Melanie Cole, MS (Host): [00:00:00] Welcome to the podcast series from the specialists at Penn Medicine. I'm Melanie Cole, today, we have part 1 of a two-part panel discussion with two Penn Medicine specialists highlighting deintensification strategies for head and neck squamous cell carcinoma. Joining me in this panel today are Dr. Karthik Rajasekaran. He's an Associate Professor of Otolaryngology, Head and Neck Surgery, and fellowship-trained in Head and Neck Oncologic and Microvascular Reconstructive Surgery; Dr. Michelle Gentile, she is an Associate Professor of Clinical Radiation Oncology.

Doctors, thank you so much for joining us today. Dr. Gentile, a subset of all SCC head and neck cancers are really—we've learned—caused by HPV. What makes these cancers different than what's been called traditional or HPV-negative head and neck SCCs?

Dr. Michelle Gentile: HPV-positive cancers are caused by [00:01:00] exposure to a virus called human papillomavirus that many of us are exposed to at a young age and naturally clear these infections. A small subset of people will develop cancers from these viruses in the oropharynx, usually many decades after they were first exposed.

So, what makes them different from other types of head and neck squamous cell carcinomas, they tend to happen in healthier patients who are never or minimal smokers, and have an excellent long-term prognosis. Usually, we quote somewhere between 90% and 95% cure rate in never smokers.

Dr. Karthik Rajasekaran: I agree with Michelle. It's interesting, when I was in training, which wasn't actually that long ago, and I trained in the Midwest, we saw a little bit more of the smoking-related cancers. And that's a very different patient demographic. These are younger patients far more common in men than women. And after the age of, 45 or 50 is when most patients present. And they're [00:02:00] usually high-functioning folks with really no symptoms except a lump in their neck.

Host: Well, this is an interesting topic, and thank you both for that introduction. Dr. Rajasekaran, tell us a little bit about deintensification treatment or deintensifying strategies in these HPV individuals. Does it increase the risk of recurrence or metastases? Tell us a little bit about the rationale for this.

Dr. Karthik Rajasekaran: So when we first started treating these patients, we were treating all squamous cell cancers the same way, as if they're smoking-related cancers. So, they're getting a lot of treatment. And Michelle will be able to kind of discuss more on the radiation [00:03:00] side, the specifics.

But we're finding that the HPV-related cancers, even though they're squamous cell cancers, they have a better prognosis. But rather than just saying, "Okay. Well, we're going to start with the lowest possible treatment, and then start ramping up we started realizing, "Okay, well, maybe these patients don't need as much treatment as we are doing with the HPV-negative or smoking-related cancers."

And around 2004, we came up with surgery, the robotic surgery as well. And we found that in some situations, if we removed or surgically resected some of these cancers, we would treat that area to the same degree as if they did not require treatment. And over the span of multiple years, we have started [00:04:00] discussing ways and started implementing ways of just reducing the amount of treatment that we give patients while ensuring that their cure rate remains the same.

Host: So then, thinking about patient selection, Dr. Gentile, speak about qualifications for deintensification candidacy in HPV-positive head and neck cancers. Does the stage of cancer matter? Tell us a little bit about what makes for good prognosis and good patient selection criteria.

Dr. Michelle Gentile: There's been lots of different deintensification trials across the United States in the last probably decade or longer. And so, eligibility is a little different from trial to trial. But generally, they follow a couple of similar features. And I would say most of the time we're reserving these trials for early-stage HPV-positive tumors that are maybe stage I or stage II.

Usually, they can't have very large T4 tumors that are considered bulky or have like really large matted nodes. And then, patients generally have to be healthy. Like, they can't have a lot of other comorbidities, which as Dr. Rajasekaran mentioned, most of these patients are pretty healthy that we're seeing with HPV-positive tumors.

Host: Dr. Rajasekaran, why don't you tell us how deintensification therapy actually works? Is there a uniformity of approach? Are there some treatments more intense than others depending on the disease state Tell us a little bit about how this actually works.

Dr. Karthik Rajasekaran: As Dr. Gentile was mentioning, the whole idea behind deintensification is trying to decrease the morbidity from treatment. We know these are very curable cancers, but we're trying with whatever modality of treatment we offer to limit the toxicities from [00:07:00] treatment.

So when the tumors look like they're very large or the lymph nodes are essentially matted or stuck to surrounding tissue, surgery would not be a great option. And so, we end up doing chemo and radiation. The patients who end up doing really well are where we have an opportunity to combine modalities, so surgery, radiation, and limited chemotherapy. So, these are patients with smaller tumors and a lower lymph node burden, meaning few lymph nodes. We usually like to see less than five lymph nodes. They're smaller. They don't look like they're stuck to surrounding tissues. Those are great patients where at least at Penn, if we remove all of this surgically, then Dr. Gentile has the opportunity of minimizing the amount of radiation that they get.

[00:08:00] Michelle and I, we have a multidisciplinary clinic, so there are patients that are on the borderline, so they see both her and I on the same day. And then, we discuss. Patient hears our opinion, we talk about our opinions, and we try to figure out, "Hey, does surgery followed by a deintensified radiation therapy make sense or not?"

If we feel like, well, we're going to do all the surgery and they're still going to need the same amount of radiation or near the same amount, then surgery does not make any sense. So, the best patients, which is probably only 20% of our cohort, they just have a tonsil or a tongue-based cancer, no lymph nodes, or just one single small lymph node. Then, yeah, we can get away with just surgery alone.

Then, probably, the next step are patients with a small tumor with fewer than five lymph nodes that we can just get away with radiation alone without [00:09:00] chemotherapy. Anything above that, at least Michelle and I, we tend not to favor surgery and just go that chemoradiation route. And those patients are the ones that we probably cannot deintensify. Would you agree, Michelle?

Dr. Michelle Gentile: Absolutely.  Karthik will send patients to me that are kind of borderline where we can talk about both options with them, whether surgery makes sense to go first, what the risks of the surgery may be that we can't predict in terms of needing more treatment—or if we both feel that it's just more straightforward for someone to get a chemoradiation approach. So, we try to really tailor the treatment to each patient so that they're getting the best care but also the best chance of less side effects.

Host: Well then, Dr. Gentile, how do you establish predictors of relative risk in these patients? How are cure rates maintained? Tell us a little bit about those.

Dr. Michelle Gentile: We're trying to do our best job of predicting ahead of time who is [00:10:00] quote-unquote low risk and will do well with deintensification. So, we have criteria for our clinical trials here at Penn. Like we discussed, generally, early stage, less than five lymph nodes, negative margins. There's very specific pathologic criteria that allow us to move forward with these deintensification approaches.

But then, once a patient has received that treatment, we follow them really closely. Usually, Dr. Rajasekaran and I are alternating visits, seeing them regularly, scoping them regularly, imaging regularly, usually every three months for the first couple years. And I would say, even with deintensification, most of these patients do really well. It's very rare to see recurrences, thankfully. And if we see something that's suspicious, generally, we're catching it very, very early and are ready to be aggressive about it.

Dr. Karthik Rajasekaran: I completely agree. It's interesting, there are no good guidelines on this. So if you pull up the national guidelines, it says, "Well, anywhere [00:11:00] from three months to one year, you can follow a patient. Scans are not necessarily needed." And Michelle and I, we came up with an algorithm that works for us. We treat patients as if they're our family members. What would we want to know? I mean, the cure rate is exceptionally high, so we're really targeting those few people that do recur. But the scope exam scans are great for areas that we cannot assess with our hands. So, the lymph nodes and things like that, if they're starting to grow, until they get very big, a physical exam is going to be challenging to determine if their cancer is back. We probably go three months, then four months. We start more frequently and then space it out as time goes on.

Host: Well then, what is the plan, Dr. Rajasekaran, if the tumor doesn't respond as [00:12:00] expected to this treatment?

Dr. Karthik Rajasekaran: Michelle, myself, and Dr. Hartner, he's one of our medical oncologists. We put our heads together and we figure it out. It really depends if the cancers come back in the same spot or in the neck, or if it spreads elsewhere. We're talking about a very small subset of patients, 5%, 7% of patients.

And in that 5-7% of patients, it really varies. There's a very small percentage where the cancer comes back locally, meaning either in the tonsil on the back part of the tongue. There's a very small percentage where it comes back in the neck, and then there's a small percentage where it goes beyond that.

So, if it is in the tonsil, like locally or regionally, it really depends on what sort of treatment they've already had. So, that's where Michelle and I will talk to see if there's a role for [00:13:00] surgery, or if the patients receive re-irradiation. Timing makes a difference. Disease burden makes a difference. All these things make a difference. So, it's a little hard to give a specific answer. It really depends on what the clinical scenario is.

Dr. Michelle Gentile: Just to add to that as well, unfortunately, some patients do develop distant disease. Again, it's not very likely. But when it happens, we also look at that very critically. And there's data showing that being aggressive for patients with very limited lesions may actually give them longer time without disease. So even in those scenarios, sometimes we think about surgery or we think about very high-dose conformal radiation called SBRT to treat just a limited number of spots.

It really is a team effort between Karthik, myself, and Lee Hartner coming up with an individualized plan for each patient.

Host: Thank you both so much for sharing your incredible expertise for other providers and giving us so much to think about today. To refer your patient to Dr. Rajasekaran or Dr. Gentile at Penn Medicine, please call our 24/7 provider-only line at 877-937-PENN, or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/refer. That concludes this episode from the specialists at Penn Medicine. I'm Melanie Cole. [00:23:00]