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Jan 23, 2020


ASCO Daily News: Welcome to the ASCO Daily News podcast. I'm Lauren Davis. And joining me today is Dr. Heath Skinner, an Associate Professor at the UPMC Hillman Cancer Center specializing in the study and treatment of head and neck cancer. Dr. Skinner maintains an active translational research lab focused upon identifying novel clinically targetable biomarkers of resistance to radiation. Dr. Skinner, welcome to the podcast.


Dr. Heath Skinner: Thanks so much for having me.


ASCO Daily News: We're glad you're here. Today we're talking about ways to improve the patient experience when they're undergoing radiation. One of the ways we want to help patients is to reduce toxicities. So what are some ways to reduce toxicities while maintaining cure rates?


Dr. Heath Skinner: So generally speaking, the side effects due to radiation are largely due to organs that don't actually have cancer cells in them receiving radiation. Unfortunately, there's no way, at least at this point, to actually make radiation appear just in the area of tumor and nowhere else nearby.


However, over the course of several decades, the field has really progressed and utilizing a number of different strategies to try to minimize the amount of radiation going to areas that don't need treatment. Broadly speaking, over that amount of time, we've honed our ability to do that via a few different ways.


Firstly, over the course, again, of several decades, we've actually progressed from back many decades ago we were actually planning radiation by drawing it on a piece of paper. Nowadays we actually use a combination of CAT scans as well as what we call motion management. For example, if I'm treating a tumor in the lung, what I will do is a series of CAT scans to try to visualize that tumor throughout breathing, throughout respiratory motion.


And then I can utilize that advanced imaging to only treat the tumor and to try to minimize the areas of uncertainty of treatment by using that for DCT or four-dimensional CAT scan. Moreover, same thing with the lung. To try to minimize tumor motion and minimize the area of normal lung that receives treatment, I can even do breath hold treatment for example, only treating the tumor when the patient is actually holding their breath, again, trying to minimize the area of normal lung that's receiving radiation.


Moreover, not only have we advanced in regards to visualizing the tumor and visualizing our treatment plan, we've actually progressed in the types of radiation that are given. Starting way back, just doing one field, one beam of radiation, then to several beams of radiation, to more recently utilizing what we call intensity modulated radiation. That's many beams of radiation or even an arc of radiation that is constantly modulated intensity based upon the planning that's done by the physician. Again, with the goal of trying to minimize dose of radiation going to normal tissues.


And finally, every day we've gone from, again, a long time ago utilizing just x-rays to visualize that the patient was largely in the right position every day for radiation, all the way to now doing daily image guidance using a combination of CAT scans and even MRI to try to make certain that the tumor is in the exact right position every day for treatment. Now that's basically technology.


Secondarily, we've tried to develop novel drugs to do one of two things, either to protect normal tissues in combination with radiation or try to make radiation work better to sensitize tumor's radiation but not sensitize normal tissues.  


Firstly, it does have a significant side effect profile in and of itself. And secondarily, the logistics of its delivery are quite difficult. Although that's an ongoing research in that field, we really don't have much in the way of FDA approved radiation mitigators in that sense.


The second part is, can we give a drug that makes tumor more sensitive to radiation while sparing normal tissue. And again, research in that field is ongoing including work in my own lab. However, it's somewhat stalled. Right now, what we do is give cytotoxic chemotherapy with radiation. However, that increases toxicity.


So the question being is, are there biologically or oncology drugs that we can give with radiation to try to widen this gap between making the tumor sensitive and not making the normal tissue sensitive to radiation. But again, that's kind of a work in progress at this point.


ASCO Daily News: It sounds like there is a lot of promising things going on in research. So I'm curious, are there clinical trials that have findings in dose de-escalation that look promising?


Dr. Heath Skinner: So that's a great question. So in my specialty in head and neck cancer, one of the biggest questions right now is how do we treat head and neck cancer that's related to human papillomavirus or HPV. So this type of head and neck cancer is indeed on the rise. Fortunately, outcomes following treatment of HPV-related head and neck cancer are very good compared to HPV negative head and neck cancer, primarily due to how sensitive this cancer is to both radiation and chemotherapy.


However, just like any form of radiation anywhere in the body, there are significant side effects both during treatment and, probably more importantly, after treatment. And unfortunately, many of these side effects can persist lifelong. Even with some of the modalities and some of the imaging and all of those things that I described to you previously, we still do have significant side effects due to radiation.


So because we know this type of tumor is sensitive to radiation and chemotherapy, there are multiple different lines of thought as to how we can maintain the current good outcome while improving toxicity. So one of the first strategies investigated in regards to randomized clinical trials using cetuximab, which is a biologic agent. It was an EGFR antibody combined with radiation.


There was some older data showing that there were improved outcomes comparing radiation versus radiation plus cetuximab. So there were two clinical trials that followed up on this finding,  RG21016 and De-ESCALATE. Both of these trials compared radiation plus cetuximab versus platinum-based chemotherapy plus radiation.


Unfortunately, both trials showed remarkably similar results. Firstly, there was no real difference in toxicity. Using cetuximab versus platinum really did not improve toxicity to any great degree. But more importantly, in both trials there was consistent detriment in survival outcomes. So cetuximab, at least at this point, doesn't really offer an excellent avenue for toxicity mitigation in these patients.


So another trial, kind of using a slightly different approach, that was just read out actually this year was HN-002, which was basically comparing two experimental arms both of which used 60 gray, which is a lower total dose of radiation than what is used commonly. One arm had radiation alone delivered six days a week as a mild kind of intensification, because typically we only deliver it five days a week.


The other arm was 60 gray delivered five days a week combined with weekly cisplatin. However, at the analysis, as it presented, basically only the combined therapy approach met the predetermined progression-free survival endpoint. Now this was a very impressive 90.5% estimated two-year progression-free survival. But again, that was only in the platinum plus radiation dose de-escalated radiation approach. So at this point, I think that this approach will likely be examined in a larger randomized trial setting.


However, reduced dose radiation is certainly not the only means being investigated to de-intensify therapy. Another approach is the use of Transoral Robotic Surgery or TORS. So this approach allows for the oncological resection of tonsillar and base of tongue primary tumors in a way far less morbid than open approaches.


Historically, to try to do surgery in the tonsil or base of tongue, it was very morbid. It was very difficult to do an open procedure in such a small area. However, with the advent of transoral robotic surgery, this has mitigated that morbidity to a great degree.


So the largest trial to date to integrate TORS into a de-escalation approach in HIV positive head and neck cancer was ECOG 3311 which took a risk adapted approach to adjuvant therapy in this setting. Basically, the surgery was done on these patients with tonsil invasive tongue tumors. And the specimens were examined by a pathologist. And then based upon that examination, the patient was stratified into four arms with basically escalating therapy ranging from observation in the lowest risk patients all the way up to adjuvant chemoradiation in those patients with very adverse pathologic features, for example, extranodal extension.


Now we don't have the actual outcomes of this trial available. It's not been reported as yet. However, we do know that about 30% of patients were in the adjuvant chemoradiation arm. Which is to say for those 30 patients, they actually had three different forms of therapy-- surgery, followed by post-operative chemotherapy, and radiation. So that's not really, at least for that group of patients, a therapeutic de-intensification. However, we do need to see the final outcomes data for this trial particularly for those patients not in that arm.


Now there was a similar trial called PATHOS or Post-operative Adjuvant Treatment for HPV-positive tumors which largely asked the same question. However, again, there are many different ways and different avenues this is being approached. Those were the ones probably furthest along.


However, there have been multiple additional single arm trials examining approaches like this. One recent trial that caught my eye was actually by Dr. [INAUDIBLE] and colleagues. It was published, I believe, this past year in the JCO. But what they did was they did TORS, transoral robotic surgery, followed by radiation only to 30 to 36 gray. So this is less than half the dose of what is commonly given today, at least in the definitive setting.


And this is delivered at 1.5 to 1.8 gray per day with concurrent docetaxel, which again is a chemotherapeutic agent we don't typically use in this setting. Now there were excellent toxicity outcomes following this regiment with good survival outcomes as well in the single arm Phase II trial. Although it does bear pointing out that about 80% of these patients had T1, T2 disease, so very kind of smallish tumors. And moreover, there were 10 patients who had a low [INAUDIBLE] recurrence in that trial. Nine of those patients actually had extracapsular extension in the lymph nodes and were in the higher dose cohort.


And finally, another approach is actually inducting chemotherapy for cytoreduction. I think in regards to randomized trial data, there is at least one randomized trial that has looked at that approach, basically to cytoreduce the patient with the hopes that if there is a good response to chemotherapy, that decreased dose of radiation can be given. However again, I think this is investigational approach.


ASCO Daily News: That's great. Sounds very promising. So we know that the staging system has changed for head and neck cancer. What do clinicians need to know about this?


Dr. Heath Skinner: So recently the head and neck staging system has actually and significantly changed. And this is largely based on a few key questions. The biggest of which is really how do we get a handle on HPV positive disease. But before we delve into, I do want to say the treatment of a particular patient has not changed. Even though their stage at presentation may have changed, their treatment for that patient has not. So just because the patient is stage one in the new staging system for an HIV positive patient does not mean that they shouldn't get chemo-radiation. The treatment has not changed for patients of a given old stage versus a new stage. The treatment has not changed.


ASCO Daily News: What has been done is to try to make the staging system more in line with prognosis. So that aside, so what are the big things? Firstly, HPV positive versus HPV negative oropharynx, this is a really big change in the staging of HPV positive disease. And it's actually been quite simplified, for lack of a better term, particularly in the nodal stage.


Dr. Heath Skinner: So with HPV positive disease, basically you have N1, N2, N3 disease. And that's it. So if you have one or more ipsilateral lymph nodes, none larger than 6 centimeter, that patient is now N1, where historically that could have been N2b. Bilateral lymph nodes will buy you stage two. And if any lymph node is larger than 6 centimeter, that's N2. And that is the HPV staging system for oropharynx for the lymph nodes.


For HPV negative nodal staging, it's actually changed based upon extranodal or extracaosular extension. And that has been taken into account, which is a good thing because we know that extracapsular extension really does affect outcome. So ECE is now in the staging system where it hadn't been previously. And I think that's probably the biggest addition, the differential between HPV positive and HPV negative disease and the addition of extracapsular extension.


Other changes, there have been some minor changes to the tumor staging within nasopharynx to try to simplify things a little bit as well as the exact delineation of nodal stage within nasopharynx. And finally, there is a separate staging classification for unknown primary head and neck cancer which is a significant clinical ideology. And that's largely saying the patient will be T0. And the nodal staging will be based upon if it is HPV positive or EBP positive. The nodal staging will be based upon either HIV positive oropharynx respectively. And if it is none of those things, then it would be based upon the nodal staging for HPV negative disease.


And then one more thing for oral cavity squamous cell carcinoma, depth of invasion is actually now incorporated in the staging system where historically it had not been. There's a little bit of difficulty there in regards to doing clinical staging because you really don't have a great handle on radiographic depth of invasion. However, I think that will be later addressed, maybe in later iterations. But at this point, depth of invasion is indeed in the oral cavity squamous cell carcinoma staging system.


ASCO Daily News: Great. That's very good clarification. Thank you. What do you think IS on the horizon for immunotherapies?


Dr. Heath Skinner: I think that this is where a lot of the excitement derives in regards to the management of head and neck cancer and, indeed, most solid tumors. So I think that there are a few key questions. Firstly, where do we integrate immunotherapy into definitive management of head and neck cancer? And I focus largely on locally advanced HPV positive and negative head and neck cancer. So that's where I guess I'll start.


So with [INAUDIBLE] which was a number of Phase I, really, trials to try to figure out how to incorporate nivolumab into platinum and/or cetuximab containing regimens. And this was, again, several different treatment schemas in that trial.


Now where the next step of this is for the cooperative groups, I'm not certain. But that has been completed. However, many of the definitive management trials, at least in the non-recurrent setting, are largely single institution at this point. At our own institution, we have a trial examining pembrolizumab either with concurrent chemoradiation in locally advanced intermediate risk HPV positive or HPV negative head and neck cancer, or in the adjuvant setting. And that trial is currently ongoing.


And additionally, we have a trial looking at, basically, those patients that I mentioned earlier, those in the arm D, it was, of course EGOG 3311, basically trying to replace post-operative concurrent chemo-radiation with post-operative radiation plus immunotherapy, in this case nivolumab. But again, there are many other trials out there looking at the same question. We don't know where to put immunotherapy. And at this point, it's larger PD1 or PDL1 driven therapy. We don't know where the best place is to insert it in the treatment package. Moreover, we don't know actually which patients are going to benefit. So that's currently an area of active research.


A second area of active research is actually what to do in the recurrent metastatic setting. So in patients that have locally regionally recurrent head and neck cancer after radiation, management of those patients is a real challenge. Surgery is very challenging to perform in an irradiated field. And moreover, re-irradiation has a significant and dramatic, in some cases, degree of toxicity. So what do we do in those patients?


So there is the KEYNOTE trial from the NRG basically looking at stereotactic radiation, which we didn't talk about much as yet. But it is basically high dose of radiation per treatment, very few radiation treatments to a small volume. And the goal of it is actually to ablate the tumor.


Standard conventionally fractionated radiation has a goal of doing just fractional DNA damage over a period of time, leading to cell death and tumor death via one mechanism versus ablation is basically a big hammer on the tumor in a short period of time. Now in small volumes, you can do that. In larger volumes, you run into toxicity concerns. So basically it's comparing SBRT versus SBRT plus immunotherapy with the goal of trying to improve outcomes in this very difficult disease setting. And that trial is currently ongoing and accruing.


And then finally, one area of particular interest is oligometastatic disease. We talked about recurrent disease and the recurrent metastatic setting, now kind of metastatic and oligometastatic head and neck cancer. There is a significant question as to whether or not using this same approach, this SBRT, this Stereotactic Radiation Therapy plus immunotherapy can actually work as a tumor vaccine. Which is to say that you give this very high dose of radiation to one tumor, can you prime the immune system in combination with IO agents to actually attack other tumors and microscopic cancer cells throughout the body


Unfortunately, in head and neck cancer, although in melanoma and a few other disease sites there are some promising data, thus far there has been one trial in head and neck cancer questioning this approach, basically using nivolumab versus nivolumab plus SBRT, which was unfortunately negative. Did not show improvements in regards to objective response rates or outcomes.


However, one question remains. Is PD1 or PDL1 therapy in this setting the best approach? There are a number of other different targets and even emerging targets and IO targets that have yet to be investigated in that setting. And I think that, again, it continues to be a very interesting an active research question.


ASCO Daily News: That's great. It sounds like there's a lot of promising research happening and all to the benefit of patients. It's been a real pleasure speaking with you today. I thank you so much for being on our podcast.


Dr. Heath Skinner: Thank you so much for having me. It's been a pleasure.


ASCO Daily News: And to our listeners, thank you for tuning into the ASCO Daily News podcast. If you're enjoying the content, we encourage you to rate us and review us on Apple Podcast.


Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.


COI Disclosure: 

Heath Skinner - No Relationships to Disclose