ASCO Guidelines: Role of Treatment Deintensification in the Management of p16+ Oropharyngeal Cancer PCO

TRANSCRIPT

An interview with Dr. David Adelstein of the Cleveland Clinic on the ASCO PCO which provides statements on the role of treatment deintensification in the management of p16+ oropharyngeal cancer. Read the full PCO at www.asco.org/head-neck-cancer-guidelines

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Hello and welcome to the ASCO Guidelines Podcast series. My name is Shannon McKernin. And today I'm interviewing Dr. David Adelstein from the Cleveland Clinic Taussig Cancer Institute. Lead author on "Role of Treatment Deintensification in the Management of p16 Positive Oropharyngeal Cancer: ASCO Provisional Clinical Opinion." 

Thank you for being here today, Dr. Adelstein.

Thank you, Shannon. Before we get started, I'd like to first note the contributions of my panel co-chair, Drew Ridge, and those of all of the other panel members. And I'd like to extend a special thank you to ASCO for their support in allowing us to put this together and specifically Nofisat Ismaila who did a tremendous amount of work in allowing us to complete this provisional clinical opinion.

First, can you give us an overview of the clinical issue for this PCO? Sure. So this really came out of the implications of human papillomavirus mediated oropharynx cancer. I think as most of the listeners know, over the last several decades we've recognized the fact that oropharynx cancer has a second ideology, that not all of it is caused by tobacco use, but that the human papillomavirus is now the major ideologic factor in North American and northern Europe. The importance of this is that the human papillomavirus-induced oropharynx cancer is a different disease. It has a number of different characteristics from the kinds of head and neck cancer we've seen in the past. It's a disease that tends to occur in younger patients, patients who are otherwise generally more healthy. It is unassociated with smoking, although it can occur in smokers. But it's much more frequent in nonsmokers.

And I think most importantly, it's a disease that has a dramatically better prognosis than the tobacco related disease. Now over the last several decades, our ability to treat advanced head and neck cancer has improved significantly, because we've begun to incorporate non-operative treatments-- chemotherapy and radiation-- and have been more aggressive in our utilization of chemotherapy and radiation with significantly greater success than we had in the past. The problem with this kind of treatment is that it is quite rigorous. And there's a good deal of acute and, more importantly, late toxicity that patients experience from these kinds of approaches. Now as we became more familiar with the importance of HPV associated oropharynx cancer, we realized that there are subgroups of these patients who have cure rates that are in excess of 90%. And the question arose whether the kinds of rigorous chemotherapy and radiation therapy treatments that we were utilizing were really necessary. Was it necessary to cause this much acute and late toxicity in patients who in vast majority of cases were going to be cured of the disease.

And it's important, because these are younger patients. And the late toxicities are going to have a major impact on their quality of life for a number of years.

What came about was the notion of treatment deintensification, the idea that perhaps it would be possible to deintensify the kinds of treatments we were giving in select patients. It's a very compelling hypothesis for medical oncologists and radiation oncologists. But there are a number of problems as we try to test this hypothesis. The first problem is how do we identify the good risk patients? There are patients with HPV-positive disease who do not do so well-- the heavy smokers and patients with very advanced tumors. And we need to be careful if we're going to be talking about giving less treatment that we don't give less treatment to the patients who have a worse prognosis. We pick the best prognosis patients.

There have been a number of what we call risk stratification schemes that have been developed looking at trying to identify the very good prognosis patients-- those patients who are HPV positive who don't smoke and who have relatively limited disease extent. There's not universal agreement on how best to define these patients. All we know is that they do exist, that you can look at patients with these characteristics and see very good outcomes. One of the issues that has come up is how do we utilize the American Joint Committee staging system-- AJCC the 8th edition. One of the things that AJCC 8 did which is new is that it defined a separate staging system for patients with HPV-positive oropharynx cancer, a system which is entirely different than the staging system that we've used for head and neck cancers for many years. This was based on the recognition that the prognosis of patients with HPV-positive disease is so good so that many patients who we would previously have considered to have stage 4 disease are now classified as having stage 1 tumors, because their prognosis is so good. And that can be confusing, because the typical thought process for an oncologist is that a patient with stage 1 disease should be treated with single modality therapy.

The reason that the HPV-positive patients have such a good prognosis, however, is that many of them have been treated with combined modality therapies. And to make the assumption that because now they're classified as stage 1 is incorrect. It is they shouldn't be treated with less intensive treatments and can be confusing. AJCC 8th edition is a prognostic robust staging system, but it really doesn't help us in defining treatment.

First problem is how best to define patients who are appropriate for deintensification. Second problem is, what do you do to deintensify? What constitutes meaningful deintensification?

Well, over the last 10 or 20 years there have been some significant advances in our standard treatments for all head and neck cancers that weren't developed the idea of deintensification. We now have tremendous experience using transoral surgical techniques, which are generally minimally morbid, much less morbid than the former open techniques that previously were used, which allows consideration of surgery for many of these patients where we wouldn't have considered it before.

Similarly, intensity modulated radiation therapy has been widely adopted, and d clearly an approach using radiation, which is far less difficult, far less toxic than the former 2D or 3D radiation planning techniques that used to be used.

But if we talk about intensification, what kinds of things can we do to deintensify our treatments? Well, one thought is to reduce the radiation dose. Then the question is, how much reduction is reasonable? And how much reduction is going to actually impact on this toxicity? And are our toxicity measuring tools adequate to even detect the difference in reduction of a radiation dose? Many of our toxicity tools are very crude. Perhaps we should be using some of the patient-reported outcome quality of life instruments that are available.

Other thoughts are, perhaps one can reduce the size of the radiation therapy field. Can we reduce the dose of the chemotherapy? Can we eliminate chemotherapy? Can we even use less intensive chemotherapy? Generally, the other treatments for this disease have employed high doses of cisplatin, which is a toxic agent.

And then there the question has been asked as to whether we can reincorporate minimally morbid transoral surgical techniques in an effort to better pathologically stage patients and define more appropriate adjuvant treatment. Perhaps not all patients need adjuvant radiation or chemotherapy and radiation.

All of these approaches are interesting. They're exciting. They're being tested. But all of the experiences is preliminary.

And that really brings us to the third and the biggest problem in any deintensification approach. And that's the need to be certain that if we deintensify our therapy, we're not going to compromise outcomes. It would not be acceptable to give less treatment or less intensive treatment if our survival were compromised. And we have to be certain that we don't do this.

So what has evolved over the past decade is a whole number of treatment approaches that have some very enthusiastic early results. But these are generally single arm phase 2 reports where there is no comparison to conventional treatment. And they become difficult to interpret, because the results in general are very good. I think what really raised a red flag for us and that really caused us to take notice was the results of the RTOG 1016 trial that we reported last year. And at the same time, the European de-escalate trial, both of which had a similar design. These were studies that were designed in an effort to see if treatment deintensification would be possible by randomly comparing the standard treatment radiation and cisplatin with what was felt to be a less intensive approach-- radiation and concurrent cetuximab. And cetuximab is an accepted agent in the United States for treating head and neck cancer.

The assumption here is that the survival would be equivalent when these two arms were compared, but that the toxicity would be improved by giving the less intensive systemic agent-- the cetuximab. The surprise when the study was analyzed was that that assumption was incorrect, that the radiation and cetuximab arm-- the deintensified arm-- actually proved inferior in terms of survival. And this was in both trials-- both the RTOG trial and the trial from Europe. And that was a big note of caution, because it was somewhat unexpected. I think we learned from that kind of a study, from a good randomized-- a large randomized trial-- that even though the outcomes may appear to be good, we need to be very careful about deintensifying our treatment until we're sure that the survival is equivalent.

So although it's tempting for the clinician to see these very exciting reports about administering less treatment with the idea of producing less toxicity, the guideline advisory committee for ASCO really thought it was important that we get the message out that this kind of approach is not a treatment standard. This remains an investigational approach, and that the treatment standards for this disease really haven't changed.

So what are the provisional clinical opinions that were made by the expert panel?

They made several statements. The first was to acknowledge that the idea of treatment deintensification is a very compelling hypothesis, and it does require careful and appropriate testing. The second was that even though we are now better at identifying good prognosis patients, and we've seen some very promising early results, and even though we're now reclassifying patients with previously advanced stage HPV-positive disease as stage 1 or stage 2 tumors, the treatment recommendations for this disease have not changed. And they're based on the results achieved using AJCC 6 and 7.

Standard of non-operated management to patients who are eligible to receive cisplatin remains high concurrent radiation and high dose cisplatin given every three weeks. If patients undergoing a surgical resection, then adjuvant chemotherapy and radiation with radiation and high dose cisplatin every three weeks is recommended in those patients with high risk factors of positive surgical margins or external tumor extension.

And most importantly, deintensification, though it's a compelling hypothesis, is something that should only be undertaken on a clinical trial.

Why is this guidance so important? And how will it affect practice? Well, I think the important thing about this guideline is that it shouldn't affect practice. The practice shouldn't change. The standards of care are not altered. And that for the clinician, this remains something that is exciting, something that should encourage enrollment on a clinical trial, but that we haven't changed treatment standards.

And finally, how will this guidance affect patients?

So from a patient's point of view, I think there is continued reason for optimism. A patient with the diagnosis of an HPV-positive oropharynx cancer is a patient with a very good prognosis. Patients are increasingly sophisticated. They read about the potential for treatment deintensification, and recognize that this is not something which is an accepted standard. But it should encourage their participation in clinical trials if [INAUDIBLE] is offered.

I think ultimately it's a remarkable thing when oncologists can consider the possibility of reducing treatment intensity because the treatment results have been so good.

Great. Thank you for your overview of this PCO. And thank you for your time today, Dr. Adelstein.

And thank you, Shannon. And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full PCO, go to www.asco.org/head-neck-cancer-guidelines. And if you've enjoyed what you've heard today, please rate and review the podcast and refer the show to a colleague.