Advances in Testing and Targeted Therapy for NSCLC: Translating Evidence to Clinical Practice - Episode 5
Shifting focus to early-stage NSCLC, expert panelists define the role of resection and consider when it is appropriate to utilize adjuvant radiation therapy.
Benjamin Levy, MD:We're going to move on now to the more exciting, well, curing patients. We are able to cure patients in the stage IV setting, but not as commonly as we are in the early stage. All these drugs are starting to move into the early stage, thankfully. We have targeted therapies that are now starting to move into early stage, of course, we've got immunotherapy, as Heather will talk about, moving into the early stage in the adjuvant setting and then the neoadjuvant explosion of data that's coming out with neoadjuvant chemo-IO [immunotherapy plus chemotherapy] is pretty remarkable. But, let's just start with every day clinic and the surgical approach for early-stage patients. Jessica, just how do you select these patients? What's the conversation for these patients that are potentially surgically resectable?
Jessica Donington, MD: In surgical patients, most stage I and stage II patients, by almost definition, have resectable disease, and so our decisions are all about physiology, and most of them—that's to be able to determine whether they're operative or not. That all kind of changes in stage III. In stage III, a lot of what determines whether someone is operable or not is the extent of nodal involvement. We've learned a lot over the past 10 years or so about using things like pneumonectomies in that population and trying to do a little bit of picking and choosing who we operate on based upon that. And I think that's really important - the physiologic assessment comes into play, because it is the one stage, stage III, where we know we have to give them systemic therapy also, and your surgery has to pair well with systemic therapy. And if not, we're not going to cure patients. So that's always been the dance of, can I operate, I want to operate, and I also want to make sure they get through their systemic therapy.
Benjamin Levy, MD: Let me ask you another unfair question, and we'll talk about neoadjuvant chemo IO, but, with the advent of durvalumab in the PACIFIC trial [NCT02125461] for stage III disease, and seeing the outcomes that we've seen at 4 years, does that alter your perception of some stage III patients, whether they should be resected or not now that we have chemoradiotherapy followed by durvalumab, with all these great outcomes. We looked at this in our own data set and it did make a dent in some of it.
Jessica Donington, MD: I think it does, I think it's a real difference, to say that we have a population that we're not operating on, that we're giving them curative therapy, and it's got a 40%, 5 year survival, that's really impressive. And sometimes you do have to convince patients, I'm not saying we're not treating you or not working to cure you, and it does set the bar high for surgeons. So, the one thing we have to assume now or have to guarantee a stage III patient is a negative margin. If I don't have a negative margin, I can't get a 40% survival, no matter how much systemic therapy I give them.
Benjamin Levy, MD: Great point.
Jessica Donington, MD: So that really makes that a really close thing that I need to be careful of, so I do think the durvalumab changed that.
Benjamin Levy, MD: For us it did. Jonathan?
Jonathan Wesley Riess, MD: I would just ask Jessica, do you think the pendulum is going to swing back, now that we have the CheckMate 816 data [NCT02998528]?
Jessica Donington, MD: Yes.
Jonathan Wesley Riess, MD: We know now at least an event-free survival benefit to immunotherapy with overall survival trending in the right direction, but don't have to fully report it.
Jessica Donington, MD: I think surgeons always questioned who is unresectable in the PACIFIC trial. Surgeons were not included. There was no definition, so I think there were a lot of people who may have been surgical candidates in there, and I think some of them will come back. The hope is that we will see a higher overall survival and that will, again, keep surgery in that stage 3IIIA discussion.
Benjamin Levy, MD: We've looked into it; even at [John] Hopkins [School of Medicine, Baltimore, Maryland,] I think some. I mean, with the PACIFIC data that’s come out, I do think that, as you've mentioned, if you can't get a negative margin, there's no way you're going to get that type of outcome that we saw in PACIFIC, and so, this did alter our perception. It goes back to the multidisciplinary tumor board too, having a collective discussion about these patients, upfront to decide what to do. Stage IIIA is a heterogeneous disease too, and, depending on who's in the room at that tumor board and what flavor of coffee they have. It may make a big difference with how the surgeon could, or how we approach these patients. Chaitali, can you give us your take on how adjuvant therapy is used at your institution? We know that adjuvant therapy—platinum-based adjuvant therapy is approved for patients in early-stage disease who are resected, we had some data before Lung ART [NCT00410683] to suggest that consolidative radiation or postoperative radiation therapy was important, maybe with N2 disease, or a positive margin, that may have changed, but just your approach on your clinical practice and some of the newer data we have with Lung ART.
Chaitali Nangia, MD: Well, in clinical practice, I think, it's very much a disciplinary approach. You look at all factors, like what are the margins of N2, and sometimes a patient will tell you or the surgeon will tell you, “I'm not so confident about this, though the pathologist is,” so, I think the decisions are best made in a multidisciplinary manner. Adjuvant chemotherapy is pretty standard, it's not something that you will not do, so, that does follow the stage III disease, and the decision for radiation, concurrent or sequential, is based on this margin status and the high-risk features. The update from the Lung ART was that, now that the PORT [NCT00880971] is done in the N2-positive disease, would modern chemotherapy, and modern radiation; it does show almost a 15% improvement in disease-free survival [DFS] at 3 years. I mean it is little bit more toxic, the late cardiopulmonary toxicity was slightly higher, but one can't negate the DFS advantage of PORT.
Benjamin Levy, MD: And I'm not sure if it showed it in OS and I think that putting the question, the role of postoperative radiation therapy.
Jessica Donington, MD: I think we use it a lot less than we used to, although I do have to say, that was older radiation techniques and I'm sure there was a lot of cardiac dosing that went on there, which probably is what impacted the overall survival. But, I do think, also, at least, maybe only in my mind, I don't think that local recurrences and systemic recurrences are the same anymore. I think we can salvage local recurrences so much better than we ever could before that, I think a lot of us are willing to hold off on that radiation for everyone with N2 disease and wait and see what happens.
Jonathan Wesley Riess, MD: Jessica, are there any N2 patients where you would consider it post surgery, like an extracapsular extension or something like that?
Jessica Donington, MD: Definitely for a positive margin, that has to be done. And I think if someone had a bad extracapsular extension, or you felt like you were leaving the highest node and things like that, that I would consider it, but it's many fewer patients than it used to be, like a postage stamp, everyone got it.
Transcript edited for clarity.