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The latest trends in prostate cancer treatment and diagnosis

TFTC consultant Tim Dudderidge discusses prostate cancer innovations

Consultant Urologist Tim Dudderidge joins OnFocus to discuss recent trends in technology and research. Tim works with the Focal Therapy Clinic and is based at University Hospital Southampton. He’s an innovator in focal therapy and has coinvestigated most of the clinical trials and studies that have built the evidence base for focal therapy and advanced its adoption and practice. Last year he was appointed as Clinical Champion for Prostate Cancer UK, which will give him even more impact on innovative clinical practice across the NHS. In this episode, Tim shares his views on some of the key issues driving practice in diagnosing and treating prostate cancer, and how this is impacting both patients and clinicians.
 

Clare Delmar

Hello and welcome to On Focus, brought to you by the Focal Therapy Clinic, where we address issues facing men diagnosed with prostate cancer that are little known, less understood, often avoided and too often ignored. Prostate cancer is the most commonly diagnosed cancer amongst men in the UK and with this sombre fact comes a multitude of challenges and opportunities. I’m Clare Delmar. Joining me today is consultant urologist Tim Dudderidge, who works with the Focal Therapy Clinic and is based at University Hospital, Southampton. Tim is an innovator in focal therapy and has co investigated most of the clinical trials and studies that have built the evidence space for focal therapy and advanced its adoption and practise. Last year, he was appointed as clinical champion for Prostate Cancer UK, which will give him even more impact on innovative clinical practise across the NHS. He’s here today to talk with me about some of the key issues driving practise in diagnosing and treating prostate cancer and how this is impacting both patients and clinicians. Tim, thanks so much for joining me today.

Tim Dudderidge

Thank you. It’s great to be back talking again about prostate cancer. It’s been a long time. It feels like there’s a lot to catch up on.

Clare Delmar

Yeah, absolutely. That’s why I thought mid summer and sort of halfway through the year, so it’s a really good opportunity to kind of round things up. So let’s start off on that sort of general point. There has been a lot going on since the start of the year at the Focal Therapy Clinic, but also in the wider prostate cancer community. Can you tell us about some of the trends you’ve seen with the patients that are coming to the Focal Therapy Clinic?

Tim Dudderidge

Sure. I think one of the things that happened a little while ago is there’s a lot of attention about another form of focal therapy, the Nanoknife. And this is mainly because they were launching a new NHS clinical service at UCL and it has been used by colleagues in London for some time and we haven’t really seen, I guess, any sort of UK data that makes us think about changing practise. But I think around the world they have been accumulating data and it looks like a very strong contender to be kind of regular tool for focal therapy. It works a bit like cryotherapy in a sense, it’s a needle based technology and that’s perhaps the most useful for targeting the front of the prostate and maybe glands which have contraindications to HIFU. And at the moment I use cryotherapy for such cases. So I’m really interested to see whether NanoKnife might offer, in certain circumstances, an advantage. Maybe it’s going to be better treating around the urethra. We have this warming catheter with cryotherapy which can sometimes inhibit the action of the ice, and that’s interesting and it might also be more sort of targeted, maybe that the extent of the ice when we’re using cryotherapy is a bit uncontrolled and maybe that’s why some people don’t preserve erections in that treatment, maybe Nanoknife will offer some advantage there. So I think this is an interesting trend and I know we’re looking at starting a Nanoknife programme as well, so I’m really excited about that.

Clare Delmar

What’s interesting is that we’re seeing, if I can even generalise a little bit more, just some new modalities for delivering focal therapy. And obviously Nanoknife is one and obviously we’re all looking at that. I’ve even engaged with people around water vapour ablation. So I guess on that specific point about the new modalities, what do you think of how these will be adopted and accepted or I should reverse that? Accepted and adopted clinically?

Tim Dudderidge

I think you don’t have to have every single tool in the box in your clinic. I think as a practitioner you need to have enough tools that you can tackle nearly all of the cases, but not necessarily all of them. And for me, I think HIFU and a needle based technology together probably covers most things. It may be that we learn a little bit more about some of the technical advantages of some of the other ablative technologies, so that maybe we have three in the clinic, but I think that there is a danger of having too many because you then start to sort of dilute the evidence base a bit and you’re not sure whether your different ablation modalities may actually be delivering the same result that you’re quoting from the evidence. Things like laser ablation are coming along using even drugs. Like, there was a study using photodynamic therapy drugs and I know there are companies developing that, even though the two CAD drugs seems to have stalled. But I think we will continue to see more and more ablation technologies coming along. And the key principles of developing a new one will be to have something that’s very easy to control, very easy to plan, where the sort of cut off between where you intend to treat and where the treatment action finishes is very tight, so that you define your treatment volume and the margin of tissue around that, that you want. But anything else beyond that is left alone, any technology that can improve on our current ways of doing that will get some attention. At the moment, my preference is to stick with HIFU and cryotherapy because technically I’m very experienced with those now and I think that if you go and see a focal therapy practitioner, what you really want to know is are they really experienced with the tools that they’re using? I’m not sure it particularly matters which tool, as long as that tool delivers a good focal treatment. It’s very much the same with, you know, it doesn’t matter how you do certain operations, as long as the person who you’re seeing doing them is doing them with a high frequency and is very experienced at them.

Clare Delmar

Yeah, absolutely. And of course, it’s also basing that treatment on precision diagnostics. The advances in imaging…

Tim Dudderidge

That’s a good segue actually into the other thing, which is coming up a lot in the the focal therapy clinic is men coming along with MRI scans and biopsies, you might say, but MRI scans, particularly, where the quality of image puts them at a bad starting point to be considered a candidate for focal therapy. And we saw this lovely publication from Dr Claire Allen from University College London, and her team looking at something that’s been coined, PI-QUAL, and this is a sort of quality assessment scoring system for MRI scans. And I think it could be a good way of individual centres self assessing their work and saying, oh, it’s just up to standard, what do you change? And in fact, in our own centre, we noticed that one of the centres that we’re using regularly for imaging is probably not as good as we’d like it, and we’re going to try and actually tweak the protocol so that it’s similar to the one that we’re using in the main centre. And I think we need to be sensitive to the quality of imaging, because if we’re not using good imaging at the very beginning of the pathway, then it tends to undermine all of the other steps that follow. And that’s also true for the biopsy technique. We do see it again, a mixture of different approaches and I’m not sure if we really know which is the right one. On the one hand, with MRI that’s done well and bearing in mind some of the people who are adopting a less intensive biopsy programme with their patients are not basing that on good imaging. But if you’ve got a really good MRI, you can argue that if you target the area of interest, maybe you don’t need to target all of the normal looking bits of prostate. Some people are adopting that and my slight worry is that sometimes they’re doing that when the imaging is not of great quality. Our approach is that we are accepting, yes, the scan is mostly right, but sometimes it’s not right, and therefore having some limited systematic biopsies, which means biopsies taken throughout the prostate, but not sort of every five millimetres, maybe three per sector, which might mean nine on each side, as a bare minimum, this gives you a kind of map of the prostate which you can really rely on because the histology doesn’t really lie. Obviously, you can have some degree of sampling and more biopsies you get, perhaps the more confident you are. But if you combine that systematic sampling with the targeted biopsies that we know we need, looking at directly at the lesions that we’ve seen on imaging, we feel that gives the best preparation for considering focal therapy. But at the same time, if somebody comes along and they’ve got good imaging and they’ve only had targeted biopsies, we might say, look, this is not exactly as we do it, but it’s a very reasonable way of doing it and we will sometimes just explain the uncertainty. Most of the patients I say will accept that if the imaging is good but if we say look your imaging was not up to standard most of those men who are keen on focal therapy will accept a re-biopsy just sort of verify it helps us to verify that the focal therapy we’re about to do is a sensible decision because the last thing we want is to do a focal therapy and then a year later discover that the other side of the prostate had just as bad cancer which was probably there but we didn’t find it properly. That’s a regular theme I think in our patients at the moment

Clare Delmar

Yeah, I can see that. I want to turn a little bit to some of the trials you’ve been involved with because as I mentioned in my introduction on a wider basis you’ve been closely involved with a number of these trials that have generated a powerful evidence base for the efficacy of focal therapy. I know one of them you’re involved with now is called CHRONOS. Can you tell us a little bit about that?

Tim Dudderidge

Yeah so the CHRONOS study was interesting because it had two branches to it and the branch that I think probably the urology community is most interested in is the CHRONOS A study and this is a randomised control trial between partial ablation or another way of saying focal therapy against whole gland radical treatment and this is within a group of men who we would consider suitable for focal therapy so typically it would be intermediate risk disease situated in one half of the gland and on the other half of the gland preferably no disease but we would accept a small amount of low risk disease that could subsequently be monitored. And so we recruited a reasonable number it was quite difficult to recruit to this trial because essentially we are asking men to suspend their preference if they have one and to try and convince them that actually it was very illogical in many ways to have a preference when we have these two good treatment approaches both of which have strengths but of course they have weaknesses too and we don’t know which package offers the best balance of strengths and weaknesses and so every time they said well I like the sound of low side effects we would say well, do we know it lasts? Is it as good as surgery and radiotherapy? Or they might say well, radical prostatectomy is well established I like the sound of something that’s tried and tested and we say yes but what about the side effects? And so constantly trying to bring people from the polar extremes of their decision making and have them hovering in the middle where they genuinely like us felt we don’t know what’s best. And if you can get the doctor and the patient on the same page with that we call that clinical equipoise where we just don’t know what’s the right thing to do. And this is the time when we can do a randomised control trial and expect men to reasonably accept and randomise allocation. And you can imagine that many men, especially when they’ve heard their friends or they might have heard in the media about some treatment that has had a good outcome, they very quickly latch on to something that they think, oh, this sounds good. And all of our clinical pathways are designed to encourage men to do that, to identify, to self identify with the treatment that they like the sound of. The trouble is that doesn’t help you when you’re trying to run a trial. And what we found was it was really quite challenging to get men to accept randomization, but some men did. And we will publish that data in the fullness of time. But we’re sort of coming around to the conclusion that it seems difficult, maybe impossible, to recruit 700 or 800 men to be randomly allocated to treatment like that. That’s how many men we would need to answer the question, which is the main question everyone wants, is which is the best approach?

Clare Delmar

Yeah, that’s really interesting. Have you seen this happen in other, even non-prostate oriented and other kinds of trials before?

Tim Dudderidge

Well, a good example in the prostate world is when robotic prostatectomy came along, it’s was very difficult to randomise people between open surgery and robotic prostatectomy. There was a three way study, I think Locro was called, and that famously didn’t recruit because the cat was out the bag. Once robotic prostatectomy was available and all the centres that were doing it, people came there and they wanted the robot because they just had this feeling it was better. Took a very, very long time to gather randomised evidence. And as is always the case with new technologies, sometimes the benefits that are presented are much more of an incremental gain rather than a sea change. So randomised control trials are really important because they tend to neutralise a lot of the perceived gains from observational studies. So I don’t discount for a minute this is an important thing to do, but in reality, the choice with focal therapy and radical therapy is a different choice to two drugs you might be comparing, or two variations of a different approach. They’re totally different philosophies. And so I guess, having tried really hard to recruit to this randomised trial, and it was too much of a struggle, I think, to try again, my feeling is that we can say that that has failed and we have to therefore rely on the next best thing, which is observational data, but with statistical methodology to try and make the comparison most fair. And maybe if we’re going to do that, rather than doing it using retrospective data that we’ve collected, we could set up a prospective, a proper trial where it’s supported by nurses, not the sort of more ad hoc data collection we have for the registries and actually maybe this is the only way we’re going to get a meaningful comparison I think the other thing to accept is that men are making these choices more of a philosophical thing. So people, if you say, look, what if this treatment is 10% less good after ten years rather than it being equally good? What if it’s 10% less good? But in the short term you benefit from lower side effects. When I explain focal therapy to men like that I’m saying it might be equally good or it might be less good, we just don’t know. But if you get less side effects for the first period of time and then maybe you have to have an extra treatment with a greater risk because even surgery patients might need extra treatment, comparative risk anyway. When you put that to men, they’re quite happy often to sort of kick the can down the road and say, I would just like to be left unaffected by side effects for as long as possible because I recognise this disease is not always a kind of lethal entity. You’re controlling, managing the disease that may never affect you anyway. So I think putting it to men like that sometimes is a way of helping them to understand the lack of evidence and the uncertainty and helping them to make a choice which is more important to them.

Clare Delmar

Yeah, it’s really interesting even just hearing you talk now the language is evolving in itself. I mean, even we talk about focal therapy and then we talk about the modalities to deliver it. But increasingly there’s this new term around ablation, which I know is a technical term, but often patients don’t understand that in order to get the information you’re describing about risks and uncertainties I think this is something that you and your colleagues at the focal therapy clinic really excel at is really helping men to understand their choices. And even use of the word managing as opposed to curing is an interesting choice of language.

Tim Dudderidge

Well, many men are cured, but the thing is cure is quite a strong word. And of course, even if you apply a curative therapy in inverted comments, lots of those men don’t get cured. So we’re always managing the disease. I think perhaps it’s more realistic to talk about managing the disease when we know that we’re leaving low grade disease for surveillance. That’s a very clear example where we’re not curing the patient, we’re just helping to prevent progression. And so I think many men understand if they look at the risk calculator. There’s this predict prostate website which is.. And men see that the incremental gain of radical treatment is maybe a few percentage points at 15 years on survival. They’re like, why do I need to put myself through radical treatment for a 3% gain at 15 years?

Clare Delmar

Yeah, that’s interesting and I just wanted to touch on as we just sort of move to the end here. I mean, the things you’ve talked about imaging, biopsies, histology, you talked about as they continue to advance, focal therapy becomes more viable for a larger number of men, even though you’re building up the database and the evidence base to support that. So how do you see this trajectory playing out in terms of focal therapy along the spectrum of active surveillance on one end and more radical procedures on the other end?

Tim Dudderidge

Well, the big picture for me is that we’ve got to reduce deaths. And the only way to do that is we’ve got to find more of the important cases earlier. But the side effect of doing that is that we’re likely to identify cases that we don’t want to know about and don’t want to treat and we’re also probably going to have to do more activity. And so there’s a sort of a funding question really as to whether this is important enough for the country that we invest in this. And so that’s a public health question. So my approach, if I was in charge of designing the whole thing, I would really start to encourage research on MR guided screening. They’ve done a bit already with Imperial, great thing with prostagram and obviously that’s paired up with PSA, of course. And then we need probably more artificial intelligence to interpret those scans because we just don’t have enough radiologists otherwise. The exciting thing as well about AI is that we’re bringing that into image screening of histology cases as well. We need to try and iron out this issue about whether we can rely on targeted biopsies alone or whether we do, as I’m doing, a lot of systematic biases that would obviously reduce a lot of costs if we could safely cut those out and give treatment based on the images alone. And I think that the way that we get to that point is by having a really rigid quality control of MRI for prostate. If we’re going to see this massive expansion in MRI for prostate, we’ve got to have some sort of standardisation and rules. You find that with cervical smearing and everything, you don’t have 20 different ways of doing that. It’s a very standardised process and that also links into the question of contrast or no contrast in the initials sort of test. And we’ve got trials ongoing through colleagues in London, they’re going to answer that question and eventually we’ll get to the point where we’re finding more cancers as a consequence of the stage shift that we’ll have in that process. We will need to do more surveillance and more focal therapy, but I’m hoping that we will be able to deploy more and more appropriate radical treatments to those people who need them. And if we could do all of that, I’m pretty convinced that we could substantially reduce the deaths from prostate cancer in this country. That for me is the dream. But there’s so many elements to achieving that. It’s a long battle, but I’m really pleased to be working with some excellent academics. Hash Ahmed, Mark Emberton, Caroline all of these people are doing amazing things to push the trials forwards. And in Southampton, we’ve really focused on supporting those trials and recruiting for them. And my other big wish is that I sort of join them and start designing my own trials, so that’s the sort of next the five year plan for me is to perhaps take a sidestep and become more of an academic. Let’s see what happens.

Clare Delmar

Well, okay, good luck with that. And on that note, I want to thank you very much for joining us and sharing what’s happening both in the trial world and on the actual clinical coalface, so to speak. So thanks, Tim. Thanks very much.

Tim Dudderidge

My pleasure. Nice to speak to you.

Clare Delmar

A transcript of this interview and links to more information about Tim and his work are available in the programme notes on our website, along with further information on diagnostics and treatment for prostate cancer and additional interviews and stories about living with prostate cancer, please visit www.thefocaltherapyclinic.co.uk and follow us on Twitter and Facebook at The Focal Therapy Clinic. Thanks for listening and from me, Claire Delmar see you next time.

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