Head & Neck Cancers Treatment Landscape & Algorithm – Dr. Fangdi Sun

Introducing Dr. Fangdi Sun and Head & Neck Cancer Topics You know, after all the conference highlights and recent FDA approvals, we're back to our treatment algorithm discussion. And today we're focusing on head and neck cancer. Hello and welcome back to the Oncology Brothers Podcast. I'm Rahul Ghosen here as always with my brother and your Co host, Rohit Ghosen. Over the next 20 minutes or so, let's appreciate the current treatment landscape for head and neck cancer, but also address some common questions that we often face in our clinic, such as what is the data for high dose versus weakly cisplatin in this disease? How's HPV positive disease behaving differently? What is the role of immunotherapy and anti EGFR? Here is the sandwich approach of periop immunotherapy and post op immunotherapy. Now the new standard of care. To walk us through all this, we're excited to have Doctor Fang D Sun, a head and neck medical oncologist from Stanford University. Fang D, thanks for joining us. Speaker 2 Thank you so much for inviting me. I'm so excited to talk about head and neck cancer because there's really been a number of changes in recent times and hopefully we can talk about all that. Speaker 3 Indeed, Fangdi, thanks so much for joining us again. So going over a broad overview, where we stand for oral cavity in general, surgery is the main modality for a limited stage. And if one is diagnosed with oropharyngeal, we focus more on organ preservation especially when larynx is concerned. So as a result chemo radiation approach and for nasal pharyngeal multi modality is what is utilized. Essential Initial Workup, Imaging, and Biomarker Testing So you think that for someone with suspected head and neck cancer, what is your initial work up and any role of biomarkers here and importantly NGS upfront, are you doing that at all? Speaker 2 In terms of diagnostic work up, I think about it in probably 3 main buckets. The first of which is, you know, most of us will really prefer to be able to directly visualize the tumor if it is in an area that we can see. Often times in the oral cavity, you may be able to see those tumors directly on your physical exam. But for many of these cancers, this is going to require a fiber optic scope. Often our ENT surgeons and other providers are able to provide that for us. In terms of imaging, we think of two components, anatomic imaging at the primary site and the neck. So our preference is typically an MRI scan of the head and neck with contrast and if we cannot get that or sometimes it's complementary to also get ACT scan. Most of us in the academic resource rich setting will admit that we do typically get PET CT scans for systemic imaging. In many cases of CT scan of the chest could also be sufficient for that purpose. When it comes to biomarkers there are a few things we definitely check, but I will admit this is an area where you know I hope to have few additional developments in the future. One that's absolutely critical is IHC for P-16 used as a proxy for HPV status and orofairings primaries which is absolutely required for pharyngeal cancers. Some places will also do an incite you hybridization for high risk HPV. Now you mentioned the use of immunotherapy in the early stage setting which we'll talk about further. Because of that, we now check PDL one IHC across the board in both early and advanced stage disease. Now when it comes to NGSI think this is probably a A wish for the future. When it comes to head and neck cancer in most cases, at the end of the day, most of these are squamous cell cancers akin to squamous cell lung cancers. There have not been many actionable targets or so. While we do occasionally send it in, particularly in the advanced setting for diagnostics, sometimes later stage therapy purposes, it really does not end up being actionable in most cases. I would not consider it a standard part of the diagnostic workup. Speaker 1 You know, as a generalist, when we're dealing with breast cancer or lung cancer in our clinic practice, we're often getting NGS upfront for a lot of these disease sites. But had a neck is 1 site where we're eagerly looking forward for actionable mutation. Even in my practice, the role of NGS here is very limited. Treatment Algorithms for Early and Locally Advanced Disease But going back for early stage here, we're often relying on surgery and adjuvant treatment is dependent on those high risk features. For locally advanced disease, we as medical oncologist play a bigger role. After your initial work up, can you walk us through your treatment algorithm? You touched on the importance of HPV testing. How is that playing a role? How is the tumor behaving differently for HPV positive versus HPV negative disease? Speaker 2 Yeah, this is such an important point to emphasize because HPV positive and negative cancers really are so distinct in many ways. If you think about risk factors for HPV negative cancers, we're thinking about classic factors like alcohol use, smokeless tobacco, cigarette smoking, and overall the prognosis is much worse for these cancers as a whole. Whereas for HPV positive cancers we're talking about high risk HPV vaccine preventable disease, typically a younger agent diagnosis and an overall better prognosis. If you think about oropharynx cancer, HPV negative and positive are distinct staging systems. And because of that the branch point treatment is actually quite different. And you know, we'll break that apart a little bit more. The schema you've shown first here is specifically what I would say is most applicable to HPV negative mucosal head and exquamous cell carcinomas. And I think we'll touch on a little bit later how HPV positive defers and how that's much more reliant in the OR a fairing site on chemo radiation. So in many situations, either definitive chemo radiation or adjuvant chemo radiation after surgery based on risk factors, as you emphasized, we are picking a systemic partner and we think of that systemic partner as a radiosensitizer to help the radiation work better is what I tell patients. As you've alluded to, cisplatin is and does remain our preferred radiosensitizer. There are traditionally two ways to administer that. One is high dose cisplatin every three weeks, usually about two to three doses. The other low dose, 40 million per meter squared weekly, typically somewhere between 5:00 and 7:00 doses. There is an ongoing cooperative group trial in the US directly studying those therapies head to head. However, I think many of us in this country have shifted towards more of the weekly dosing in part because in the adjuvant setting their data from the Japanese cooperative groups that those regimens are associated with lower risks of permanent hearing impairment and kidney injury. So I think many of us versus lean a bit towards the weekly dosing although neither has proven to be better. What do we do when someone cisplatin ineligible? We have you know direct data in the HPV positive population that cisplatin radiosensitizers superior to cituximab and that's one of the older RTOG trials. We have retrospective data that carboplatin based regiments of which weekly carbotaxyl is a common 1 is probably somewhere in between cisplatin and cituximab in terms of efficacy. However, we don't have true level 1 evidence to show where in you know the hierarchy the carboplatin regimen sit, although I think many of us think of them as somewhere in between. As I mentioned in the definitive or curative setting, the newest data we have is from the KEYNOTE 689 trial. This trial specifically looked at patients with locally advanced the stage 3 to 4A mucosal head and exquamous cell carcinoma that was resectable upfront. And in those patients, they were randomized to either perioperative pembrolizumab for a year versus control all over laid upon the standard of care of surgery followed by adjuvant radiation or chemo radiation. This trial did meet its primary endpoint. So it did show an improvement in event free survival with a hazard ratio about point .7. Best for this isn't yet mature. And you know what this ends up looking like and has been FDA approved is 2 cycles of neoadjuvant pembro amongst patients who are PO1CPS1 or greater followed by surgery and then adjuvant pembro along with radiation or chemo radiation as we usually do. Now I want to be really careful about what this trial does and does not represent. The FDA approval is PDL 1 positive only in part because there are less than 5% of patients with PDL one negative in the study. And then secondly, this is not a study of HPV positive disease. Really all the patients except for about 3% were P-16 HPV negative. I would not use such a regimen amongst the P-16 HPV positive population. And the other thing that is playing out in real world practice is patient selection for such a strategy. At the end of the day, this is neoadjuvant pembro. The response rates are not perfect and we end up losing some patients who aren't able to make it to surgery. There will be further intensified neoadjuvant strategies in the future. There's a lot of discussions at tumor boards these days about if a patient is appropriate for this regimen, particularly if they're currently resectable, but may not be resectable if they were to have tumor progression on the neoadjuvant pembrolizumab and. Speaker 3 When combining pembrolizumab in adjuvant setting, are you waiting for radiation to get over or combining that with chemotherapy? How are you maneuvering through that? Speaker 2 So with this particular perioperative regimen, the pembrolizumab was started at the time of adjuvant radiation. Patients are receiving it both with radiation and for that tail afterwards to finish up the one year course. Speaker 1 Right. I think the reason why you're bringing that up is initial data of concurrent radiation and immunotherapy. We all got spooked saying there might be higher toxicity, but we've seen even with our lung cancer trials that that has thankfully not played out. We're not seeing higher toxicities even when we're combining immunotherapy and radiation care together. Post-Treatment Surveillance and Multidisciplinary Team Approach And you know, right now it's three of us, three medical oncologist, but head and neck cancer is also one place where outcomes and survivals and including your quality of life is so much better with multi D approach. And here I'm not just talking about radiation or surgery, but having that nutrition and speech on board as well to ensure our patients can get through these treatments well is very, very important before switching gears to metastatic disease. Thank they went monitoring these patients after their definitive treatment. How frequently are you monitoring scans? The role of CT chest during surveillance? Is there any role of HPHPVDNA titer if this is HPV positive disease? Speaker 2 You're asking some excellent and also very provocative questions. In some sense, if particularly for the patients getting chemo radiation, it is quite standard to get repeat imaging around the three month mark after they finish that therapy, in part to allow time for the inflammation and healing after that therapy. For many of us, that will mean an MRI scan or CT scan, whatever you got up front, plus a PET CT for systemic imaging. If there is anything equivocal on those scans. Sometimes we will repeat again at about 6 months. But honestly, for most patients in our setting, we end up, you know, sort of stopping the standard imaging around 3 months. From there on out, our surveillance is largely endoscopic and by physical exam and places where that may be less accessible. I don't think it's wrong to get additional imaging. We've just never shown in a standardized manner that it's beneficial to get that imaging. As for the HPV blood tests or DNA tests, there are a number available commercially and I think even more in development. One important point to emphasize is that not all patients have positive HPV DNA in the blood at baseline, but is helpful to understand if you are going to use this test, whether that test is positive to begin with, if you're going to use that in surveillance. Some of us are using it in our case. Many of these are part of a research protocol. I do not think it is yet standard, but it may help clue you in towards people to be more careful about surveillance and do some additional targeted imaging if you'd find a positive test in the surveillance setting. Speaker 3 Thanks for touching on this HPVDNA titer story. I feel like it's very similar to what we are doing it for colorectal cancer, which is CTDNA. We'll see how the prospective trials play out in this arena. Systemic Therapy for Metastatic Disease and PD-L1 Scores Now focusing on metastatic space, how are you utilizing systemic therapy, especially when we are talking about the PDL one score? One has to divide this in PDL one negative versus PDL 1 positive and in PDL 1 positive. Are you utilizing pembrolizumab as a single agent or along with chemotherapy? Speaker 2 So our first sign therapy for metastatic disease or disease that we don't deem resectable and doesn't have a definitive option is really based on the keynote O48 study, which is now about 5 or 6 years old. That study actually had three arms, pembro monotherapy, pembro with chemo or the reference standard at that point, which was cetuximab with chemo. From that we came to understand that overall survival in patients who are PDL 11 plus or greater was improved with pembro alone compared to the control of cetuximab with chemo. We learned from that study that overall survival in the overall population was better with pembro and chemo compared to the control arm for patients who are PO1 positive. So one plus or greater, we technically have the option of either pembro monotherapy or pembro with chemo. How do I choose between the two? There is practice variation here. How I think about it is that if you look at the median OS between pembro monotherapy and pembro plus chemo, they actually end up being pretty similar around 12 to 13 months. The difference I really think about is the response rate for these regimens. So if pembro monotherapy, it was close to 20%, whereas pembro plus chemo is closer to 35%. So if I have a patient in whom I'm really worried about tumor growth causing worsening symptoms or just putting them in a bad place, I will lean towards pembro plus chemo in the PDL 1 positive group. Whereas in many other patients we are able to get away with just pembro monotherapy alone, which certainly has fewer side effects by itself. Now the PO1 negative population is a little bit harder. Many of these studies are analyzed sequentially. They start at the PO1 high populations, expand each step of their statistical analysis. So our actual understanding of the negative population is not great. We do still have the option of pembrolizumab plus chemotherapy, but many of us will still consider pituximab plus chemotherapy as well, which was the reference regimen in that Keno O 48 study. Speaker 1 In a patient that has PDA 1 positive disease and is on monotherapy pembrolizumab at the time of Do you add chemotherapy and continue with your pembrolizumab or do you often drop pembrolizumab and move on with chemotherapy alone? Speaker 2 There's not a perfect answer to that. It depends to some extent if a patient has been on it for a while and you know clearly has progressed, you know unequivocally we will mostly switch to chemotherapy and often that chemotherapy will pair with cetuximab. There are, I would say rare situations in which I have given a patient a few doses of pembrolizumab, toeing the line between pembro versus pembro plus chemo and you know things are not going as well as we would like. Sometimes we will add chemo to those situations, but I would say that is a case by case situation. Speaker 3 Thanks for covering that, Fangy. Treatment Differences and HPV Vaccination for Prevention Now focusing on HPV positive oropharyngeal cancer. If you can go where how the treatment differs here versus HPV negative disease and also role of HPV vaccination and prevention here, especially when CDC guidelines are wishy washy from the group of ages 27 to 45. Speaker 2 Yeah, I think there's two things to really emphasize for oropharynx cancer and prickly HPV positive disease is one that it is particularly radiation chemotherapy sensitive. So particularly in the local regionally advanced setting, this is a chemo radiation disease and we try to lean away from surgery because of the morbidity associated with treatment. In terms of vaccination, it is true that vaccination is more strongly recommended for those who are younger because of the typical age of sexual activity exposure and HPV exposure For our individual patients. I do take this as sort of a local opportunity to educate their community and people around them that this is very much a vaccine preventable disease with a relatively well tolerated safe vaccine. At the end of the day, it often comes down to insurance coverage, but if a patient or their family member is able to get it covered, I do recommend it for future prevention. Not in the individual patient who already has the cancer, of course, but potentially in that family members and those around them. Speaker 3 And the partnering up with our radiation oncology colleagues is extremely important because of the responsiveness. Unique Treatment Approaches for Nasopharyngeal Carcinoma Before we close, we will definitely want to touch on nasopharyngeal, which is a huge subset, but the treatment differs here slightly and it's rather a bit unique. For early stage, that is T1 N 0, we see a role of definitive radiation therapy alone and adding on to chemotherapy if the high risk features are present. And for T2N0 or stage 1B, concrete chemoradiation therapy is the way to go. For stage two or three, we have the role of induction and then followed by consolidation therapy and then the questionable role of adjuvant Cape cytopine. Your thoughts around this, are you utilizing adjuvant Cape cytopine for all your patients or some of the patients? Speaker 2 That's a really good question. The paradigm of induction systemic which is typically preferred over adjuvant and that's most often Gen. CIS followed by concurrent chemo radiation as well established and supported by you know international guidelines. When I'm talking about nasopharyngeal carcinoma here, I'm really referring to EBV positive disease. Very often on tissue we're doing incite you hybridization. Most of the studies I'm referencing are all done in endemic regions where essentially everyone is EBV positive and so there's no reason necessarily to test, but in our US populations it is very important to have that testing. Adjuvant capecitabine is really interesting. Specifically, this is adjuvant metronomic capecitabine. Instead of the two weeks on, one week off that you might be used to and say breast cancer, this is given continuously for an entire year at a slightly lower dose. There's a trial from about four years ago that showed improved overall survival well as failure free survival in such a population. I do routinely recommend it in my practice. However, I will admit that it is not universally accepted despite this evidence. This is in part because there are ongoing studies which are looking to move immunotherapy into the local regionally advanced setting in NPC. The caveat there, however, is although many of those studies currently appear promising, none have yet demonstrated overall survival benefit and none are yet, you know, officially approved in that setting. In my mind, immunotherapy remains exploratory in early stage nasopharyngeal cancer and keeps sight of being with its overall survival benefit continues to be something I recommend in this setting. Speaker 1 All right, now on to advanced or metastatic misopharyngeal disease and friendly thoughts on monitoring EBV titers here. Speaker 2 Yeah, excellent question. You know, the paradigm here, if you think about what agents we're giving is not that different from some of the other head and neck cancers, but the specific agents to some extent actually are. This is a cisplatin GEM cytobine backbone with PD1 inhibition and the specific PD1 inhibitors approved here are Tori, Palabab and Pampulumab. Now EVV titers is a very interesting question. You had mentioned before that for those very small tumors in which we're thinking about radiation, radiation or chemo radiation, we use it and we'll think about it. But even there, the exact threshold cut off is not necessarily standardized in the advanced setting. There are many who will check it. But to be honest, I very rarely make actual treatment decisions based on changes in the ebb tighter. And my preference in general is not to check it unless I'm looking at someone in surveillance and trying to use that as another piece of my surveillance plan after definitive treatment. Multidisciplinary Care and Exciting Future in Oncology And then the as we close, any final thoughts for our listeners when treating head and neck cancers? Speaker 2 Yeah. I think a few important things to emphasize. Multidisciplinary collaboration is so key in head and neck cancer, almost more so than any of the other disease sites and oncology. So many of our treatment decisions, particularly in the definitive setting are really patient and disease specific in a way that isn't captured by staging systems or risk models. Even the definition of resectable is very much patient specific based on values and organ preservation. The other thing that we already emphasized is to check for key biomarkers. In some cases like the Oro fairings, this is absolutely required for diagnosis. In terms of P-16 and PDL, one now is something that we use in both the early and late stage settings. And then I think lastly, it's just very exciting time in head and neck cancer. We have a new perioperative approval, albeit imperfect. There are new therapies in the advanced setting in clinical trials, the number of which I think will soon emerge hopefully in the clinic as well. And so we hope that very soon we'll have additional options for our patients, both early and advanced stage. Speaker 1 Absolutely, yeah. Now this is again one disease site where Multi D definitely has to be at the center of all what we're doing. Fangdi, thank you so much for walking us through the current standard of care and head and neck cancer. For our listeners, let's do a quick recap. Key Takeaways and Closing Remarks from the Discussion In today's discussion with doctor Fangdi San from Stanford University, we covered the treatment algorithm for head and neck cancer starting with initial work up, including the importance of HPV testing and EBV testing. For early stage disease. Surgery or definitive radiation is the key, with adjuvant therapy based on risk features such as positive. Speaker 3 Margins In locally advanced settings, conquering chemo radiation with cisplatin remains the standard with some nuances for HPV positive oropharyngeal cases. For metastatic disease, IO chemo combinations are leading the way. We also touched on imaging for monitoring, supportive care, integration and the selective role of expanding molecular testing. Finally, we also highlighted specifics of nasopharyngeal cancer. Speaker 1 Thanks again for joining us. Stay tuned for future episodes as we continue to bridge the gap in oncology. We are the oncology brothers.