"A Cause for Action: The Time for Change"
Tuesday 9th November 2004, The Congress Centre , London
Professor Malcolm Mason, Cancer Research Wales Professor of Oncology
Vivienne Parry : Now we come to our next section which is gathering together two people who are leading lights in the treatment of prostate cancer and who are going to give two different perspectives about the way ahead and the new methods of treatment that are coming up. First can I welcome Professor Roger Kirby - the ubiquitous Roger Kirby - Professor of Urology at St George's. I think you have performed over 1,000 radical prostatectomies which is an extraordinary number and still counting presumably.
Professor Roger Kirby : Nine hundred and eighty-six actually, 14 to go. Any volunteers in the audience?
Vivienne Parry: You have 12 minutes.
Professor Roger Kirby : Thank you very much Vivienne. It is wonderful to be here and it is wonderful to speak after two such eminent speakers.
I really enjoyed John's story and I liked particularly two analogies - the prostate cancer journey and the analogy of the mountain that we have to climb - and the fact that we are only in the foothills right now. I would agree with both of those, and what I will try and do is take you on a little journey into the future. One has to say that not everything in the future is easy to predict, but I think that we are on the verge of making earlier and more accurate diagnoses.
There are more minimally invasive treatments for localised disease that, for the first time, really offer the potential for cure - the new forms of chemotherapy and immunotherapy that Malcolm will talk about. And there's some real new data on the effective treatment of hormone relapse prostate cancer - perhaps the most difficult problem that we clinicians have to deal with. Well, this in a way illustrates the prostate cancer journey from the small tumour in the prostate to a nodule that you can feel as an urologist - into invasive cancer which spreads into the seminal vesicles and outside the prostate into the neurovascular bundles behind the prostate - and beyond that into the skeleton and to the lymph nodes [Slide 3]. The problem and the dilemma that John has already mentioned is that not all cancers do spread - prostate cancers especially. What we have to do is identify critically the ones that do spread and pose a risk to the individual and those which will stay dormant. Chris Parker will tell you a lot about the new information on that later.
PSA measurement has been mentioned [Slide 4]. It's definitely the most controversial area in the whole of medicine. Some people have said PSA stands for the "promotion of stress and anxiety". Other people say that it is "providentially sent antigen" for urologists to keep busy in their clinics. The truth is that from recent headlines you would have seen in The Times, and elsewhere, the PSA test is useless. It does bitterly lack sensitivity and specificity - that's the ability to distinguish those who have a cancer from those who do not have a cancer. That really is our mission.
And two new bits of data - one suggesting that of those people who have a PSA less than 4, 17% actually have prostate cancer. So it is not good at telling us who doesn't have prostate cancer.
Dr Stamey, who is one of the originators of the PSA test, is also reported last month in the Journal of Urology as saying that there is now a lack of correlation between the absolute PSA value and the size of the tumour in the prostate when we take it out. So this does leave us with a bit of a dilemma.
Luckily, on the horizon, there is a new test called the PCA3 or the UPM3 test [Slide 8]. Very briefly, what this test is, after a massage of the prostate - which is uncomfortable but not painful - you can collect the first 20ml of urine that the patient passes and you can send that off for molecular testing using the UPM3 test. It's available in America. We hope to introduce it to the UK soon. Without going into all the details, the bottom line on this test is that in 43 patients it seems more accurate than the PSA, so it's the first in the new generation of molecular tests that will help us distinguish more accurately who does have prostate cancer and who does not.
The negative predictive value - you can see there - those who do not have prostate cancer 87% [Slide 10]. The positive predictive value, those who do have prostate cancer - nearly three quarters - 74%. An interesting test. Overall accuracy of 81%.
Well, we are also getting better at analysing how advanced the cancer is when we diagnose it. This is an MRI - using some new technology - an MRI Spectroscopy with the latest MRI machines from New York. You can see there in that prostate a large tumour [Slide 13]. So being able to stage the disease more accurately is one of our aims in the future and the technology is evolving. Well, John has mentioned the difficult choices that patients face when confronted with a diagnosis. Here's a list of what's available [Slide 14]. A nd just running through very quickly that list - the problem is how do those patients decide and where will new directions take us into the future?
This is a patient of mine. I won't run through the whole video now but he explains, (he is a doctor actually), he has a positive biopsy and he explains the difficulty encountered by him when he had to choose between surgery and brachytherapy and other treatments. In the end he selected surgery. [links to Video Footage 1 - 1 min 17 secs: Video 1 ( dial-up 56-64kbs, 404kb)
Video 1 (DSL/cable, 3,343kb)]. I won't run that on because he describes very nicely the dilemmas for him - how he went to Seattle to look at brachytherapy. He went down to MD Anderson to look at surgery. He took every bit of advice he could. He is a good example of the sort of counselling that the modern patient requires. And again just reiterating some of John's view there.
As Vivienne mentioned, I have taken a lot of people's prostates out, but we are looking at new technologies to do that. Laparoscopic surgery - and there is, even now, in London the first robot removing the prostate robotically. [links to Video Footage 2 - 1 min 52 secs: Video 2 (dial-up 56-64kbs, 565kb), Video 2 (DSL/cable, 4,827kb)]. This is a fancy bit of gear. Surgery will never be the same again - I think that's probably true. You can even do a radical prostatectomy using a robot sitting in America with the patient in the UK. Quite an interesting prospect.
The problem with radical prostatectomy is that even though you remove the whole prostate, what you find is multiple tumours and the tumours are often close to the edge of the prostate as shown on that slide there [Slide 18]. But in spite of that, we now have data from Scandinavia suggesting that the rate at which patients develop metastases after radical prostatectomy is virtually 50% of those who had followed watchful waiting. So that is some encouraging data.
Just looking at other technologies, ever so briefly, because I know that we must move on - brachytherapy was mentioned. Only 2% of patients in the UK with localised prostate cancer are treated with brachytherapy as opposed to 30% in the USA. So this is definitely a treatment that needs to be introduced more widely into the UK [Slide 20]. We could discuss it if we had some time and the ways and means that it is being undertaken right now. I went to New York just a few months ago to watch the best known American brachytherapist in action and I was really impressed by this new form of treatment and also impressed by the ten-year results that had been reported from Seattle and elsewhere. Just a few pictures of how brachytherapy is undertaken, ever so quickly [Slide 21], [Slide 22], [Slide 23], [Slide 24].
The problem with brachytherapy and radiotherapy and also with surgery is that there is a failure rate with all of these treatments and what we need is better ways of treating failures. (link to Video Footage 3).
Again, because I don't have time to replay the whole video clip, that patient had radiotherapy, had a rising PSA and then came to see me to ask whether the prostate could be removed. In general, removal of the prostate after radiotherapy is a hazardous procedure for the patient, so we decided to treat him with a new technology of cryotherapy - freezing the prostate with some new technology. Just one or two pictures to show how that's done with needles placed into the prostate [Slide 26], [Slide 27], [Slide 28]. An ice-ball actually forms in the prostate. The most amazing thing is to see this ice-ball developing in the gland [Slide 29]. In his case - I don't think he will mind me telling you this - so far, six months after treatment, his PSA is undetectable and it's had very few side effects. A new treatment option for men in whom radiotherapy hasn't been successful. Occasionally, surgery can also fail, I have to admit.
So new treatments - well I am going to leave this more to Malcolm than for me - that we are beginning to understand the genetic pathways - the journey through which people pass to get prostate cancer and the journey through which they pass once they have it. As we understand these molecular mechanisms, then new treatments will evolve and there are some real prospects on the horizon of chemotherapy and immunotherapy and of new drugs that really offer the hope for prostate cancer and maybe down the line -in the future - that we no longer operate on people's prostates at all. Instead that we use medical therapies, as we do in other areas in medicine - and surgery and indeed radiotherapy may become something of the past.
Two last lines. Of course, every time someone famous gets prostate cancer, the media pick up on that and important messages are put out to the public. Robert De Niro - lives in New York - with prostate cancer - had to choose between brachytherapy and radiotherapy for his localised prostate cancer. This is a picture I picked off the web of Lord Hanson who has already been mentioned [Slide 32]. I think that his donation of half a million pounds to establish The Prostate Cancer Charity with Jonathan Waxman and now with John Neate really has made enormous strides for this disease area. So I am going to finish with that summary slide there [Slide 33]. I won't read it out to you, because it really says what I have just said. I think there is a message of hope out there and I think that with the help of all the different charities and the hard work of the researchers and now with government support as well, the future to climb up to the top of Everest 29,500 feet is possible for us all. Thank you very much.
Vivienne Parry: Can I ask you to come and sit up? What I would like to do is take questions after our next speaker. So, Malcolm, can I invite you to the podium? Malcolm Mason is the Cancer Research Wales Professor of Oncology. He leads the Cochrane Unit specialising in urological cancers. You are going to look at the chemotherapy and immunotherapy aspects of treatment.
Professor Malcolm Mason: Thank you very much Vivienne and my thanks to all the previous speakers - a growing list now - including Roger. Thank you for setting the scene so beautifully.
I am going to focus, as Roger said, on more advanced disease. I thought that what I'd start with - well short of actually just having a magic answer that would solve the whole problem - what would be my three wishes? And I decided on these three [Slide 2]. The first would be that I would like to be able to understand the biological basis of what is 'significant' disease. Roger has mentioned - and Chris Parker will say a bit more about this concept - that there are some prostate cancers which are more significant than others. What's the basis of that?
My second wish would be to understand what the basis is for hormone resistance - why do prostate cancers which previously responded to hormone therapy, turn into prostate cancers that are not responding to them?
And finally - I will have to explain what I mean when I get to it - I think my third wish would be to find a good, surrogate endpoint for overall survival. If that sounds bizarre, I can probably explain that to you in a little bit. And in putting those three wishes together, you will have to decide which, if any, of these three categories, I fall into and I shall make no further comment on that.
But starting off with understanding the biological basis of significant disease -and explaining to you why I am putting this into a talk that's really about advanced disease.
Why do treatments fail? Well, it must be either because of the time at which we treat patients who we think have disease in the prostate only - they actually have already got secondary spread to other parts of the body, as Roger has shown, and we just can't detect them. That would be one reason, or alternatively, we failed to actually get rid of the primary disease - perhaps, as has been the case with the gentlemen/patient that Roger showed you. But on top of that there is the concept of developing hormone resistant disease. And that is - if you would like - a final, almost pre-requisite, to the ul tim ate failure of treatment - the picture on the right shows a bone scan and an x-ray picture taken from a patient who has secondary disease in the bones. All too commonly this is the scenario we see as oncologists.
And cancer spreading to the bones seems to be a particular problem with prostate cancer. But if you look at the whole picture and look at all of the prostate cancers that are diagnosed, most of them are actually insignificant. My definition of that is to say which are prostate cancers, that if we left them alone, would not result in death from prostate cancer? I don't want to stray into Chris Parker 's territory, except to say that one es tim ate from a very eminent epidemiologist a few years ago was that about one in 17 of the cancers we diagnose currently actually need treatment in the sense of that strict definition. The point about this is that if we could only understand the biological basis, I think that we will be much further on in treating not only early disease, but also more advanced disease. It is very likely that genes of the sort which Roger showed you in his last slide are responsible for this whole disease pathway, from early disease through to more advanced disease. In reality, it may well be that we are gradually beginning to learn that it may not be just one gene - or a few genes or interactions - it could be interactions between a handful of genes or maybe hundreds or thousands of genes.
This diagram [Slide 6] here shows a relatively new technique whereby, by taking a biopsy of prostate cancer, we can see by screening thousands of genes at once - which ones are under-active, either because they had been lost or because they mutated and which ones have become over-active. So in these diagrams the red genes are under active and the green genes are over active. The point is that we have the technology to look at very, very large numbers of interactions. And I think understanding these is the key to the illness and will be the key to the solution of the problem.
And what about hormone resistance? Of course the biological basis for hormone resistance may also be tied up in this business of significant versus insignificant disease, but I think one of the things we are just beginning to do and which we will have developed in the future is the ability to see the whole picture.
This is supposed to show a cancer cell with three things influencing it [Slide 8]. At the top is testosterone, the male hormone. Most of our treatments for advanced disease and, increasingly, for less advanced disease, interfere with the action of the male hormone. This is the basis of hormone therapy - androgen-deprivation therapy, or however it is known. But there are other pathways and this is just to simplify that diagram Roger showed and I am picking out two others - they are not the only two - but two which I think will turn out to be extremely important. One is EGF, Epidermal Growth Factor, and the other one is IGF1 or Insulin Light Growth Factor 1. And these are two other influences which along with testosterone appear to influence the development and the behaviour of prostate cancer and exert their influence on DNA. And maybe we have got to get a whole lot smarter about the way we think about therapies and rather than just targeting testosterone as we have been for the last 40 or 50 years, we need to think about targeting these other pathways as well. The drugs are becoming available to enable us to do it.
My third wish was finding the surrogate endpoint for overall survival. What do I mean by that? Overall survival - how long people live with prostate cancer - is hugely important. And it really does matter. This is data that was presented at a meeting, I think nearly two years ago, by Professor Richard Peto [Slide 10], looking at the effects of giving hormone therapy early compared to giving it later in men with advanced disease. The point I want to make is not to emphasize the figures - which probably reflect the state of play in patients who were treated a very long time ago - so I wouldn't read too much into the actual percentages - but what I do want you to look at is the time scale. Here we can see a suggestion that early hormone therapy makes a difference to survival. The curve at the top shows patients treated early on. The curve at the bottom show patients whose treatment was deferred. And what we can see is a survival difference which is of the order of about 7% - so maybe worthwhile - but not as large as we would like it. But look at the time scale - that's ten years. It's taken that long to be able to see that sort of difference and that's a very long time. The problem with overall survival is that although that is something that we can use for patients with very, very advanced disease that is resistant to hormone therapy, we want to treat patients at an earlier stage than that. We have to treat patients earlier than that. We have to test the treatments in patients at an earlier stage than that. The problem is that we are all in a hurry. Ten years is too long a time to wait to get the answers, so what do we do?
Well, this problem has generated what I regard as a veritable industry in looking at alternative endpoints to survival and that's what I mean by surrogate endpoint. Many of them revolve around PSA, though not the only ones, and here are just a few of the ways that people have been looking at it. And perhaps my view of the landscape is that for the moment it's a bit like the picture there. It's certainly cluttered and much of what is cluttered in the landscape may turn out not to be very useful. We need to move on somehow.
If we are thinking about biological treatments of the future, I think we maybe need to look at biological endpoints. Here I am going to be controversial. I am really going to ask you as experts to think about this. One thing we could do - and one thing which is done in breast cancer, which is a much more accessible disease - is to test treatments by repeating biopsies on the tumours. But of course taking a biopsy from a breast tumour is rather different from taking a biopsy from a prostate tumour, but should that stop us? So the questions I ask - and I don't know the answer -is whether it is possible to test these compounds by taking a biopsy before treatment, by giving a month's worth of treatment and then repeating the biopsy. That means the endpoint that we are looking at would be a biological one. We will be asking the question, does this biological treatment hit the target that we expect it to? What is its effect on that target? What is its effect on other targets? And after that, take it into clinical trials and hopefully get an answer a little bit more quickly and hopefully get some information that will allow us to use intelligent combinations of different biological agents. At the moment the information we have is scanty. There is a temptation to throw everything in together. We need to be able to be a bit more intelligent about it.
Well, what of the immediate future? There is some very good news around as both Jonathan and Roger had mentioned. We now have data to suggest that chemotherapy for prostate cancer really does prolong survival [Slide 15]. We now have a class of drugs called bisphosphonates which are drugs that prevent the bone destruction [Slide 16]. Remember that bone scan that I showed you from that patient? These are drugs which reduce the complications of bone metastases - a secondary disease in bones.
We have another class of agents called Cox-2 inhibitors which are of very wide interest, despite recent problems that you may have read about. They may be very beneficial as anticancer agents and what we want to do really is to put all these treatments together.
There is a study which is just about to start called The Stampede Study in the UK. It is going to be an international study, led by the UK , and I'm briefly going to show you how that works. The idea is that this is a randomized trial where patients who are starting hormone therapy will also be randomized to receive one, or a combination, of these various other drugs. It is going to go through several phases [Slide 19]. The first phase is a pilot phase to confirm the safety, which we think will be confirmed, but some of these combinations are fairly new. And the first stage is where we look at this thing called "failure-free survival". I don't have time to go into it, but it is a way of ul tim ately looking at overall survival which is still the most important thing - but the key thing is to get these drugs into clinical trial very, very quickly [Slide 20].
It is going to be a very, very large trial internationally, looking eventually at something like 3,600 patients [Slide 21]. I think that this signals the way forward for studying treatment in terms of the designer study. So I think we need better definitions of which patients are in danger. We need to look at systemic treatments for those patients in intelligent combinations at an early stage and particularly - and maybe my plea to the pharmaceutical companies is to consider whether we can test them very, very rapidly at an early stage for biological effectiveness in the way that I suggested and then go on to clinical testing in a stampede type of design. And I think that way we can transform the landscape from the one I showed you into something that looks a little more like this (picture of countryside).
Thank you very much.
Vivienne Parry: With two terrific speakers there, I am sure you've all got some questions, but can I ask a question? Can I ask the whole audience, would you be prepared to have two biopsies, one before and one after treatment if you felt it was going to advance the cause of prostate cancer in the future? ( Several hands were raised) Okay, now I am going to ask a different question - I'm gong to ask people who have had a biopsy whether they would have another? ( Hands were raised) Okay, we are going to go to some questions. We don't have that much time. So if this is a question which I feel really is a sort of personal description type of question, I am going to cut you off short, because I think we need general interest type questions. So where shall we start? Lady right here.
Delegate: First line treatment instead of radiotherapy?
Professor Roger Kirby: First line treatment is an evolving treatment right now. We are cautiously introducing it mainly for patients who have failed at radiotherapy. But surely it does have a place as a primary treatment and the advantage of it is that it can be repeated. Unlike radiotherapy, where you only have one bite of the cherry, you can use this treatment - but you do have to be cautious with it because the ice-ball kills tissue, and you have to be sure that you are only killing the cancer within the prostate and not damaging the rectum or other adjacent structures. So it is a very interesting new treatment -no doubt that it is one that will see used more in the UK. It is widely used in the US.
Delegate: Usage of ultrasound?
Professor Roger Kirby: Ah, you have been reading the Telegraph on Saturday now haven't you? My telephone line has been jammed with calls ever since Mark Emberton came out with that. That is another new, interesting technology. The problem is that machines cost over £1 million. Right now it is in its clinical trials phase. We don't know whether it really works reliably, but it's a very interesting new modality. It offers the prospect of treatment without any incision and as Mark Emberton said in the Telegraph, it could be used by nurses rather than by trained doctors. Very interesting. Watch this space.
Delegate: Continuation from ultrasound therapy. If it fails, can a radical prostatectomy still be carried out?
Professor Roger Kirby: Yes, I have actually done that in one case. The ice treatment does cause some scarring, because it causes some tissue damage, but actually it is easier to operate after cryotherapy rather than after radiotherapy. Surgery after radiotherapy is not a good combination, because things don't heal so well and you can't rely on accurate healing so we avoid surgery after radiotherapy if we can. But we have done it after cryotherapy. We hope we don't need it, because cryotherapy's worked.
Delegate: You haven't mentioned treatments - the after-effect of impotence.
Professor Malcolm Mason: I think Roger can speak better for normalities like radical surgery. It is extremely important in the case of treatments like radiotherapy - there are prospects, as we get more accurate with the planning, that we can maybe reduce the rate of those complications. I know - and Roger will be able to say more about that - there are newer techniques that spare the nerves so that in many cases, it is much less of a problem than it used to be, but it is still a problem. I know it's certainly one that I discuss with all of my patients who I see together with my surgical colleague.
Professor Roger Kirby: I agree with all that and I would also say that treatments for erectile dysfunction are improving just in the same way as prostate cancer has transformed in ten years. The treatment for erection difficulties has transformed as well with Viagra and so on. But it's still a big problem. It still does scare men and it keeps them away from urologists. We need to sort it, but it's a tricky one.
Vivienne Parry: As if anyone would be scared of you. I am going to take three more questions. The gentlemen over there, one over there and Sandy. Right, let's start with the gentlemen over there.
Delegate: How useful is Gleason score?
Professor Jonathan Waxman: Well, Gleason score gives you an idea of an outlook. Unfortunately, the higher-grade tumours have poorer outlook. It is useful overall. It gives you an idea of the prospects for a cure. It gives you an idea of the grade - of how well someone is going to do. It is probably absolutely the most important indicator of a prognosis.
Professor Malcolm Mason: One other thing which is helping us with patients treated with combination of hormone therapy and radiotherapy is that Gleason score is beginning to give us a guide as to how long to continue with the hormone therapy. There are suggestions that for men with a high Gleason score, they may benefit from a longer course of hormone therapy than patients with a lower Gleason score, so it is beginning to impact a little bit in treatment in that sense.
Vivienne Parry: Gentleman over there.
Delegate: Is there anything being developed to take away the pain from the biopsies? It's like having a tooth out without having an injection.
Vivienne Parry: Can I just say that actually pain killers used in men for dental pain don't actually work on men - they work in women. That's why women have always said that men are wimps during dental treatments, because the pain killers don't work.
Professor Jonathan Waxman: Well, generally what we do in most cases now is a local anaesthetic into the prostate - so two injections are made. And with that there should be no pain.
Professor Roger Kirby: You can also do it under light sedation. We need to work a lot harder to make it a painless procedure. There are also problems with bleeding and infection after a biopsy so it is a problematic area. We're working on it.
Vivienne Parry: Special pain killers for men. Sandy ?
Delegate ( Sandy Tyndale-Biscoe ): I'm sorry I want to get back to sex again. All the talk about prostate and sex concentrates on erections and leaves out the main points which is the prostate has a job to do in sex and without it you can do it, but you can't ejaculate. Is there any treatment forthcoming or promising which will leave men with a working prostate?
Professor Roger Kirby: Well, I take them out - they don't work once I've taken them out, that's for sure. We'd like to maintain sexual function, but to adequately control the disease, that is the future hope really. Probably we are going to look to new molecular treatments to achieve that. Almost any physical treatment aims to destroy the cancer and unfortunately it destroys the ejaculatory function as well, and it damages erection. So it's a massive issue and loads of work needs to be done but we are all working so hard to try and achieve the perfect world where we cure the cancer but don't damage the patient at all.
Vivienne Parry: Thank you very much. Can I congratulate all of these people for very interesting and fascinating exhibitions of their work. We are going to go to our next session now and I know that many of you will have more questions to ask so perhaps you can ask them during the coffee break. And your presentations will be available? ( Presenters responded with a yes) Thank you very much indeed.