APCCC 2019 PRESENTATION SLIDES

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Oligorecurrent Prostate Cancer Presentation - Piet Ost

Piet Ost discusses the treatment of oligorecurrent prostate cancer after local therapy at the Advanced Prostate Cancer Consensus Conference (APCCC 2019). Currently, there is no consensus definition for oligometastatic disease although a consensus working definition is being developed by the EORTC-ESTRO group. Highlighting findings from his own trial, Dr. Ost also frames these two main points during his presentation: Phase II trials indicate that metastasis-directed therapy is feasible, well-tolerated and improves biochemical response and progression-free survival compared to observation, and metastasis-directed therapy in other tumor types have demonstrated an improvement in overall survival and metastasis-directed therapy should not be considered standard of care based on phase II trials.

Biography:

Piet Ost, MD, Ph.D., Radiation Oncologist, Assistant professor, Faculty of Medicine and Health Sciences, Ghent University Hospital, Member of the Steering Committee of ION (immuno-oncology network) Ghent Vice-chairman of the Young Academic Urologist Prostate Cancer Working group of the EAU, Ghent, Belgium


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Piet Ost: Thank you. Thank you for the nice introduction and the nice invitation. This is a lovely city of Ghent where I am from. Also very lovely to visit. And my Twitter handle is on there, so please tweet a lot. I need the chocolates to bribe the two kids, more on the picture. Put in some alcohol as well. I need to bribe my wife as well because I'm going on too many conferences. These are my disclosures but non-relevant for the oligomets because we want to irradiate, we don't care about systemic drugs of course.

And what am I talking about? I'm talking about the patient in the middle, and that's oligorecurrence. Meaning the primary is controlled with whatever means. We don't have any evidence that there is local disease, but with whatever imaging we use we find different spots and these spots that's the question, what should we do with them? And indeed there is no consensus definition. At a certain point the question was asked to Ralph Weichselbaum, why did you choose five metastases? Why five? Why not six?

This was his answer. I was hoping to get a biology answer here. Genomic answer. No, no. He said, "I originally said five because someone asked me and I said five." This is what we've been doing for over 20 years. Someone said something, nobody checked it. This is what we've been doing. Nevertheless, we have to try to move forward and there's now, between all these different terminologies there's an EORTC-ESTRO consensus and I know there's work with ESTRO as well to get some of these wordings and definitions standardized, and that's work coming up. And I do believe that there will be, at someday, a molecular characterization that we can say these are the slow progressors. These are the fast progressors, and this is work with GAP6 for Movember, we're supporting this. So I think that might get you some new evidence.

So if you have a biochemical recurrence, we know everybody says now, do PSMA. What if you do PSMA early? Well we will get more oligomets, that's for sure. There are numerous trials on looking where there are spots. The faster you do your imaging, the lower volume you will see. So if you want oligomets and you want to go with radiotherapy, do it very early.

So where do you expect these recurrences? This is some work from our group. On the left-hand side, you see the choline. The majority of recurrences will be in the pelvis. The same on the right-hand side with actually PSMA. A lot of these recurrences again will be in the pelvis, and about 20% will be distanced. So that's important. If you do PSMA you already almost can predict where the recurrences are. So already think about what you will do with them before you do imaging. I will not discuss whether or not it's useful, but this is where you will actually find them.

So, what about metastasis-directed therapy? Is there any use or is there no evidence? I will ask you to get the voting up. So use your voting cards. I want to be the first one without a bell. I didn't make that. So I want to be the first one using the voting cards. So the biological rationale, if metastasis are able to metastasize, just irradiate them. You will delay progression. As simple as that. So two years ago, I was standing in St. Gallen, and this just came out. Everybody was saying, you are chasing Pokemons, Pokemon. Everybody was laughing with us. We had a very fun discussion. Now, these authors are very esteemed authors there. You probably saw them already on stage, but during the night you can recognize them with a different attitude. That's after drinks when you meet them.

Nevertheless, they had a point. This is the chart with level of evidence. Two years ago, the level of evidence for SBRT of metastasis was extremely low, so I fully agree with them that at that time point I didn't have that much to say. Although I did keep up with my 10 minutes. So this is a typical patient I want you to vote on. Radical prostatectomy, salvage radiotherapy, PSA starts to go up pretty fast. We do novel imaging. We did both MRI because we want to please our radiologist. Also, we did some call line back in the day, but you can think it's PSMA. It doesn't matter. And you find a solitary spot in the bone. Important question. This is not the Italian flag, but these are the cards I got. It's not a subliminal message. I know we are going to move to Lugano next time, but voting. Who wants SBRT puts up the green one. Who doesn't want SBRT ... Probably need to take a picture. Please vote. I need to take ... Is there anyone taping this? This is the best picture, I think, of the...

All right guys. I'm seeing a lot of green cards here. And actually two years ago we did that voting, after we said there was no evidence whatsoever, this is what everybody voted on. All the experts said go for SBRT. There was discussion whether or not to add anything. But everybody said SBRT. You're also saying SBRT. So now I have to get down to the evidence, and that will be sobering. There's actually two trials done now. Two small phase two trials. One that I did, so I'm biased. The other ones is now done by Phu Tran at Hopkins. Comparing SBRT, we also included surgery, not important, so local therapy through the mets, versus observation. First one of us is published. You see a nice PSA response. In the majority of cases we treated, but in some cases we irradiated PSA went up and new lesions appeared. Tip of the iceberg.

Actually the same has been seen now by Phu Tran, although he sees even more durable responses, although he didn't use PSMA yet. So two trials actually with the same setup. They did a two-one randomization, we did a one-one. Nevertheless shows you that if you irradiate metastatic lesions, your PSA goes down. Makes sense. We looked at an endpoint progression-free survival or ADT-free survival, whatever you want to call it, and you can see that both studies confirmed that if you do SBRT to the lesions versus no treatment, luckily SBRT is better in postponing disease progression.

Why did we do this concept? Because I wanted to make sure that if we intervene it's better than doing nothing. If this study would have shown that actually we didn't improve anything, I would have stopped. So please consider this as a proof of concept. Don't consider this as decisive evidence, and that we should go for SBRT. This is looking at toxicity. It appears to be that if you go for SBRT, quality of life is maintained, so that's good. At least we're not causing too much harm as Johann De Bono, this morning, suggested that watch out for doing too much harm.

What about the cost of MDT? This is new, unpublished. Go on and tweet, I would say. We did a study to find out if it was cost-effective. Yes or no. These are very difficult analyses. I gave them to specialized people. Don't ask questions about it. We made a mark of model. Again, very difficult to understand, but we put in all the elements which attribute to cost. So, we put in imaging, PSMA imaging, we put on choline imaging, we put in anything, all the treatments you can have, ADT, cost of ADT, quality of life gained, quality of life lost. And we tried to look into is it cost-effective to go for them immediately versus immediate ADT versus observation and delayed ADT. This is the summary slide. On the Y-axis, you can actually see the probability that it's cost-effective. On the X-axis, you see the threshold or the actual cost, and you see three lines. The red line is actually the one with SBRT or MDT going for the lesions. The blue one is surveillance. And the green one is actually the immediate ADT. It appears to be, if you're willing to spend more than 10,000 euro per quality gained, the probability that your strategy is cost-effective is over 50%. if you want to even spend more money per quali, which most countries do, up to 40,000, you will be cost-effective going for SBRT.

Just a take-home message that this might be a good thing as compared to immediate ADT, which is the lower one. Immediate ADT gives you a very big cost and the potential decline in immediate quality of life. So these are also things we have to consider. And probably there's some reviewers of this paper in the audience. You know, that's a good paper. You don't have any comments. I will be very, very grateful to you. What about other tumor types? Other tumor types have looked into survival, and that's important. This isn't lung cancer, so SBRT versus standard of care. So adding SBRT, the upper curve, this is the progression-free survival. They now have updated that. There is an overall survival benefit to eradiate oligometastases in lung cancer.

SABR comments, another one. Observed or the standard of care versus standard of care plus adding SBRT. There is a survival benefit by adding actually SBRT. So this is pulling evidence from other tumor types and this is probably where prostate cancer will evolve. But it takes a longer time to develop or to die from disease. So it will take a while. But do mind that in the SABR comment, prostate cancer was actually allowed.

As you can appreciate this is just published yesterday in the red journal, quality of life is maintained with SBRT. You don't see a declining. So again, SBRT or metastasis directed therapy as something with low toxicity or potentially low toxicity. Do mind the SABR comment, that two great five toxicities and that's something we hopefully now know how to avoid.

So for me to conclude there are interesting phase two trials that indicate that it's feasible, it seems very well tolerated, improves biochemical relapse-free survival, improves progression-free survival. In other tumor types it improves overall survival. But in my opinion, at this time point, it should not be considered standard of care. We should give the [inaudible 00:10:33] to do the randomized trials and they are upcoming. A lot of phase three trials in many different settings. So I think if we keep on this pace, we will get there in 25 years probably. Thank you.

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