Barbara A. Burtness, MD: I think the first important thing to say is that the old staging system retains a lot of prognostic power in the HPV-negative patients. But there have been a number of, first, institutional series and, then, database-derived papers, which have demonstrated that for HPV-positive patients, the cure rate for stage 4a and stage 4b disease remained quite high and the staging system was not useful. I think, probably, many people watching this video will have had the experience of patients with head and neck cancer asking, “What do you mean, I have stage 4 disease?” and you’re saying, “No, you’re highly curable.” So, there was a need for a new staging system. The finding of multiple nodes, which drove the N2b designation in the past, has really been rendered much less significant in the new staging system.

So, the stage 4 patients will be only those patients with distant disease. The stage 3 patients will be only those patients with bulky disease, whether that’s T4 cancer or N3 cancer. The data coming from both institutional series and retrospective data do show that this significantly outperforms the 7th edition. There has been some back-and-forth about whether or not using only surgical data is appropriate. There’s a paper from Zain Husain’s group that uses National Cancer Database information that includes radiation therapy and comes up with a very slightly different approach. But the overall message is that patients with HPV-positive disease can have quite a good prognosis, even if they have nodal involvement.

Ezra Cohen, MD: Yes. It just didn’t align to continue calling these patients stage 4 when they were clearly doing as well or even better than patients with stage 3 HPV-negative disease. So, I think the 8th edition has better aligned that. What other changes are there in the staging system? Jared, do you want to comment?

Jared Weiss, MD: Well, I think Barbara has hit nicely on the key point, which was downstaging the nodal status of HPV-driven disease, because it’s very common with HPV to see these large cystic nodes that don’t convey the negative prognosis. In my mind, the second biggest change was adding extracapsular extension into the staging system. This was done for the upstaging of N1 nodes with extracapsular extension to be N2a and upstaging multiple nodes with extracapsular extension to actually be N3b. And there were some data at ASCO looking at to what extent this really affected prognosis. What they showed was that, for multiple nodes being upstaged, it was clear that there was a big difference in prognosis between those groups. It wasn’t clear for a single small node, whether or not that difference really was as critical.

But I think extracapsular extension in our practice already influences us in terms of what we’re going to do, more toward a chemotherapy-radiation strategy. There isn’t a study to cite that I can think of to say that, but we all say, “Look, if there’s ECE present, we know that if we do a surgical approach, we’re going to have to do chemotherapy-radiation after.” And so, in more of a common-sense direction than perhaps a data-driven way, I think we’re all doing mostly the same thing with those patients anyway, which is that we’re giving them chemotherapy-radiation—perhaps whatever we perceive to be our most aggressive chemotherapy-radiation, be that bolus cisplatin or a clinical study.

Barbara A. Burtness, MD: I think, just in terms of where the data come from, that there were older studies. Perhaps they weren’t entirely IMRT-driven studies, but they demonstrated that patients who needed 3 modalities were more likely to be feeding-tube dependent than patients who only got 2.

Jared Weiss, MD: For sure.

Barbara A. Burtness, MD: And so, you think you’re sparing them maybe 1 week of radiation by doing the surgery up front, but you may be costing them something in their following recovery. So, our approach is quite similar.

Ezra Cohen, MD: Yes. I think we always have to keep in mind with these patients that, of course, cure is paramount, but we also want people to try to return to as normal a function as possible.

Jared Weiss, MD: I would say that’s the key way to phrase it, right? It’s not, for example, laryngectomy-free survival. It’s, “How are you eating? How are you talking? What is your function?” You see a change in clinical trial design towards doing just that, and I think in our tumor boards, as well, you hear this being more a part of the conversation. On the one hand, radiation is not all homogenate. It’s probably between about 50 and 70 gray. If you look at historic data, you have the steepest difference in affecting constrictor muscle function and influencing larynx function. On the other hand, these are the same patients for whom we have newer surgeries, transoral approaches, that might do better. So, with all of this complication of the biology and of the stage of these different modalities, it comes down to a conversation, where what’s important is having the right experts in the room talking about both probability of cure and probability of different functional outcomes. And a lot of this comes down to that; more than an absolute answer that you could write out on a table and put in a review article.

Ezra Cohen, MD: Josh, tell us a little bit about how you’re perceiving this and the changes.

Joshua M. Bauml, MD: I think one of the findings from the retrospective series, showing a lack of a prognostic role for the old staging system in HPV-positive disease, that was most alarming was the line that shows the survival for stage 1 was the same as for A. That’s hugely problematic, and it really points to the differential biology. But I think what we’re really at is the infancy of understanding how to apply these biomarkers to these patients. What I hope we’ll have in the future is a staging system that is based on more eloquent science than the tumor is busting out of a node. That’s bad. I think that we can get to a better level of understanding with these patients, and I think that is clearly the next step for these patients.

Jared Weiss, MD: And wouldn’t it be nice to have a staging system with breakpoints that tell you what to do instead of just the prognosis of your patient?

Joshua M. Bauml, MD: Right. And so, the other thing is, how do we apply this new stating system? How do we apply that to our management? We know from the large studies in chemoradiation that ECS, positive surgical margins, are associated with benefit from chemotherapy. The inclusion of p16 positivity in those studies was limited. So, how do we apply those data to patients with p16-positive disease?

Barbara A. Burtness, MD: I actually am not sure that we’re ever going to get to a staging system that’s going to have what you just mentioned—instructions—because the management is changing. Our approach to head and neck cancers, after many decades of not changing all that much, has become extremely dynamic.

Transcript Edited for Clarity