Prof Nicholas James – Queen Elizabeth Hospital Birmingham & University of Birmingham, UK
Prof Jeffrey Karnes – Mayo Clinic, Rochester, USA
Prof Fred Witjes – Radboud University, Nijmegen, Netherlands

NJ: Good afternoon, my name is Nick James. I’m here with Jeff Karnes and Fred Witjes in sunny Barcelona for the European Multidisciplinary Urology Conference. We’re here to talk about the highlights of the meeting here in Barcelona and I’d like to start with something that actually was quite a small thing but quite an important practice point which is if you have a patient who has got hydronephrosis and a bulky bladder tumour and you want to give them platinum do you stent or do you put a neph tube in? Our practice has been to stent because we worry about chemo with a percutaneous hole as being a route in for infection. But George Thalmann showed data from his own department relating to risk of upper tract recurrence if you put a stent in as opposed to leaving a percutaneous tube as the route in, which was data I hadn’t seen before and was very interesting and quite an important practice point – it’s not an uncommon problem. So I’m just very interested in your take on that.

JK: I agree with that. It mirrors my practice but for different reasons so it was news to me to see the data from Bern with the upper tract recurrence. But the one reason that I prefer a percutaneous tube over a stent, if they’re going to go to surgery, it’s just because the stent usually incites a lot of inflammation of the ureter, can complicate the anastomosis of the bowel to the ureter. Even if patients are going trimodal therapy I usually prefer the percutaneous nephrostomy tube to the stent just because a little bit of local irritation from the Double-J and the radiation.

FW: Yes, I agree on that, especially during surgery Double-J gives some inflammation, it’s not the best thing to have. If there’s hydronephrosis that means that there is, of course, tumour at the urethral ostium which sometimes means it’s difficult to get in a tube, either from below or from above. So we usually give a perc.

NJ: Yes, and as we were saying earlier, the thing you can do, of course, if you get a good response you can take the thing out. I entirely agree about doing radiotherapy with tubes inside, you get more irritation. So my second highlight was Silke Gillessen’s presentation on the APCC consensus meeting and there were some quite striking bits of data she presented. I was very struck, and as surgeons I’d be interested in your take on this, that at both the meeting and in the audience today she got us to vote on how many lymph nodes you should take out with a high risk N0 M0 prostate cancer. So quite a technical thing but there was a remarkable degree of consensus on it. Everybody said you should take out 10-20 nodes or something in an area with no data really. I’d just be interested in what you do and whether you think you could even get data, whether the data might be relevant.

JK: I think it mirrors a little bit the bladder cancer practice, that the more lymph nodes you take the better you stage the patient. Really the take home is if they have a risk of lymph node involvement then you should do an extended pelvic node dissection and not just a sampling. I think most people would agree on that. The number of nodes is dependent on the institution; you could do the same dissection at least some place in the US and go to a different place in the US and maybe get different nodes related to the handling and everything. But the extent is the most valuable aspect of doing a pelvic node dissection. There was some data in patients who have a pathologic node finding but clinical node negative, that the more lymph nodes that you sample the better the outcome in pathologic node positive disease.

NJ: That may well be a surrogate for the competency of the surgeon, of course, rather than the therapeutic efficacy of the actual procedure.

JK: Absolutely, and also mirroring what we see in bladder cancer.

FW: I do agree, it’s not basically the number, it’s more the extent. There has been a very nice study from the Netherlands that was in bladder cancer, by the way, looking at a group of surgeons operating in two hospitals. Everything the same – same surgeon, same patients, everything the same – but different pathologists and the number of nodes in one centre was 16 and the average number in the other centre was 27 and the outcome was exactly the same. So it’s basically more the extent. I was, by the way, looking at Silke’s presentation, surprised that there were 150 questions were there is no consensus. There are more no consensus than there is consensus.

NJ: Absolutely, yes. But for the node thing, though, because this is an endless discussion we have in our MDT and one surgeon there’s always like 30 nodes and another one there will be 5 from the same department. The guy who is the most senior guy in the department who does the most nodes, he says this isn’t a therapeutic procedure, this is just very detailed staging. Do you think it is therapeutic or do you think it is just fancy staging and if you think it’s staging do you think things like PSMA-PET will make that sort of pathological staging redundant?

FW: It’s predominantly staging although we all have, as urologists, and you know them too, Nick, patients that have had one or two nodes that never get a recurrence again. What I now see when we do MRI scans for nodes or PSMA scans for nodes, you see nodes on spots where I basically never went before, bi-rectally or on other spots. So, again, our usual extended node section probably doesn’t cover it all. But if we would cover it all maybe there is some therapeutic value in that.

JK: I agree, the whole realm of molecular imaging, especially in the post-definitive therapy recurrent status, has shown us all these sorts of atypical nodal spread that never would have been in our template when we did the original surgery. In addition I do think it’s predominantly staging, I do think there is a therapeutic aspect to the pelvic node dissection and some of that comes from the salvage lymph node removals that we see or even the salvage radiation therapy we see to limited oligometastatic nodal disease where there have been some decent long-term cures.

FW: Jeff, do you change your node dissection based on imaging, primary or salvage of course?

JK: We do PET Choline imaging, however it’s not indicated in the primary staging. So it’s rare for us to have a primary staging PET scan just because it’s not reimbursed in the United States.

NJ: So it’s creeping as well. So one of the areas, coming back to the consensus conference where actually mostly there was no consensus, we’ve invented a whole new disease which is oligometastatic, primary oligometastatic recurrence, oligoprogression, in patients with multiple…

JK: …There’s no D0 disease anymore, it seems like.

NJ: In our practice M0 CRPC has almost entirely disappeared because we’ve just watched people’s PSAs go up and we do PET scans and then, as you say, you find nodes in places that were never in the standard anatomical distribution of nodes that we may or may not have irradiated already. So I think there’s going to be a lot of very interesting stuff coming out around that.

FW: We’ll get a totally new patient cohort with outcomes we don’t know yet.

NJ: Certainly in our practice we’re just imaging more and more because, unlike the States, we’ve got really good access to imaging so we’re imaging more and more and treating less and less. Increasingly you do a PET scan and you find there’s one node, you do a sort of involved field around it with a three month shot of hormone therapy then stop everything again and then a year later they pop up something else. They end up on a…

FW: That’s what you mean with more imaging and treating less because I would guess, based on imaging, you would treat more?

NJ: Yes, because in the past their PSA would have got to 20 or whatever it got to, our threshold for PSA, for M0 rising PSA starting hormone therapy was going up and up and up anyway, but it was arbitrary. The striking thing is patients’ PSAs will go really high and you can’t find anything, even on a PET scan. They’re much better off not on treatment, I think.

JK: I think the whole concept of metastasis directed therapy is one of the explanations I give patients is let’s try to make this a chronic disease. There are certain, some of these prostate cancers, typically the Gleason 7s, that you can pick away at , if you will, a combination of surgery, radiation, ablations.

NJ: Yes, it generates lots of heat.

FW: Or wait and see. The statistician’s view that was presented yesterday on PSA screening, for example, if you see how few patients have problems in ten years, that was 1%. So the guy said, ‘I’m not going to have a PSA test.’

NJ: That was one of the very striking things about the ProtecT trial, wasn’t it? It was published previously, not this year, but very striking that nobody was dying from prostate cancer. One of the things, just to segue into the STAMPEDE data, I’ll talk about that tomorrow, I know it’s CRPC day today, as it were. But we showed some data at ESMO, we showed the abiraterone data at ASCO and obviously it exactly mirrors the LATITUDE data as well so you’ve got this massive effect on survival and an even bigger effect on failure free survival, obviously depending exactly how you measure it. But the very striking thing was all the effects were bigger in the M0 subpopulation than they were in the M1 population, STAMPEDE has the whole lot. So we showed data at ESMO on just the M0 outcomes, the survival is immature, but of the N0 M0 patients who had had ADT radiotherapy plus or minus abiraterone virtually none of them had died and these are patients T3/4, PSA 40 or above, Gleason 8-10. It was really high risk patients and even the node positives over 95% of them were alive at four years if they had all three. It was quite striking.

FW: Yes, but you’re running into logistical problems, financial problems, I’m afraid, and what about quality of life?

NJ: The interesting thing about the financial problem is that the effect on relapse is massive. So you’ve got a 70% reduction in relapse and in the M0 we cap the treatments at two years. So at four years you’ve got something like 50% of relapse with ADT radiotherapy versus under 10% had relapsed if you added abi. So you’ve got a very large period not having any treatment if you shove relapse that far out. We’ve just done, and this data is not even in the public domain, but we’ve just done the health economic analysis on the docetaxel STAMPEDE stuff, we’re going to show that at GU ASCO. It turns out the effect on delaying relapse is the same, it’s a 40% delay in relapse, not quite as big but it’s the same sort of phenomenon that you stop your treatment and then you don’t have any treatment for a very long period of time if you’ve shoved the relapse out 40%. That completely wipes out the cost of the docetaxel and gives you a quality of life gain even though you’ve given them chemo at the beginning. So the docetaxel data, the health economics is cost saving, it’s more cost effective in M0 than in M1. It’s a pretty modest cost in M1 as well. So compared to abiraterone, obviously, it’s very different. The thing about abiraterone, though, if you look at the average length of treatment on abiraterone in the metastatic patients in STAMPEDE and in LATITUDE it’s remarkably similar, it’s about three years. The average length of treatment with abiraterone or enzalutamide in CRPC is about eighteen months. So you’re not paying for three years of treatment, you’re paying for eighteen months of treatment but if you look at what you get for that, if you give eighteen months of treatment to CRPC you get a six months survival gain; if you give three years, so an extra eighteen months, you get a three year survival gain. So the extra eighteen months gives you an extra two and a half years of survival. So probably it’s more cost effective in up front than in relapse but it is actually also more costly, of course.

FW: Yes, but I guess in the end if people relapse again they’re probably going to use the same drugs again.

NJ: We showed data on that at ESMO, on patterns of care. In the middle the abiraterone and the docetaxel arms overlapped in STAMPEDE so we’ve got 600 men effectively randomised to abiraterone or docetaxel as up front therapy. So we were able to look at the impact on survival; Matt Sydes did a really nice presentation on this data at ESMO so I’ll talk about it a bit tomorrow, but basically the effect on overall survival was the same. You’d have thought from the hazard ratios that it was going to be bigger with abiraterone but it turns out that for the patients actually randomised head-to-head it was the same. Time to progression was much longer on abiraterone but, of course, you’ve given abiraterone until they’re abiraterone resistant whereas you’ve just given six shots of docetaxel and then you come back. So you’ve actually given a lot less treatment to the docetaxel patients. But if you looked at endpoints like skeletal events the time to skeletal event was the same on abiraterone or docetaxel because it’s quite a late thing. So basically what happens is if you give up front abiraterone you’re going to have a long period relapse free but actually once you relapse things happen fast whereas it’s the other way around with docetaxel – you’ve got a shorter period of time to relapse but you’ve got a lot more options, including abiraterone, still to come. So things happen much more slowly. So what you get first, not very surprisingly, affects what happens later.

JK: In 2018 what do you think the standard of care is going to be for a newly diagnosed castrate sensitive prostate cancer?

NJ: In the UK NHS England just sent a letter round saying ‘Guys, you’re not allowed to use abiraterone,’ whereas docetaxel is already NICE approved and reimbursed and all the rest of it. So that’s not going to… whatever the science says, the funders in the UK are saying give the cheap stuff, guys. So obviously that begs the question if you’re not fit for chemo but are fit for abiraterone, which is obviously quite a lot of patients, obviously you’d like to give these patients abiraterone. How does that pan out in the States where you may or may not have a co-pay to give with it? I’ve heard that clinicians are offering people docetaxel for that reason, for the cost.

JK: Absolutely. Most insurance companies are not picking up the abiraterone for first line in castrate sensitive. They’re not picking it up currently.

FW: It’s the same for the Netherlands, it’s not reimbursed in the first line. So it is in the second line but I guess that will change over the coming years.

JK: They’re just pretty fresh.

FW: Do you think there’s any role for profiling, like the AR-V7 or whatever?

NJ: The trouble is if you look at the profile… if you look at mCRPC you’ve got an 85% response rate so you can at best only pick 15% out. It’s probably a higher still response rate first line because everything works better if you haven’t had prior treatment. Talking to people like Gerhardt Attard and Johann de Bono who are part of the STAMPEDE team, they were saying the rates of AR-V7 in newly diagnosed patients are actually very low so you wouldn’t be able to take very many. But if you did do it I guess you’d say those patients should get chemo but it wouldn’t help you very much.

FW: A small percentage.

JK: Going back to the comparison of abiraterone versus docetaxel with the PARP inhibitors, which I assume are more expensive than conventional platinum chemotherapy which has been shown to be sensitive to those BRCA type tumours.

NJ: Yes, one of the things that’s happening a lot in the UK and I assume it’s happening everywhere is it varies as to how easily we can get the sequencing done and how comprehensively. But I’m guessing that it’s going to become more commercially available anyway. But you’ve got patients who have got a very clear family history, for example, do you think just give them a shot of platinum-based chemo just to see what happens. We’ve got a few patients where they’ve had amazing responses, having failed to respond to docetaxel, say. You’re right, it’s a lot cheaper. It’s like with the abiraterone -docetaxel thing though, people would rather take pills than have chemo, understandably. So, yes, obviously none of these things are licensed in prostate yet so there’s a bit more game to be played here before we end up.

FW: But that will change in the coming few years I guess. What about immunotherapy? I heard yesterday about cold tumour, warm tumour or hot tumours. Is there a role for any kind of pre-treatment for prostate cancer before giving or looking at immunotherapy?

NJ: Again, that’s another thing we’re looking at putting into STAMPEDE. Tom Powles has been key to the whole story, he’s been looking at it for us, and at the moment there doesn’t seem to be any very convincing phenotype that you can use to identify responsiveness, just coming back to the responsiveness thing, but these drugs work so well almost everywhere else you’d imagine there must be some sort of role. But again there’s a bit of work to be done to figure out exactly where.

FW: You don’t see that coming within a few years?

NJ: There are trials recruiting, we’ve got a trial that’s opening where there are… microsatellite instability, for example. If you’ve got a lot of that it appears to… All of these things get more common as you go down through multiple lines of treatment. Obviously we’re shoving patients through lots of lines of treatment now so we’re going to see these things appearing late in the pathway increasingly. They’re so well tolerated, they’re really very easy drugs to give. You get a small number of patients will get really bad immune colitis or lung or whatever but most of these drugs are very well tolerated, you can give them to sick people.

FW: Do you think that, for example, what Silke told, that if you were to irradiate the tumour that you will induce the ability to give immunotherapy?

NJ: That is one of the things that is very interesting. It does appear that, slightly surprisingly because you would think radiotherapy would be immunosuppressive, but it appears that it is immunostimulatory. Particularly if you give a small number of big fractions it appears to be immunostimulatory. If you look at how radiation kills cells at the 2Gy/fraction type standard doses that are used, mostly you’re looking at single stranded DNA breaks, some double strand breaks, and if you line the single strand breaks up you can’t repair them, you don’t actually kill the cancer cells or kill any cells at standard doses, it’s below it. But if you go to much bigger doses per fraction you start disrupting cell membranes and all sorts of things so you’re actually getting necrosis as opposed to apoptosis and that’s much more immunogenic. So there is some sort of explanation about how radiotherapy might be immunogenic around inducing necrosis and therefore inflammation versus inducing apoptosis where you don’t get a lot of inflammation. So it does kind of make sense.

FW: As I say what was presented yesterday by the combination of abiraterone and immunotherapy, again that apparently also gives some kind of response reaction which improves the efficacy of immunotherapy.

NJ: Generally in oncology the lesson is that things work better in combination. If you just do one thing on its own – surgery, radiotherapy, whatever – you’ll get whatever result you’ll get but to get better results you have to start adding drugs or whatever in. That’s the lesson with bladder cancer, isn’t it? The surgical results have been consistent but no improvement. It’s not plausible you can improve it really. You can do an operation better but fundamentally you either take the thing out and it’s gone or it’s not gone.

FW: You have to combine treatments, that’s obvious.

NJ: So I think the immunotherapies in bladder are going to be transformational.

FW: Now there are trials in every stage of bladder cancer, even in high risk non-invasive, so it’s expanding a lot.

NJ: I’m particularly interested in that because obviously that’s an area where you have an immune treatment already approved which, as far as I can see, it does work but it’s quite toxic. Not that many patients get all the way through a full induction maintenance.

FW: That’s true.

NJ: So there’s got to be better ways of doing an immune system tweak than giving somebody BCG.

FW: Yes, and if you can choose from pills or an intravesical instillation I think the choice again will be not that difficult.

NJ: I think those trials are going to be very interesting.

FW: It was very nice to see what’s happening now in prostate cancer whereas ten years ago we didn’t have anything. I’m very curious to see what we’re going to treat in a few years and what the sequence is going to be because that’s another question. But the landscape is going to change significantly in the coming few years.

NJ: It is, yes. It’s worth remembering, isn’t it, ten years ago docetaxel had just been approved a year or so previously and that was the only drug apart from ADT and stuff. No, it’s very interesting. I’ll wrap up by thanking you both and enjoy the rest of the conference.