Recurrent Respiratory Papillomatosis (RRP) all you need to know - approaches from around the world

In this episode of the podcast, host Natalie Watson explores the comprehensive management of Recurrent Respiratory Papillomatosis (RRP), bringing together three top experts:  Dr Andile Sibiya from South Africa, Mr Adam Donne from the UK, and Prof Craig Derkay from the USA. The discussion covers various aspects of RRP, including differences in patient presentation and healthcare systems across the three countries, the impact of HPV vaccination, and evolving treatment modalities. 

Dr. Sibiya discusses the challenges in South Africa, highlighting delays in diagnosis and access to specialized ENT services, particularly for pediatric patients. She emphasizes the need for centralizing care for younger children and the limitations posed by a tiered healthcare system. Sibiya also mentions the significant disease burden and the approach of using surgery as a primary treatment, with consideration for adjuvant therapies, despite limited access to certain treatments like Bevacizumab.

Adam Donne outlines the situation in the UK, where the National Health Service facilitates early referral for hoarseness, a red flag symptom. He notes the prevalence of RRP and the transition from primarily surgical treatments to incorporating adjuvant therapies such as the Quadrivalent vaccine, Cidofovir, and Bevacizumab. Donne underscores the importance of specialist centres and the evolving treatment landscape, reflecting a shift towards medical management.

Craig Derkay provides insights from the US, describing the typical presentation of RRP in children and adults and the role of tertiary care centres in managing the disease. He highlights the promising results of intravenous Bevacizumab in reducing the need for repeated surgeries and the psychological burden on patients. Derkay also discusses the potential of new DNA vaccines in phase three trials, which show promise in significantly reducing or even curing RRP.

The episode concludes with a consensus on the need for earlier adoption of adjuvant therapies to minimize long-term damage and improve patient outcomes, alongside excitement about future developments in vaccine research. The experts agree on the importance of a multidisciplinary approach, involving patients and families in treatment decisions and maintaining a focus on innovative solutions to improve the care and prognosis of RRP patients.

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Transcript

Andile Sibiya

I think, key for us is maintaining a good airway for this child without doing any further harm. And some of that has led to an evolution and even the modalities that we use surgically to treat papillomatosis.

Adam Donne

So there's evidence to suggest that vaccinated mothers do have anti HPV antibodies that are shown to be present in cord blood. So that protection is really quite profound biologically.

Craig Derkay

Disease that is recurring. The ability to prevent further damage to the vocal cords, which inevitably results from repeated surgical interventions, by using medical management for this disease is very attractive.

Host: Natalie Watson

Welcome to BLA Connections: A Clear Voice. I'm your host Natalie Watson, and I'm delighted to bring you discussions and insights from experts from across the globe on all things laryngology.

Today is a very special podcast, stretching across three time zones around the globe; a veritable feat to get three of the top experts on recurrent respiratory papillomatosis, also termed RRP together, for the benefits of education in laryngology.

In today's episode, we speak to Dr Andile Sibiya from South Africa, previous guest to the BLA Connections: A Clear Voice podcast, and an ENT surgeon with special interest, expertise and training in advanced otology and laryngology. She's passionate about developing and implementing strategies for improving clinical service delivery, and access to specialised care. She's got experience in medical education, strategic planning, business unit development with her MBA, and clinical research.

I also introduce Adam Donne, the UK’s leading expert in RRP. Adam graduated from Manchester Medical School in 1993. He trained in the North Western Deanery and did a PhD in molecular biology of respiratory papillomatosis, and undertook a paediatric ENT fellowship at Evelina Children's Hospital in London. He has been a consultant paediatric ENT surgeon for the past 15 years, and currently, he is ENT curriculum lead, and honorary Clinical Associate Professor at the University of Liverpool, lead examination writer for the JCIE FRCS Part Three written exam, and previously was paediatric section co editor of e-lefENT and paediatric section editor of Clinical Otolaryngology journal, chapter author, and editor of seven textbooks, including being chief editor of Scott Brown's next addition, author of around 50 papers, council member of our beloved BLA, and BOARS. He is clinical lead for the NIHR RfPB funded national respiratory papillomatosis registry. And although the registry has now closed, its data analysis is well underway.

Finally, we welcome Craig Derkay, the world expert on RRP. Fine-endowed professor of paediatric otolaryngology at Eastern Virginia Medical School, and the Chief of Paediatric otolaryngology at the Children's Hospital of the King's Daughters in Norfolk, Virginia, USA. He is chair of the RRP task force created by the American Society of Paediatric Otolaryngology, PI for two CDC-funded national registry studies concerning juvenile and adult-onset RRP, author of over 160 peer-reviewed publications, and over 30 textbook chapters, and most importantly, grandfather to three rambunctious toddlers.

Welcome all! So to start with, concerning recurrent respiratory papillomatosis, let's start with the USA. How does the health service and patient presentations differ between South Africa and the UK? I guess, explain to us what it's like in the US (the patient presentation).

Craig Derkay

So most commonly in the US, the children begin with a presentation to their primary care doctor, or perhaps urgent care, or emergency room, with a voice change associated with Strider. With the voice change being progressive over time. They typically present between the ages of two and four. And it's not uncommon for there to be a significant delay, up to a year, from the beginning of the symptoms until someone finally puts a flexible scope in the child's nose and realises that what they're dealing with is a respiratory papilloma.

In the adult population, they get diagnosed a little bit more expeditiously, in that it tends to be between the ages of 20 and 40, and they will almost always present with a voice change. And we've recently noted a third group of patients, which are the elderly, those over the age of 60, for various theoretical reasons are coming to the attention of health care workers in their sixth and seventh decades with respiratory papilloma.

Host: Natalie Watson

And once they're in the secondary health system - so they've seen their primary physician in the community, and they're under ENT, are there clumps of tertiary centres who deal with RRP? Or is it mostly ENT services that deal with this in the US?

Craig Derkay

So it does vary in that there are very competent general otolaryngologists who are capable of making that initial diagnosis. But because the RRP patient needs repeated specialised care, it's rare for that general otolaryngologist to take over that care by themselves. They almost always will refer them to a tertiary care centre, or a University, or Children's Hospital. The exception to that is, the US is a large country. There are folks who live in rural parts of the country that are many hours away from a major medical center. And in those answers, the general otolaryngologist will continue to care for the child, with some guidance from the specialist.

Host: Natalie Watson

And so let's just move straight to South Africa. So how does the health service provision in South Africa’s RRP differ? And do the patient presentations differ?

Dr Andile Sibiya

So I think in South Africa, the presentation is very similar to that which we've heard described for the USA, with the misdiagnosis, and delays in reaching an ENT specialist, particularly for the paediatric population. With our tiered healthcare system, we do find that there is a delay even in our adults reaching the ENT service, simply because they need to go through those different tiers of care, to get to an ENT surgeon, which isn't always available at our regional and district services. So we certainly have that as an issue. But once they get to us, you know, they're obviously in the right place.

When you look at the health care system, with us, the central hospitals are our quaternary hospitals, in my province in particular, it is the only one that has capacity and infrastructure to address the very young children, those who would be under the age of five, five or six. Our preferred technique, obviously being tubeless anaesthesia, means that the infrastructure around you, the people, places, you know, your rescue methods, the availability of a high care and ICU bed, mean, for that reason, as a service for ENT within the province, we agreed that all children would come to us. So that's all the children under the age of about five or six. And then as they get older, and maybe their inter-surgical time may increase, and there's better support for them from home, all of those circumstances taken into account, we may then refer them back to a different site. And some of those are two to three hours away from us. So the sooner we're able to do that, the better for the families, and the patients themselves. But all the little ones come to us here centrally.

Host: Natalie Watson

And in the UK is there any difference?

Adam Donne

Well I think there are a lot of similarities in the things that we've heard both from the USA and South Africa. I think we are fortunate in the UK that we have a National Health Service, and hoarseness is considered a red flag symptom. So our primary care doctors have a low threshold for referring relatively early. However, I agreed with Craig's sentiment that actually anybody can misdiagnose this, and if they are going to misdiagnose this, asthma is most likely to be the primary diagnosis that's made.

Age is similar in the UK to how it is in the US. Globally, there have been reports that children can be born with respiratory papillomatosis. And I've certainly had a couple of cases where I've operated on young children less than, or around two years of age, the mothers coming to collect the child from recovery would cry because it's the first time they've heard their child's voice, they tell me, which is clearly quite an emotional situation. But I think that as Craig said, in the US, general ENT surgeons have been able to manage this condition. But I think our RRP is changing somewhat. And I think it's maybe changing a little bit more away from the surgical, more to the medical. And I think perhaps the prevalence is changing. So there may be something to be said for having maybe specialist centres in the future as that happens.

Host: Natalie Watson

Well, these are the things that we're going to touch on during the podcast. So let's see what's revealed. So as you talked about prevalence, Adam, what’s the current prevalence in the UK?

Adam Donne

Well the latest study that's been done was in 2016, and it was some work that I was involved in. And we didn't discriminate between children or adults, we just looked at the condition as a whole. And we found that our prevalence in 2016 was probably in the order of about 1.5, per 100,000. But that's different, I think, to the figures. I think one of the earliest sets of prevalence figures were published here by Craig in 1995, where the prevalence was around 4 per 100,000. And then, I think in South Africa, in 2014, it was just under 4 per 100,000. So fairly similar rates over ultimately about 20 years.

Host: Natalie Watson

Right. We will talk about how vaccination has changed that. Craig, you were talking about, and you mentioned earlier when we were talking offline about some prevalence studies, have you any updates from any of those figures?

Craig Derkay

Yes. So I've been involved with our CDC, in looking at the effect of the HPV vaccine on reducing the incidence and the prevalence of juvenile onset, and now adult onset RRP. And so our most recent publication, which came out in January of 2023, showed a dramatic decline from that original 4.3 per 100,000, to now closer to 0.2 to 0.4 per 100,000.

Host: Natalie Watson

Wow. So that really justifies International Programs of HPV vaccines.

Craig Derkay

I would agree with that statement. And, the CDC was so impressed with the five-year data that they have re-upped for another three years of surveillance because the trend continues to go down. Now, have you heard about COVID? Which has interfered a bit with the vaccination programs. We are starting to see children once again get their HPV vaccines, but there was a little dip during the pandemic. And that may affect down the road a little bit the continued decline in incidence. But we have achieved what we consider herd immunity in the population. Even those who have not gotten vaccinated, benefit from the fact that their neighbours are vaccinated. We are confident that the climbs that we're seeing are real, that we've looked throughout our country at large geographic specialty centres, and everyone is seeing this dramatic decline. Whereas I, at the peak, was managing 20 to 30 active papilloma patients. I currently have two, and I'm considered to be a bit of an expert in the field, and get referrals from outside of our catchment area. So I think that similar to acute epiglottitis, before the HIb vaccine was used in the late 1980s, I think that our otolaryngology house staff may not become familiar in the future with juvenile onset or RRP.

Host: Natalie Watson

Yeah, well, we can only but hope.

Dr Andile Sibiya

I just wanted to comment on the incidence and prevalence in South Africa. You are quite right that Riaz Seedat his numbers looked at just under 4 per 100,000. We're actually just looking at our provincial data with him, he's actually involved in our study as well. And we've been quite alarmed. We don't have the actual prevalence yet. But just as a crude indication, we're still seeing about 20 patients, new children per year, just in our unit alone, for the past three or four years, we've just had a look at that. So it's about 20 - 25 new cases a year in a population under six. And if we look at our population data, that's about 2 million children under the age of nine in our province, 2.2 million children in our province. So, you know, there’s obviously a bit of maths involved in getting the exact prevalence and sort of looking at that better, but we're certainly not seeing some of the impact of vaccination yet. And in our setting, I think that's largely due to the limited rollout. So we, in our state program, only have the Cervarix, that's the bivalent vaccine, and the private patients are able to access Gardasil. It is still almost exclusively young girls who are being vaccinated. And so we still have a lot of limitations. We're still very far, I think, from seeing some of those downstream effects and benefits of the vaccination.

Host: Natalie Watson

Yeah, I mean, we were in a similar situation in the UK until we increased the catchment to include boys as well. And also, of course, upgraded the HPV vaccine to the Gardasil to cover the strains that are the subtypes, that are more prevalent in the larynx. So moving forward from this, let's talk about why RRP is so difficult to cure. Craig?

Craig Derkay

Well just biologically, the virus is very good at hiding itself from the immune system. And we do not have this all figured out yet. There's some very smart people working on this, but the HPV virus is very ubiquitous in human populations, but only a very small fraction of people that get exposed to the virus go on to develop a papilloma or wart in their general urinary tract, or their respiratory tract. And what differs in the immune system of those that develop an infection, and can't clear that infection, from those where it's a short lived and relatively benign experience, we don't have that fully sorted out.

Host: Natalie Watson

Is anyone looking at the immune profile of these patients clinically from your own work? Are you looking at immunoglobulin levels or anything in particular?

Craig Derkay

So the forefront of research is taking place at Long Island Jewish Hospital, and the folks there have really focused on T cells. And when we measure anti HPV antibodies in patients with respiratory papilloma disease, a surprisingly large number of patients who are immune competent, failed to make a response to their HPV infection - when you measure their antibodies, they're extremely low or completely absent. Which may be an explanation as to why providing the vaccine, which is meant to be a preventive vaccine (it's really not designed to be a therapeutic vaccine because it does not make an established lesion go away), but it seems to help a proportion of the RRP population that receive it, perhaps because it restores some of those anti HPV antibodies that they're not producing on their own.

Host: Natalie Watson

Really interesting, and I think in the next few years, we'll find out more. I mean, you were mentioning earlier that you've got this 60 plus age cohort now that are presenting as well, and we've certainly seen in our adult population in London, some growth in that. As we know, this kind of immune competency does decrease as we age.

Craig Derkay

And I think there’s, from a social standpoint, that sometimes we poopoo the fact that seniors still engage in sexual activity, and develop new partners later in life, move into senior living situations where there is not a fear of being pregnant, and the virus has an opportunity to spread once again.

Adam Donne

It's interesting because actually, if we look at cervical smear testing, looking at the HPV profiles of women of different ages, we can see that there are variations depending on geography, and a variation in HPV amount positivity depending on age, and there's a typical U shaped distribution curve. I mean, this was published by Silvia de Sanjosé in 2007 in Lancet Infect Diseases, how, as the population gets older, the amount of HPV increases again. Now that was predominantly before the Quadrivalent vaccine had been established in national programs, but it says something very interesting. And it kind of indicates what Craig is saying here about activities. But it may also as you state nationally, it may be something about immunity that we still don't quite yet understand.

I think the other thing that's interesting is how the prophylactic vaccine works. And I think there's evidence to suggest that vaccinated mothers do have anti HPV antibodies that are shown to be present in cord blood. So that protection is really quite profound biologically.

Host: Natalie Watson

So moving on, let's talk about how we treat RRP in the three different time zones. We've got surgery versus adjuvant versus anything else. So in the UK, from my understanding, in our practice, the primary treatment really is still surgery. But of course, there's lots of other things that we can do. Just as a general setup of how you would approach the treatment protocol for this. Let's start with you Andile, how do you go forward with treating someone who presents with RRP?

Dr Andile Sibiya

In our units, I think the primary approach is based on the clinical presentation, and severity of obstruction. I think key for us is maintaining a good airway for this child without doing any further harm. And some of that has led to an evolution of even the modalities that we use surgically to treat papillomatosis. And so, primarily for us, this is a surgical disease, and it remains a surgical disease. We have historically had situations where we've had such a burden of disease, and so few practitioners in the system, that we were defaulting particularly here to tracheostomies, because we just couldn't keep up. But that's really changed. And again, the principle is to be preemptive, you know, trying to to reduce the disease load on the cords, on the airway, before the child becomes obstructive. And so those I think would be the two key things it’s primarily surgery, and prevent any further complications and avoid getting a disease that advances.

There's still a lot that we don't understand, I think in the context of this disease, even the role of coinfection, not just with other subtypes of genotypes of HPV, but even other viral agents. And what that does to disease, that, for us is the mainstay of treatment. We have very limited access to some of the adjuncts that are used in other places, so certainly the Gardasil, the Quadrivalent, and now the new one, the nonavalent one. I think would be a huge addition in our system. And I think that's something we're looking at not just from prevention, but also from a therapeutic perspective, and seeing what that would do. And then, of course, the role of adjuncts, such as Avastin, we don't have access to yet, but certainly looking at what we can do.

Host: Natalie Watson

Amazing, shall we go to the US?

Craig Derkay

Sure. So surgery has always been the mainstay of diagnosis and treatment in the US. But we are entering a phase where the adjuvant therapies may turn this into more of a medical illness than a surgical illness. The analogy we give is insulin for the treatment of diabetes, that it doesn't cure diabetes, but it stabilises the disease. And that's what we found with the intravenous use of Bevacizumab, but in those patients who have disease that is recurrent, the ability to prevent further damage to the vocal cords, which inevitably result from repeated surgical interventions, by using medical management for this disease, is very attractive.

The group from Johns Hopkins University in Baltimore, led by Simon Best, have recently presented their data on 200 of their respiratory papilloma patients, and this shouldn't be a big surprise to laryngologists, but almost no one gets by without having some permanent damage to their larynx when they have papilloma disease. Some have lifelong permanent damage, with anterior commissure scarring, and permanent voice changes, even after the papilloma has abated. And so the opportunity to treat this disease medically, while we wait for a cure to become available, is very exciting. It does require resources, it requires collaboration with our medical oncology colleagues, that patients are managed in infusion centres, and surgery is only offered when there's breakthrough, but somewhere on the order of 80% to 90% of papilloma patients do get a favourable response with IV Bevacizumab. And when I say favourable, I mean, complete elimination of their laryngeal disease, not necessarily pulmonary disease, but their laryngeal disease can be kept at bay with an infusion at 8 to 10 to 12 week intervals. And if you ask the patients, and this is important, because, you know, we're surgeons and, and we calculate things based on inner surgical intervals, and how often the patients come in to visit with us. But if you ask the patients, their preference between going to the operating room, or being in a laryngologist office, and having laser treatments done three and four times a year, versus showing up at the infusion centre for 90 minutes, and getting an IV infusion, and being done with it - no anaesthesia, no airway risk, and a voice that is serviceable, without further damage, they're going to vote for medical management.

Host: Natalie Watson

So at the moment in the US, what's the provision for paediatric, plus and minus adults, to have this IV treatment?

Craig Derkay

So it is off label, the Bevacizumab is approved for use for treatment of many cancers, but it is not currently approved for treatment of respiratory papilloma disease. But that's sort of a technicality. That means there's extra work on the part of the surgeons to present the data to the insurance company, and oh, by the way, it does turn out to be less expensive for the third party insurance coverage, that going to the operating room three or four times a year is far more expensive than using biosimilar Bevacizumab in an infusion centre. And so the economics of it, even though it is an off label treatment, it’s relatively easy to convince the insurance provider that this is the safest, and most effective, and least expensive way, to treat many of these patients.

Host: Natalie Watson

And can we be giving these to children as well? What's the lowest age you would recommend?

Craig Derkay

So in conjunction with our medical oncologist, it is administered to children as young as two and three.

Host: Natalie Watson

I know that some patients are worried about fertility, and impact on having children etc. Is there any contraindication with regards to that?

Craig Derkay

Not that we know of, there is effect in terms of potential for liver toxicities, and kidney toxicities. And so those are closely monitored when the children are on this regimen. But fertility is not something that is currently thought to be a risk factor.

Dr Andile Sibiya

So in our context, actually at our Drug Council, we actually had that concern raised by oncologists, our paediatric oncologists, in terms of how we select up for the potential risk, because certainly not necessarily from the papillomatosis perspective, but just as a general oncological medication perspective, there are some concerns about Avastin and female fertility in particular. And so the long term implications of giving this drug to young children is something that has been raised as a real concern. And I just don't think there's enough sort of long term information yet, for us to be able to make that decision here.

At the moment, because the access is so limited, it really does become sort of patient, you know, have the discussion, and say, well, here are our options, what else do we have? But I don't know if that's really a fair thing to do if you've got a three or four year old little girl, and you're trying to make that decision. It certainly has left us in a bit of a difficult situation, particularly in our private sector patients, where we can access it more easily. How do you quite rationally have that conversation, when you don't know with certainty what the fertility impact will be.

Craig Derkay

Though we have long term data with Avastin to use in young children with papilloma disease, we do have long term data with its use in neurofibromatosis type two. And so, again, it's not a large population that has received this, but there is a 10 to 12 year follow-up on these patients. And it seems that when you're weighing the risks and benefits, the benefits of the medicine versus the risk of repeated anaesthesia, and repeated surgical manipulation of the larynx, seems to favour us moving towards medical management.

Host: Natalie Watson

So in the UK Adam are you using it?

Adam Donne

Well I am as it happens, but just to put it into perspective, I think looking at the UK registry, I think it's fair to say as Andile and Craig say, I mean, the mainstay of treatment is surgical. I think from the registry, we can see that 40% of children end up having some form of adjuvant therapy, whereas it tends to be about 17% in adults. And I agree that there is seemingly a change from the surgical to the medical, because actually, infections aren't treated with surgery normally, except HPV infection of the cervix, which is treated surgically. So there's this theme about human papilloma virus, which incidentally, only infects humans. I have had patients who have Bevacizumab, but actually unlike (and maybe I've misunderstood) but unlike Craig's cohort, who can have IV infusion, come in for an IV infusion, in our children, we would have to have that as a portacath, because we just think it's so much kinder, we have found it to be effective. And just with children, it may be different in the way it's administered, to that of adults, I don't know what you think to that Craig?

Craig Derkay

So the typical child will respond to the Bevacizumab. And you can stretch their interval from initially 2 to 4 weeks, to 8 weeks, to 10 weeks, to 12 weeks. And if they are responding in a typical fashion, then the need for a portacath for an infusion that is going on only once every four months, really doesn't justify having a portacath. If you have someone who has pulmonary disease and is going to need the infusions more frequently, then that’s certainly a kinder way to administer the medicine. But it's my experience that a portacath is not necessary in most of the children getting Bevacizumab, and there's a debate. I mean, this is an ongoing technology. And there's a debate within our community as to whether to initiate the adjuvant therapy much earlier in the course of the disease, in order to prevent the sequelae from repeated surgeries.

So we had initially recommended that it not even be considered unless a child was requiring more than four surgical interventions in a year, where the disease had spread outside of the larynx. And we're rethinking that, and proposing to families earlier in the course of the disease, to give this a try, to avoid the repeated need to go to the operating room. Again, until we come up with a cure, and there is a cure that seems to be within our reach with the new DNA vaccines.

Host: Natalie Watson

Well, fingers crossed. Now, there are some centres, particularly in Europe, who are doing lots of intralesional Bevacizumab injections, even under local. Does anyone have any experience with that?

Craig Derkay

So I do, and for many years, we use Cidofovir as our preferred intralesional agent, and it's still my preferred intralesional agent - I think its safety profile has stood up over time. There had initially been a scare about dysplasia and the possibility of it making the patients more prone to malignant transformation, but that has not proven to be the case. And given a choice between the use of Cidofovir or intralesional Bevacizumab? I think that this Cidofovir has shown itself to be more effective, that close to half of the patients over time will have a significant clinical response to the intralesional Cidofovir. And something like a third of the patients given intralesional Bevacizumab have had a similar response. I think it's going to be practitioner specific, what they're comfortable using. But there's no question that the systemic use of Bevacizumab is far more effective than the intralesional use.

Host: Natalie Watson

Right. And just focusing on, if anyone is not aware of exactly what we use for surgical management, I mean as a brief summary. You can either use cold steel microdebrider, excision, or treatment of the lesions. Then we have a kind of lasers. So anything from CO2, green lasers, blue lasers, KTP, lasers have all been used. There's been other heated instruments like Coblation, and Helica. So there's quite a number of different modalities that one can use to try and exterminate these lesions, but they tend to just come back.

And again, with the lasers, and the more heated elements, they tend to avoid those in the paediatric population, to try and prevent scar and long-term sequelae. So if you are revising for any exams and things, these are things to be aware of. Anything else that I've missed in that kind of little summary of surgical interventions?

Adam Donne

I think the UK registry at least, indicated that there was far more microdebrider used in children than adults, and there was greater spread in adults. And maybe we need to understand why that is. And yes, of course, there's an anxiety about the collateral thermal damage that a laser might have. But it's also because, I think, the surgeons that do papillomatosis surgery in adults tend to be head, neck, cancer surgeons, and they're more familiar with using lasers and the larynx. And I just wonder whether that's their go-to instrument, in a more comfortable setting. I've read the papers on cold ablation - some of these papers seem very encouraging. But if we're completely objective about this, I think respiratory papillomatosis is a condition where everybody who treats it gets a little bit excited about the next new thing that comes along. RRP has a history of that repeatedly. My feeling is, it's all to do with how comfortable the operator is, and the second consideration is the side effects that may occur with that surgery. But I'm not sure how different it really is, because surgery, I don't think is the cure. It's all about time. And I think the Bevacizumab works probably because it's giving time for the immune system to alter and recognise, because HPV comes and goes in almost everyone in the population. So I'm interested to hear what people think about the different surgical modalities.

Craig Derkay

So as a paediatric otolaryngologist, the microdebrider is my go to instrument, but I have a laser setup as well. And there are patients based on where the papilloma is residing, in which multi modality surgical therapy is necessary. I think that the adults who have papilloma disease are more often treated with the laser because it can be used often in the office setting, and a general anaesthetic. And so that trade off is favourable for utilising blue laser, KTP laser, CO2 laser, in the office setting under a local anaesthetic.

Getting to one of Adam's other points, I think that the surgeon has to be comfortable with the instrument that's in their hands. And so when you have that long laundry list of different hammers to treat the same nail, it does speak to the fact that there's probably not one that is greatly superior to all the others.

Host: Natalie Watson

Yeah, you're totally right. And you Andile, have you any opinion on the surgical approach?

Dr Andile Sibiya

I think I would echo what Adam had said. And that is thinking as well about the potential harm from each instrument that you use. With our setting and the disease burden, it's not always a highly experienced or senior laryngologist, who's doing this procedure. And so the tools in their hands all have potential risk, if you're not quite sure what you're doing. And I think you alluded to it earlier, this is not something we're curing with surgery, we're just trying to buy time and care as much as possible without doing harm, particularly to you know, deeper structures, if possible. And so for us, that's what guides a lot of our decision making.

All of our registrar's are taught to use cold steel primarily as the initial modality. But even with that, if you're not cautious of your methodology, and you're plucking and pulling, instead of rotating sort of, you know, off, you're going to do harm. But we teach that as the primary mode, because that allows people to establish an airway if a patient comes in with extremists. And then we actually do use quite a lot of coblation in our setting, we actually find that a much gentler tool in the hands of somebody less experienced than, for instance, a microdebrider. And so we actually have a preference towards teaching that as a secondary instrument, rather than a microdebrider. But again, similar to everywhere else, there's a lot of more experienced surgeons who would default to something else. The laser, we use lasers as well, we use microdebriders. But again, those in terms of our disease, depend on where you are.

The other consideration, I think that is quite important for us, is the instrument costs. And so single use items versus repeat use items, cost of the infrastructure, so getting a laser system in versus getting a blue light system, or getting a coblation device, and what that means to each of our institutions.

And then of course, there's that very sort of back of the mind risk of aerosolization, not just into the patient, but also into your operating theatre and how that guides the tools that you're using having suction on hand if your device doesn't already have one built in. So some of those considerations as well.

Host: Natalie Watson

Certainly, and in the OR or in the office, we all wear FFP free masks now. But I think before COVID, those FFP free masks probably were not that well used, and therefore you know, who knows who would have been infected from it.

Craig Derkay

We have just closed the study of looking at occupational exposure, otolaryngologist and anesthesiologist, obstetrician gynaecologist, to HPV, that we have vaccinated our otolaryngology surgeons who fall outside of the initial guidelines for vaccination, to prevent us from developing papilloma disease through our occupation.

And the other point, I'd like to add is that, to do this well as a surgical disease, you need expert anaesthesia assistants. And I think as surgeons, we recognise that if the person on the other side of the drapes is not competent, or comfortable with the patient's disease, then the surgeon becomes uncomfortable. And the ability to give total intravenous propofol anaesthesia and give you enough time, especially in a diseased larynx, to do what you need to do, is really essential to do a good job surgically. And that's not always available everywhere.

Host: Natalie Watson

Yeah. Generally, we use tubeless anaesthesia for this, but I know there are lots of people who don't like tubeless anaesthesia because of infection risk.

Adam Donne

The other thing which isn't really talked about, and is important for all different forms of surgery for this condition, is residual disease, be it because we can't just access the area, or because we decide to leave some disease behind. And our registry data in the UK has shown that this is really quite a lot more in children than in adults. And there are obvious reasons for that, size being one of them. And I think it's important to understand, well the impression I get, certainly from the surgeons in the UK, that they're quite comfortable to leave some disease in the anterior commissure in particular, because it means that they're hopefully not going to get quite so much scarring, but there's no guarantee that you won't get the scarring just because you leave the disease that because sometimes the papillomas, well very often the papilloma grows across. I don't know what people think about that. I was interested in Craig's comments about starting off with a microdebrider, and then having the laser on the ready. And I was wondering whether he was going to say he would go for all the disease?

Craig Derkay

No, I believe they’ll be back another day to fight the battle, but I will go up one side of the larynx and leave the papilloma near the commissure on the other side, and then the next time I'll come up the other side and leave it on the original side, and kind of minimise how much is being left behind, because that certainly affects the voice more than leaving a little papiloma on the undersurface of the true cord. But you can do more damage by being aggressive. And again, we teach our house staff to be comfortable coming back another day.

Host: Natalie Watson

Yeah, I do a mixed multi modal approach as well and get one side, and six weeks later, I'll come and do the other side. But also, I sometimes just use the laser, if it's kind of sessile on the top, just use the laser. But I think, you know, there's just so many ways to skin a cat with this disease, with regards to the surgical aspects.

Dr Andile Sibiya

One of the other things, of course, for us is just keeping in mind what the general natural history is, in terms of remission, particularly for the juvenile onset patients, and how we expect that most of them will go into remission when they hit puberty. Now for us, we've got a couple of patients who have such aggressive laryngeal disease, for whatever reason, late referrals, that you're not going to touch it. Some of them even have trachies. So we've got quite a high tracheostomy paediatric population with papillomatosis. And for some of them, the disease that isn't that larynx, is just so extensive, that really trying to do anything, won't be worth it. If you're looking at a 10 or 11 year old child, and they're happy with that tracheostomy, they've had it for a year or two, we often have to sort of ask ourselves, you know, what are we hoping to achieve with the surgery in this particular child? And how much are we actually going to clear? We have taken one or two and then said, we're going to sit down and see if we can get good clearance on this child. But if it's an aggressive disease, and they're coming back in four to six weeks for revision, then we're forced to stop again and say, well, in a year or two, we may be seeing this going away. And we have seen that.

Craig Derkay

There’s also that when you place a tracheostomy, that you now have a junction of squamous epithelial junction that is prone for papilloma to migrate to, and so the concern of these now spreading down the respiratory tract is just another obstacle towards treating these children. I mean, you have to do it and especially in a lower resource situation where children may not live close to or have access to transportation to get to you quickly, that tracheostomy is the safest and life saving approach to this. But in a closer monitored situation, it has its own drawbacks.

Dr Andile Sibiya

100% agree with you. And in fact, we've seen the consequences of having so many patients with tracheostomies. A lot of those were placed in a few years ago. Probably about seven or eight years ago, we had two ENT surgeons at this facility treating that entire population group, and that's all ENT patients serviced by two surgeons in a province with 12 million patients. And so really in terms of what resources were available, I think it really was just one of those critical times. So we have a lot of those patients who are still with us. Probably in the last three years, I think we've put in fewer than two tracheostomies, simply because we've changed some of our approaches and getting patients in earlier. But again, you're 100% correct that once you put in a tracheostomy, we've got to know that we're causing oftentimes more harm in a patient who may rather have been done better with surgery. So we see that we have a really high rate of patients with pulmonary disease, some of the main stage pulmonary disease, and probably too which we suspect to have malignancy, but because they're just so far advanced. We don't have biopsies on those children.

Adam Donne

I think this is probably therefore a good point at which to talk about management signposts. In other words, for people who may be listening to this podcast, at what point does one introduce adjuvant therapy?

I think we'd all agree that we all start with surgery. I think Craig has also mentioned the number of surgeries indicates an element of severity. And certainly in the UK, I think we would add to that point, consider adjuvant therapy. Now within that list, what do we have? We have Quadrivalent vaccine, we have Cidofovir and we have Bevacizumab. We actually have Alpha Interferon, which there's a pegylated form of, which isn't as unpleasant as it used to be, but still, few people tend to ever go to that option. I think most people would use a Quadrivalent vaccine early, even if they haven't had four surgeries per annum. And I think in the UK at about four surgeries per annum, the question is asked about whether cidofovir should be used. I think most people would use Cidofovir before trying Bevacizumab, but for the really severe cases. And you know, I mean the cases that require monthly clearance, or six weekly clearance, or the papillomas extend beyond the larynx, that's when in the UK I think we would be thinking about Bevacizumab. I'd be interested to know what my colleagues feel about that kind of management approach? Does it differ significantly from what you do?

Craig Derkay

It does not differ significantly. In the US, we call it shared decision-making. And so we put the options out there for the families to decide, with guidance from their surgeons. And so that stepwise approach is currently what we do. But I will say that the pendulum is shifting in the US towards earlier adoption of an adjuvant therapy, whether it be Cidofovir, or intravenous Bev, they’re thinking about it earlier in the course of disease than what we previously did, because of recognition of the damage to the larynx that is cumulative over time. And something we haven't spoken about yet is the psychological damage that children, the burden of repeated surgeries, repeated visits to the operating room, has on young children and their families, and trying to minimise that. But again, it's not that the surgeon themselves decides what's going to be the mode of treatment, it's that we involve the families in the decision making, and they help guide us guide them.

Host: Natalie Watson

I’m aware that once they're on the Avastin or the Bevacizumab, how do you know when to trial it off?

Craig Derkay

So it is monitoring. And the way I do it personally is, we'll stretch out the intervals and judge it based on voice. And then I'm very liberal about putting a flexible scope in a child's nose in the office, to look at the larynx, and see if there is a regrowth, then typically you can stretch those intervals out relatively rapidly. But if it’s too long, the papilloma will return. My analogy about insulin, that you can adjust the insulin dose based on your blood sugars, and once you sign up for Avastin, you're committing towards a long-term use of the medicine, but it's often preferable to go that route, than repeated visits to the operating room.

Host: Natalie Watson

And I think with the NHS in particular, they would want to have a protocol, individualised to say yes, once they have achieved X number of surgical procedures a year, we will then fund the Avastin, through the medical oncologists. We would have to have that all through NICE guidelines and say that we can actually provide that for all.

Dr Andile Sibiya

Certainly even in our setting, despite the concerns I've raised around potential fertility impact. Certainly the submissions that we've put through to our Pharmaceutical Council are very clear, in that the priority group for us is those who have the aggressive disease, the more than 3 a year, more than 10 in a lifetime, extension into the trachea or other sub-sites, and then the pulmonary extension. So those certainly are the ones where I think the evidence is strong enough to say that this may be worth exploring. We're not yet at the point of bringing it in earlier, although we are recommending it in our guidelines and submission for younger children. Because we know that the younger you present, the more likely you are to have a more aggressive disease. And so we certainly are recommending it in that submission within those criteria. Although it's not routinely in use yet, that's what we've put forward.

Host: Natalie Watson

Now, does anyone have any advice on supplements to boost one's immune system? So a recent one has been AHCC, very popular in some groups, you know, their patient groups, etc. So, has anyone got any experience of giving or advising AHCC supplementation to help boost the immune system?

Craig Derkay

You should eat your cruciferous vegetables. There was some data in the 1990s about the benefits of cauliflower, and broccoli, as a potential boost. But when that was looked at more closely, those on placebo had the same trajectory of their papillomas.

Adam Donne

That’s Indole-3-Carbinol and Diindolylmethane, isn’t it? Is that what you’re talking about?

Craig Derkay

Yes, but you can do that in your diet by eating cruciferous vegetables, which are good for you anyway.

Host: Natalie Watson

Well, the AHCC is an extract of Shirataki mushrooms, so there's been quite a lot, I mean even comments in nature…

Craig Derkay

But Adam had the comment earlier, that we get excited about modalities because of one or two patients who seem to respond to it, and we get all excited and then it's the flavour of the month, and we find that it is truly not that beneficial. I will say the science behind Bevacizumab interfering with the blood supply to the papilloma makes sense, that the use of the vaccine in a patient who has papilloma disease, if you remove the papilloma down to what's visible, and you administer the vaccine at that juncture, then it seems to prevent the regrowth of the papilloma. They won't establish papilloma disappear. But if you've freshly surgically removed it, then giving the vaccine at that juncture in their therapy may prevent a new papilloma from forming in that surgical bed. And that's been reinforced in the OBGYN literature in the use of LEEP for women with condyloma. And so that's been our approach, that our first adjuvant will be to introduce the vaccine in the younger child who is under the age of nine, and not eligible to receive the vaccine. Although in the teenagers now, we're only giving two doses. And worldwide, the WHO is trying to promote a one dose mass vaccination program in low resource countries, that for the papiloma patient, we recommend three doses.

Host: Natalie Watson

Right. So I think we should bring this to a close. We have spoken extensively about RRP. We haven't even talked about subtypes, but we have delved into the prevalence, looked at the different provisions of health services, in South Africa, in the UK, and the US. We can see that the presentations are fairly similar in the paediatric and adult, and older adult population. And we've also looked at certain treatment modalities, and adjuvant treatments, away from the surgical. So any final words from firstly, Andile?

Dr Andile Sibiya

From my side, I think one of the things that we haven't quite had a chance to touch on is this idea of malignancy, and not so much malignant transformation, because that's often referenced in the primary site, which is the larynx, but the idea of transformation and malignancy when you've got disseminated disease. We've got patients 22 years old and younger who have gotten nasopharyngeal carcinoma and pulmonary cancer, all quite certainly as a result of juvenile papillomatosis. And so I think for me, that really leads me to thinking a lot about how we reframe some of the language and terminology around HPV.

Often, you know, pharma refers to high risk, high risk papilloma, and you know, and they talk about 16 and 18, and how a lot of the attention in terms of our research agendas, or diagnostics, or vaccine development is centred around that. But I think we need to be really conscious of the risk of these subtypes as well. They are high risk, particularly when you've got children who are developing preventable disease.

Host: Natalie Watson

You're talking about the 6 and 11?

Dr Andile Sibiya
The 6 and 11. And whatever else that might be there that we don't know yet. Right? Because that's still also a little bit unclear in terms of some of our techniques for sequencing, is what the impact of some of those infections might be. So I think for me, that's probably one of the key things, is sort of thinking about, that it reminds me a lot of what the laryngologist was saying around speaking about subglottic stenosis, as acute laryngeal injury, or post intubation injury. So this awareness of where diseases are coming from, and their impact. 

And so for me, one of the things we do now is we take away this reference to high risk only when you're referring to 16 and 18. Because even 6 and 11 is high risk in our setting. And I think that will impact, hopefully, research agendas, which obviously goes into R&D, and what happens there. But also, I mean, I think, Adam, you've mentioned quite a bit here in terms of education and awareness, and treatment pathways, and red flagging for expedited referral, so that we get patients in earlier, and the correct patients in, and I know from my side I would rather have actually, yes, it was Asthma, in my hands, than a child who has been treated elsewhere for a year and a half for Asthma, who actually was papillomatosis.

Host: Natalie Watson

Thank you Andile, Adam?

Adam Donne

I think the concept of high risk is actually something that came out of In Vitro studies. So the definition of high risk came about specifically for 16 and 18, because if those live viruses are inserted into human cells, there's about a 30% chance they'll become malignant. But I agree. It's not just about the cell, it's about the system. I think RRP is becoming quieter, because of the lower prevalence. But I think we are still troubled by those really difficult cases, where we've used everything that's available at the time it's available, and those patients still have papillomatosis. So those recalcitrant cases, that fortunately haven't progressed, but remain stubborn in their presentation. That's that's the real remaining legacy, I think of this condition as it peters out.

Host: Natalie Watson

Thank you Adam, and finally Craig?

Craig Derkay

So I'm very excited about these new DNA vaccines, there are two that are about to enter phase three trials in the US, one through the INOVIO company and the other through Presagen, and independently, two major multi-institutional trials showed a 50% or greater, complete response to the vaccine, the participants within 50%, requiring no surgery in the 12 months, to 18 months, that they were followed after receiving the vaccine. And so the FDA has expedited the phase three trials, which are currently being designed, and this is a potential cure. The biology of the vaccine gets at actually curing the patient of papilloma. And so that's something on our radar that we are anxiously looking for as an additional tool.

Host: Natalie Watson

Brilliant. Well, what an amazing and positive way to end such a wonderful podcast streaming from the US, the UK, and South Africa. So thank you so much all for joining. Really appreciate all your time and effort, and all your time and effort with not just the podcast, but treating your patients, and developing a brighter future for them.

Thank you for having us!

We hope you've enjoyed listening to BLA Connections: A Clear Voice. I've been your host Natalie Watson. Please do tune in this series, for more laryngology topics. We would also love to hear from you. Please feel free to email with any topics you would like us to explore, any questions you have, along with any suggested experts you would like to hear from. Also, if you'd like to contribute to these podcasts, please email enquiries@britishlaryngological.org

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