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Promising Developments in Locally Advanced NSCLC

Panelists:Walter Curran, JR., MD, FACR, Winship Cancer Institute of Emory University; Mark G. Kris, MD, Memorial Sloan Kettering Cancer Center; Jyoti D. Patel, MD, University of Chicago
Published: Tuesday, Apr 03, 2018



Transcript: 

Mark Kris, MD: Walter, can you just tell us what the radiation oncology community is doing, now, to move this field forward? Are there trials underway, now—ones that you’re involved with or any that are part of the groups that you’re affiliated with?

Walter J. Curran Jr., MD: I’ll talk about a couple of trials in stage 3 disease, in general, and then specifically about trials with checkpoint inhibitors. One area that I think is very interesting is using what’s called adaptive design studies, where you actually use what happens to the patient during the course of the trial to influence what you do. We finished enrollment in NRG Oncology, in RTOG, for an adaptive design trial where we got a mid-course PET scan. We were able to modify the radiation field based on a response to a 3- or 4-week PET. We don’t have the data, but we did demonstrate the ability for multiple centers to actually do that. It is possible that in those patients, where there’s a shrinkage, we could dose escalate more safely than we could in PET nonresponders. So, that’s pretty interesting.

There are trials that are either ongoing or in design, where we’re taking this landmark PACIFIC trial. We are using that as the background in the control study and we are adding checkpoint inhibition during radiation. It really has to be done carefully. It has to be done with sort of dose-limiting toxicity studies before the full randomization takes place. And finally, I agree that induction chemotherapy never added much to concurrent chemoradiation. I am still pushing for the idea of checkpoint inhibition as a window of opportunity for those patients with stage 3 disease who are not so symptomatic, where you’d feel like you are risking something by not starting radiation on day 1. I think we could get some of the same exciting data that you’re talking about in operable patients.

Mark Kris, MD: Yes. The one thing that we’ve learned in the neoadjuvant trials is that there is not a strong correlation between imaging studies and pathologic response. If you’re going to look at what happens to the lesion in these patients, you have to be very, very careful. We’ve seen very profound pathologic responses, with no question of response, yet no improvement on CT, and no improvement or sometimes even an increase on PET scans. So, you have to be very careful there. You mentioned using your PET scan to help with making decisions for treatment. I believe there was some older literature that suggested that PET could somehow be influenced by radiation. Is that true, or is that debunked at this point?

Walter J. Curran Jr., MD: That’s true. But, if you’re looking at a 3- or 4-week PET, you don’t usually get the inflammation. So, if you have a 30-day gap between PET 1 and PET 2, you’re really going to be looking at biologic response, not the inflammation associated with that, which you might see within 6 weeks at the end of chemoradiation.

Mark Kris, MD: Jyoti, what are your thoughts about other trials, moving forward, in this space? Do you have any questions? What would you like to see answered?

Jyoti D. Patel, MD: Certainly, we talked a little bit about surgery, upfront. But, can we intercalate surgery into this paradigm? Half of all patients with resectable stage III disease get chemoradiation in the country, right? It’s regional or site specific. We don’t have the best answer. Would there be a scenario in which we treat patients with chemoradiation, and then they undergo resection, and then they are treated with immunotherapy? There’s an ongoing study, through the Hoosier Cancer Research Network, that’s looking at pembrolizumab in that setting—allocating appropriate therapy to those who were not in this trial. Addressing unfit patients or patients with comorbidities is a huge unmet need. Again, this trial was a little different because patients were randomized after concurrent chemoradiation. If we look at the proportion of patients in the United States with locally advanced disease who are eligible for our current clinical trials, it’s still a minority—those who have pristine pulmonary function, and performance status, and lack of weight loss. So, we’re really looking at a subset of the patients in whom we need to improve care.

Mark Kris, MD: I’m still unaware of any evidence that suggests that an induction therapy of any kind makes unresectable people resectable. People have said this, but there is no data to support that. I would be very careful, in 2018, to have a multidisciplinary decision and to make a clear decision whether somebody is resectable or not. And if a patient is resectable, they’re resectable that day. If they’re not, they should get concurrent chemoradiation. For you to be faced with somebody after some induction chemotherapy and then have a decision not to proceed with surgery, I believe that compromises your ability to deliver a curative therapy program. I’d be really, really careful about that. Again, there is the need for a multimodality discussion and a clear multimodality plan. I see these cases all the time in our tumor board. People come to our place from other institutions. That decision-making process hasn’t happened. I can’t emphasize enough to put your team together and work something out. Make up a plan and stick with it. Obviously, the condition can change, but the overall plan should not change.

Walter J. Curran Jr., MD: Having clarity, early on, as you’re describing, is very helpful to the patient and his or her family, as well.

Transcript Edited for Clarity 
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Transcript: 

Mark Kris, MD: Walter, can you just tell us what the radiation oncology community is doing, now, to move this field forward? Are there trials underway, now—ones that you’re involved with or any that are part of the groups that you’re affiliated with?

Walter J. Curran Jr., MD: I’ll talk about a couple of trials in stage 3 disease, in general, and then specifically about trials with checkpoint inhibitors. One area that I think is very interesting is using what’s called adaptive design studies, where you actually use what happens to the patient during the course of the trial to influence what you do. We finished enrollment in NRG Oncology, in RTOG, for an adaptive design trial where we got a mid-course PET scan. We were able to modify the radiation field based on a response to a 3- or 4-week PET. We don’t have the data, but we did demonstrate the ability for multiple centers to actually do that. It is possible that in those patients, where there’s a shrinkage, we could dose escalate more safely than we could in PET nonresponders. So, that’s pretty interesting.

There are trials that are either ongoing or in design, where we’re taking this landmark PACIFIC trial. We are using that as the background in the control study and we are adding checkpoint inhibition during radiation. It really has to be done carefully. It has to be done with sort of dose-limiting toxicity studies before the full randomization takes place. And finally, I agree that induction chemotherapy never added much to concurrent chemoradiation. I am still pushing for the idea of checkpoint inhibition as a window of opportunity for those patients with stage 3 disease who are not so symptomatic, where you’d feel like you are risking something by not starting radiation on day 1. I think we could get some of the same exciting data that you’re talking about in operable patients.

Mark Kris, MD: Yes. The one thing that we’ve learned in the neoadjuvant trials is that there is not a strong correlation between imaging studies and pathologic response. If you’re going to look at what happens to the lesion in these patients, you have to be very, very careful. We’ve seen very profound pathologic responses, with no question of response, yet no improvement on CT, and no improvement or sometimes even an increase on PET scans. So, you have to be very careful there. You mentioned using your PET scan to help with making decisions for treatment. I believe there was some older literature that suggested that PET could somehow be influenced by radiation. Is that true, or is that debunked at this point?

Walter J. Curran Jr., MD: That’s true. But, if you’re looking at a 3- or 4-week PET, you don’t usually get the inflammation. So, if you have a 30-day gap between PET 1 and PET 2, you’re really going to be looking at biologic response, not the inflammation associated with that, which you might see within 6 weeks at the end of chemoradiation.

Mark Kris, MD: Jyoti, what are your thoughts about other trials, moving forward, in this space? Do you have any questions? What would you like to see answered?

Jyoti D. Patel, MD: Certainly, we talked a little bit about surgery, upfront. But, can we intercalate surgery into this paradigm? Half of all patients with resectable stage III disease get chemoradiation in the country, right? It’s regional or site specific. We don’t have the best answer. Would there be a scenario in which we treat patients with chemoradiation, and then they undergo resection, and then they are treated with immunotherapy? There’s an ongoing study, through the Hoosier Cancer Research Network, that’s looking at pembrolizumab in that setting—allocating appropriate therapy to those who were not in this trial. Addressing unfit patients or patients with comorbidities is a huge unmet need. Again, this trial was a little different because patients were randomized after concurrent chemoradiation. If we look at the proportion of patients in the United States with locally advanced disease who are eligible for our current clinical trials, it’s still a minority—those who have pristine pulmonary function, and performance status, and lack of weight loss. So, we’re really looking at a subset of the patients in whom we need to improve care.

Mark Kris, MD: I’m still unaware of any evidence that suggests that an induction therapy of any kind makes unresectable people resectable. People have said this, but there is no data to support that. I would be very careful, in 2018, to have a multidisciplinary decision and to make a clear decision whether somebody is resectable or not. And if a patient is resectable, they’re resectable that day. If they’re not, they should get concurrent chemoradiation. For you to be faced with somebody after some induction chemotherapy and then have a decision not to proceed with surgery, I believe that compromises your ability to deliver a curative therapy program. I’d be really, really careful about that. Again, there is the need for a multimodality discussion and a clear multimodality plan. I see these cases all the time in our tumor board. People come to our place from other institutions. That decision-making process hasn’t happened. I can’t emphasize enough to put your team together and work something out. Make up a plan and stick with it. Obviously, the condition can change, but the overall plan should not change.

Walter J. Curran Jr., MD: Having clarity, early on, as you’re describing, is very helpful to the patient and his or her family, as well.

Transcript Edited for Clarity 
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