Tim Dudderidge discusses recent findings of randomised controlled trials

The Focal Therapy Clinic urologist Tim Dudderidge, joins OnFocus to discuss how clinical trials are designed to advance innovations in clinical practice and how they ultimately bring choice and benefit to patients. Tim discusses his involvement in the CHRONOS trials which will investigate outcomes of men undergoing focal therapy vs surgery for localised prostate cancer. He also explains how a registry of men who have received HIFU treatment in the UK is providing a valuable data resource for statistical comparisons of treatments for men with localised prostate cancer, and highlights this week’s publication of a landmark study showing comparable outcomes for men undergoing focal therapy and prostatectomy. https://clinicaltrials.gov/ct2/show/NCT04049747 Focal Therapy v Prostatectomy study Please find below a written transcript of the interview, and call The Focal Therapy Clinic today to discuss your prostate cancer treatment options: 020-7036-8870

The evidence supporting minimally invasive treatments for prostate cancer

Clare Delmar:

Hello and welcome to On Focus brought to you by The Focal Therapy Clinic, where we connect you with issues facing men diagnosed with prostate cancer that are little known, less understood and often ignored. Prostate cancer is now the most commonly diagnosed cancer in the UK, and with this somber fact comes a multitude of challenges and opportunities. I'm Clare Delmar. Joining me today is Tim Dudderidge consultant urologist at Southampton University NHS Trust and The Focal Therapy Clinic. Tim is a recognised innovator in advancing both the imaging led diagnostic pathway for prostate cancer and minimally invasive treatments, including focal therapy. We're going to discuss how much of this innovation has been led by clinical trials and explore how these trials deliver new procedures and treatments to patients. Tim, welcome to On Focus and thanks so much for joining me today.

Tim Dudderidge:

Hi, Clare. Thanks for having me.

Clare Delmar:

Fabulous. So we're going to talk about clinical trials, and I think this phrase is something that most of our listeners, if not the entire world, knows a little bit more about because of Covid. And we keep hearing about trials for treatments and therapies and vaccines. So it's made all of us acutely aware of their importance. And therefore, I thought it was a good time to tap into this, to talk about how clinical trials have led to some of the big advancements in prostate cancer diagnostics and treatments like focal therapy. Now, since you've been involved in many of these, I thought it would be great if you could start off by telling us about them and most importantly, just start with some definitions. So, for example, what is a RCT or the randomised controlled trial?

Tim Dudderidge:

So a randomised control trial is really the goal of comparative effectiveness when we're trying to tell a patient which is better treatment A or treatment B? And the reason that we have to have a randomised control trial is that all sorts of different other study designs that we use, that are usually much easier to conduct than a randomised controlled trial, they're subject to bias and confounding, and that basically means that the patient may report things differently. The doctors may observe things differently. We may subconsciously or consciously be seeking a certain outcome from a study that leads to the data sort of tending to give us the answer that we want to hear. And that's just partly of human nature, both the optimism of patients and doctors wanting to see new things work. But of course, there are lots of examples where in the past things we thought worked and we thought the data was telling us that they worked, when you actually conduct the study really well and to this very high standard called a randomised controlled trial, that actually some of the things that you thought you believed to work actually turn out to be just as good as the sugar pill. The reason I refer to the sugar pill, which is otherwise known as the placebo, is that most of this study design came through the pharmaceutical industry. And actually what we found as surgeons is trying to incorporate this very challenging study design into surgical practices is really, I think, probably harder than it is to do when you're testing a medication, which you can design to look exactly the same. Whereas anyone having an operation, for instance, through an incision or having keyhole surgery, it's very obvious to the surgeon and the patient there's a big difference there. But really, we all want to be able to do randomised controlled trials so we can tell patients what is better. And there's one other thing to say. A systematic review is something that we can conduct when we've got multiple randomised control trials. And sometimes what you find is that you run the same sort of trial multiple times in different locations around the world, is that you get subtly different answers some time. And a systematic review is a good way of trying to bring all that data together and give one final answer to that question.

Clare Delmar:

OK, I'm actually going to come to that in a few minutes because there is a review that I want to chat with you about. But before I do that, you mentioned about bias. So, I mean, does the source of funding influence the process and the outcomes? Is that sometimes a source of bias?

Tim Dudderidge:

Well, it can do. And that's why it's important when you've got a commercially funded study, that there is a degree of separation from the company that's funding it and the people conducting the study. And the more separation, the better. But it's understandable that commercial trials are there to answer commercially valuable questions and so often the study design. This is particularly so in the study of drugs. The study design will be very much focused around the funders objectives, but they do have independent data monitoring committees, safety monitoring committees and other structural things within the study that mean that people can hopefully regard the outcomes from those studies as being valid. But it's not uncommon for a commercially sponsored trial to shortly be followed, once something is become established, by academic funded studies to really hone down the questions. But often with surgical studies, there's not often the opportunity to repeat randomised controlled trials, because the moment in time where people have something called clinical equipoise, and that's basically both the surgeon and the doctor believing that either choice in the trial could be equally good. With surgery, once you've got a really bit of solid data that shows one operation or no operation or whatever is better than the alternative, then it's very hard to look at patient in the eye and say, we're going to put you in a randomised study when somebody down the road might be regarding that new intervention as the standard now. And so it's very important with surgery, that when something innovative comes along, that at the earliest time point possible, a randomised controlled trial is undertaken. Because if you wait too long, you may miss the opportunity to do that randomised controlled trial simply because neither the surgeons nor the patients will kind of go ahead with it, even though they might say scientifically it's needed. It might be that the funders, the health care funders really want to know if this is a good intervention or not. If you get to a certain point in time where something becomes the normal, it's very hard then to turn around and say, we're not going to do this unless you're randomised between either no treatment and an operation or treatment A versus treatment B. So I think the timing of randomised controlled trials is very important.

Clare Delmar:

Oh, that's interesting. So then how would they influence clinical practice? I mean, what do you see as sort of a pathway or is there a uniform pathway? Does it depend on the health system? Does it depend on what the trial is actually investigating?

Tim Dudderidge:

There is a sort of pathway that's well-recognized in the pharmaceutical industry. And so to a certain extent, that is mirrored in surgical practice. But effectively, you, first of all, have to have an intervention where you've got a sort of theoretical basis for that intervention. And one of the earliest things that you must do is assess the safety of the treatment and to see that there's some early sign of treatment effect. Obviously you can do a safety report of an operation or something like that and make sure that people are not having too many side effects. So the monitoring of side effects is one of the earliest parts of the research. Phase one is the typical name given in the drug study where you're establishing the dose of the drug. So that's perhaps not a good analogy for surgical studies. But in phase two studies, you're there really with a group of patients looking at the side effect profile and at the same time collecting some data on the treatment effects. And that's quite easy, for instance, when you've got something where you can monitor a scan or you can monitor a blood test, for instance, looking at cancer outcomes. PSA testing is quite handy for most prostate studies. And increasingly, when we're looking at ablation, where we're looking at the combination of PSA and of imaging and of biopsy results. And so you would sort of start off by looking at what's the side effect of that intervention, then start looking at some cancer outcomes in terms of maybe a one year scan and biopsy and PSA results. And does that indicate the cancer successfully treated? And then the next level from that really is more longer term cohort data. So you're taking as large a group of patients as you can who have met certain study entry criteria and you'll just monitor their outcomes at set time points. And at this point, we've got two types of study. You've got the formal research study where everything is carefully funded to be checked at certain time intervals and everything is done by a very rigid set of rules. But then you've got a slightly less onerous form of study which can be done without some of that research framework, which is called a registry study. And that's where all the cases will be perhaps undertaken according to local practice, but then uploaded onto a study registry, which can then be scrutinised by multiple centres. And so, for instance, in the UK for HIFU, the high intensity focus ultrasound, we have had the Index study, which has been organised through UCL and Imperial more recently. And the Index study has also been complemented by the UK Heat Registry, which is for sort of non-study patients. And that's provided us with much of the UK's really good data collection on focal ablation with HIFU. But we're now moving on to a new phase where we're moving away from cohort studies to the randomised control trial and we're running the Chronos A and B here in Southampton, which is again organised by Imperial. And this is a randomised control trial with an interesting design because the objective in Chronos A, the main objective is to run a randomised controlled trial between the standard whole gland radical treatments and focal therapy and we're allowing whatever whole gland treatment, surgery or radiotherapy that you choose to have and also either form of commonly used focal treatment. So that's HIFU and cryotherapy. And that really is the most important thing for the UK to be focusing on within the focal therapy community is to try and see if we can recruit men to the study. And basically, that study requires me, and this is exactly how I feel, to look at a patient in the eye and someone who's got disease just on one side of the prostate, that's important disease. And say to them, I don't know what's best, for you to have focal therapy with hemiablation of the prostate with HIFU, for instance, or to have nerve sparing radical prostatectomy, because although these treatments are both quite distinctly different, the side effect profile of HIFU will be lower. But we have an uncertainty about the long term comparative effectiveness, which is why we're doing a study. On the other hand, surgery which may well have been demonstrated to have these long term outcomes that we can predict. It's not like you get a guarantee of no repeat treatment. It's just that we know at 10 and 15 years what the likelihood is of you having to have repeat treatment, whereas we don't know the likelihood of repeated treatment for HIFU yet. But the side effect profile of surgery is that much more challenging for patients. You know, incontinence happens very frequently, although it recovers, thankfully, in most patients. Erectile dysfunction is also a significant issue for many patients. So we know that those side effects are there and the question is, is that cost worth paying? And is there a difference in the comparative success of getting rid of the cancer that sort of justifies those additional side effects? And we don't know the answer to that question. So if I can look a patient directly in the eye and say that I do both of these treatments, I am an advocate of both, I'm sitting on the fence here. And yes, you could choose you might look at the situation, say, well, you obviously prefer one over the other. But scientifically, the most robust reaction to this situation is to say, I don't know what's best. We're going to let the randomisation take care of the decision making and in the process contribute to a study where eventually we will know which is the best of these treatments.

Clare Delmar:

That's interesting. So the question, its main question of Chronos is what? What is the main investigation then?

Tim Dudderidge:

The main objective is to establish that failure free survival, the comparative success in getting to a ten year time point free of any kind of disease progression and failure in the sense of having to have surgery or radiotherapy as a salvage treatment, having hormone therapy because the disease metastasises, measuring metastases, dying of prostate cancer, all of these things count as failures within the study. And we're really looking at the primary endpoint is to study that and see which is the best treatment. And of course, we will be studying the side effect profiles of these treatments as well. But the next part of Chronos is interesting, because when you pose that question to patients and you say, look, I have an equipoise position on this, a substantial number of men will come back to it and say, well, I don't, I favour focal. About two thirds say that to me and one third say I favour surgery. That's of the people who have a decision, a preference. And I would say at the moment, I haven't really got a good feel for it, but I'd say at least half of men have a preference and don't want to be randomised, and so it is quite challenging to recruit to these randomised controlled trials because even though the doctors say to them, we don't know which is best, patients will look at the two choices and they find it difficult because it's not like looking at two different tablets that look the same. Looking at a pathway of HIFU and looking at the pathway of surgery. They look so different, it's very hard not to have a preference, and that's what I'm finding. So even in the hands of committed researchers, it's a challenge to successfully deliver this kind of recruitment.

Clare Delmar:

Yeah, that's interesting.

Tim Dudderidge:

So that's why we've got the second arm of the study, which is called Chronos B. In Chronos B, it accepts that the patient has made a preference towards treatment - focal ablation. And we've got another question we want to ask, which is can we improve the outcome of ablation with the use of drugs as sort of what we call neoadjuvant therapies? That's drugs given before the treatment. And this is something that mirrors the practice in radiotherapy where men are given hormonal therapy. So we're using one of the same drugs, bicalutamide, but also using finasteride as another drug for neoadjuvant therapy. So that study is now pretty much fully recruited. And we will find out in the next few years whether there's evidence that using drugs like that before HIFU can actually improve the outcome, and that will be very exciting.

Clare Delmar:

What do those drugs do? You mentioned neoadjuvant, but could you explain what that means?

Tim Dudderidge:

These drugs are both focused at shrinking the size of the prostate before treatment. And also there's an anticancer effect of bicalutamide. So that may in itself be helpful.

Clare Delmar:

Interesting. So you said that the Chronos trials are fully recruited or partially recruited.

Tim Dudderidge:

The Chronos B study is very nearly fully recruited, but then we will be focusing on Chronos A and so in effect, the main research objective will be to try and encourage men to accept this clinical equipoise and allow themselves to be randomised between surgery and ablation.

Clare Delmar:

Well, I'll make sure that we put a link on the website.

Tim Dudderidge:

They do have a website. Yeah.

Clare Delmar:

Yeah. And just a final question about back to the sort of bigger realm of studies overall. There was some discussion earlier. Well, the end of last year, beginning of this year on a review of various published information about focal therapy. And this was something through the European Urology Oncology Group, and they were quite critical of focal therapy outcomes. And this was having reviewed evidence gained not only through RCTs, but other bits of research. And I just wanted to ask you what you thought about how you would address that, because obviously a lot of these studies might have various biases or as you say, they don't have the time sort of horizons because focal therapy is relatively new that other procedures or other approaches have. So what would you say to somebody who said, well, I read this in this particular journal and what do you think about it?

Tim Dudderidge:

So I think it's important to say that a systematic review is only really helpful when you've got a lot of randomised controlled data. And in their review, they've done an extensive search. But I could have told you straightaway that there's only one completed randomised controlled trial. And so it could have saved them a lot of time. And they found three other retrospective studies that were of value. In fact, we just published another study, which would have been important in this systematic review, which hasn't been included, but I can mention that as well. But the main randomised controlled trial that they would have included in their analysis was one conducted at University College London. It was actually a multicenter European study led by Mark Emberton. And that study was looking at a vascular photodynamic therapy treatment where effectively around and these were mainly basically they were low grade lesions. So Gleason six or grade group one lesions. And using this treatment, there were some clear advantages over active surveillance, which is the standard care for low grade disease. So although I'm not sure particularly that this study has a big influence on clinical practice because PDT is not in widespread use, first of all. And second of all, I think although there was some improvement measures seen against active surveillance, I think obviously with active surveillance, you know, we do have ways of monitoring patients and allowing a smaller group of patients to receive treatment when they show signs of progression. And I think that is perhaps more the accepted strategy in the UK. But it was importantly the first study to show that focal therapy can have a positive influence on the management of men with prostate cancer and as a stepping stone to the current larger, randomised controlled trial that we plan to conduct with Chronos A, it sets out important principles. And I think when we study as we are in Chronos A more clinically significant disease, where the treatment effect will be much more profound. And actually we're comparing to the alternative of surgery where the side effects are so much more significant. I think we're really studying a more important health problem than was studied in that study. So I think that was the main study they looked at. All of the other studies that they've kind of summarised would have been low quality studies from an evidence hierarchy point of view. And so it's not at all it's not at all surprising, therefore, that they will call for further research. In fact, that was that's a fairly obvious statement when you're looking at the field, which is only developing. So we are in the process of gathering that evidence. But the best evidence, I think, which was missed out in this study, unfortunately, has just been published by the Imperial Group and the sort of UK focal users group which I'm part of, is this propensity score matching study, which is basically taking the UK's focal HIFU registry data and comparing it to similar men who had surgery. And they've done a statistical method to try and match up these cases so that we effectively try, instead of trying to compare apples and oranges, that we're as closely as possible matching apples with apples, and that methodology is not anywhere near as good as a randomised controlled trial, but it comes as close as you can get, in my opinion, to that kind of ideal study methodology. And so this is literally just been published in the last few days, I think this study and with prostate cancer and prosthetic diseases and hopefully you can share a link to that. But this study, about five hundred focal therapy men, so it's a good size group. 420 of those men had high intensity focus ultrasound (HIFU), and they did a matching and eventually ended up with a group who matched up with 246 radical prostatectomy patients. They ended up with 246 of each in the final analysis. And they found that over the course of eight years the patients had cancer outcomes that were similar between focal therapy and radical prostatectomy. And I think that this is really important data because notwithstanding the fact it's not a randomised control trial, it's the biggest and most statistically well powered answer to that question. And I think we can make a simple statement to men, which is in the medium term, it seems probable that the risk of you, if you meet the sort of entry criteria which were part of this study group's entry for HIFU, if you've got those criteria in your disease and you were to go through HIFU, you can be reasonably confident of an equivalent outcome to surgery at around eight years. And it's not as robust a kind of response as you get from a randomised control trial. It's as good as we've got at the moment, and that gives men an idea about what they can expect.

Clare Delmar:

And of course, give them reduced side effects, which, of course, is...

Tim Dudderidge:

Yes.

Clare Delmar:

And yeah. Well, I'll put a link on that and on the transcript as well. And I mean, just another note of observation. You know, it's always incredible to hear how much of this is actually being done here in the UK. It really is sort of a hub, if not an epicenter of this kind of work.

Tim Dudderidge:

Yeah.

Clare Delmar:

And people like you are really driving this forward. So,  thanks for that. And thanks very much for joining me today. I think this is a really, really important topic and I really look forward to seeing the publication of the study you've just talked about. Thanks, Tim.

Tim Dudderidge:

Thank you.

Clare Delmar:

A transcript of this interview is available on our website, along with several links to the trials discussed. Visit www.thefocaltherapyclinic.co.uk, where you can learn about alternative treatments for prostate cancer, how we approach patient care at The Focal Therapy Clinic and access additional interviews with both patients and clinicians about their experiences. Thanks for listening and from me, Clare Delmar, see you next time.

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