation, and only puts radiation up front. And we know from a lot of studies in the past that radiation may not have a role in adjuvant setting, although arguably in the neoadjuvant setting perhaps it has a better defined role than the adjuvant setting, because it may increase the rate of R0 resections and resectability, perhaps. That question still needs to be answered.

The gist of the study is that it appears in both borderline resectable, as well as in clearly resectable tumors, that giving a neoadjuvant approach improves outcome versus an adjuvant approach, which is pretty consistent with the study that Dr Sohal discussed with the Japanese study comparing this approach as well. But I think the intriguing thing about the study is that the results were again, pretty impressive. It brings again the question of radiation. Most of the other studies have not included or excluded radiation. This was included, this 1 included radiation in a randomized setting, although the randomization didn’t include the question of radiation.

But today I feel that we are obliged to consider radiation; we’re under obligation to consider radiation neoadjuvantly. I still say no for radiation in adjuvant therapy. I don’t think it has a role. Once you have the surgery, don’t do radiation. But before surgery, I think this study says that we should consider, strongly consider, radiation as part of our regimen. So chemotherapy followed by chemotherapy and radiation followed by surgery seems to be a very acceptable strategy.

I still think, though, at the day we need to ask the question in a randomized setting: Does radiation really matter in this, in the neoadjuvant setting? We don’t have that answer today. We think it probably helps. Now, I want to make it clear, I don’t think it improves survival. I think it improves the chances of a good resection, and it proves local control. What improves survival are 2 things: chemo and surgery. Radiation doesn’t add much to survival.


Transcript Edited for Clarity
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Transcript:

Davendra Sohal, MD, MPH:
So preoperative chemo is, of course, what we are moving toward. The rationale behind this approach is that we use early aggressive chemotherapy regimens—FOLFIRINOX, gem [gemcitabine], nab-paclitaxel, etc—to control systemic disease early. We hit the patient hard, as I mentioned, that in the adjuvant setting we, it is difficult to deliver these chemotherapies after significant surgery. And probably in the neoadjuvant setting they are better tolerated. However, the risk is that patients might fail to get to surgery, but that seems to be a small proportion. In our SWOG S1505 study being presented at ASCO GI [Gastrointestinal Cancers Symposium], for example, we have shown that there is certainly feasibility and safety of this approach of using preoperative chemotherapy. So that’s what we’re moving toward. It also allows us to study the biology of the disease and the response in an in vivo setting, by giving chemotherapy before resection to allow radiologic and other responses assessments.

So for SWOG 1505, the results are being presented, the initial results, for the first time at ASCO GI this year. We are presenting results on the feasibility, eligibility, and safety. We enrolled 147 patients on this study nationwide. It accrued rapidly. The results show, however, that on central radiology review, about 29% of cases were found to be ineligible for resectability criteria under the Intergroup definition. And this ineligibility is based on central retrospective scanned reviews, some involvement in a third of the cases, arterial involvement in half the cases. And in fact, suspicion of metastatic disease in almost 70% of the cases. These are non-mutually exclusive reasons for ineligibility.

Furthermore, however, chemotherapy was well tolerated in 102 patients where we started. A significant proportion were able to achieve, to complete preoperative chemotherapy for 3 months, and 77% of patients went on to surgical resection that was planned. The reasons for not going to surgical resection: a third of the cases were because of progression of disease. Another third are because of toxicity from preoperative chemotherapy and then a smattering of other reasons. But this is in line with prior data from single-agent chemotherapy studies or even with multiagent chemotherapy, for which we did not see an increase in the rate of patients falling out and not being able to get to surgery.

The gemcitabine plus S-1 adjuvant trial in Japan was a very well conducted study, asked an important question of the role of doublet chemotherapy in the neoadjuvant setting. It enrolled about 360 patients, and they treated these patients with gemcitabine plus S-1 for 4 weeks in fact, which is not a long neoadjuvant course. But even that 4-week treatment with gemcitabine plus S-1 prior to resection improved median overall survival from 26 months approximately to 36 months approximately. Both arms, whether up-front surgery or with preoperative chemotherapy, achieved surgical resection rates and R0 resection rates equally. And in both arms patients received adjuvant S-1 for about 6 months, so it is interesting to note that even with 1 month of preoperative chemotherapy there was a significant improvement in overall survival that lends itself to the idea further supporting the use of neoadjuvant therapy.

Tanios Bekaii-Saab, MD: You know, for the longest time we really just wanted to move this therapy up front. There were a lot of studies that looked at before and after, so neoadjuvant versus adjuvant; perioperative split here, split there. But it was mostly smaller studies that were almost introspective analyses. And we had our bias. I always thought that we really need to move the treatment ahead because, again, those patients get so beat after surgery. I mean, you’ve got to salvage them appropriately. And part of the deal is that before surgery they are more capable to get more aggressive treatment. And we know from other cancers that you can do that, and you do it, and in fact in some cancers you essentially even produce better response and better outcomes.

So this PREOPANC study tried to answer this question. Now the problem, of course, with the design of the study is that it was a question of chemotherapy followed by chemotherapy and gemcitabine, which is not our standard today. But at least it’s a proof of concept followed by gemcitabine and radiation, followed by more gemcitabine, versus surgery followed by gemcitabine. So there are some limitations to how you interpret the study. One, does it apply to the world we live in today. The answer is no, except it gives the headline; it doesn’t give the juice. The second question is, of course, the role of radiation, and only puts radiation up front. And we know from a lot of studies in the past that radiation may not have a role in adjuvant setting, although arguably in the neoadjuvant setting perhaps it has a better defined role than the adjuvant setting, because it may increase the rate of R0 resections and resectability, perhaps. That question still needs to be answered.

The gist of the study is that it appears in both borderline resectable, as well as in clearly resectable tumors, that giving a neoadjuvant approach improves outcome versus an adjuvant approach, which is pretty consistent with the study that Dr Sohal discussed with the Japanese study comparing this approach as well. But I think the intriguing thing about the study is that the results were again, pretty impressive. It brings again the question of radiation. Most of the other studies have not included or excluded radiation. This was included, this 1 included radiation in a randomized setting, although the randomization didn’t include the question of radiation.

But today I feel that we are obliged to consider radiation; we’re under obligation to consider radiation neoadjuvantly. I still say no for radiation in adjuvant therapy. I don’t think it has a role. Once you have the surgery, don’t do radiation. But before surgery, I think this study says that we should consider, strongly consider, radiation as part of our regimen. So chemotherapy followed by chemotherapy and radiation followed by surgery seems to be a very acceptable strategy.

I still think, though, at the day we need to ask the question in a randomized setting: Does radiation really matter in this, in the neoadjuvant setting? We don’t have that answer today. We think it probably helps. Now, I want to make it clear, I don’t think it improves survival. I think it improves the chances of a good resection, and it proves local control. What improves survival are 2 things: chemo and surgery. Radiation doesn’t add much to survival.


Transcript Edited for Clarity
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