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Stefano Fanti: Good morning everybody. It's a great honor to be here. Thank you, Professor Montorsi, for the invitation, and I'm really delighted and happy.

Well, these are my disclosure, a collection. But the most important one is that I'm proudly a nuclear medicine physician. So be ready, me trying to convince you that the skepticism of Alberto regarding the use of PSMA is absolutely out of place, because I'm a really strong PSMA believer. Be aware of this bias because it's the most important.

My talk will rapidly go regarding the use of PET imaging in genitourinary cancer will be rapid, because mostly I will concentrate on prostate and PSMA, because it's really our daily bread and butter. So no doubt that I will spend much more time there. And the reason is super easy. I mean, there is an unbalance, regarding the number of scans that I'm doing every day for prostate cancer and for the remaining part of genitourinary cancer, which is clearly, in favor of prostate nowadays. So that's the reason why I keep very short, and I will just refer to the guidelines of EAU, regarding the use of PET imaging within other genitourinary malignancy. And in particular, what's about the upper urinary tract urothelial carcinoma?

Well, it just mentioned it very briefly in the guideline, that you may try using FDG for nodal evaluation, and that's essentially all we can offer to you. The literature is honestly very, very small, and I'm really happy that one of the largest series that we published jointly by San Raffaele in Bologna, and their institution a few years ago, reporting some 100 cases. But again, the data are not really impressive, and there's just sort of little application.

And quite similar for penile cancer. The point is the same. With FDG, you can see some more nodes, so you can make a better nodal staging. Is not really something every day done, but it's something that you may use. Like in this case you see, if you have a hot lymph node, you're very much reassured that it's pathological, even if a good radiologist would always make the right diagnosis in this case.

And testicular cancer. Testicular cancer, in seminoma, honestly, FDG has a little more value and indication, as compared to the other that I just showed to you. It's not about real staging, it's mostly about evaluation of residual mass after therapy. So what we can do, is to discriminate if there is a active viable tumor, or if it's only fibrosis. Or at least, if the therapy has been effective.

We published a few years ago, our papers, and that's a clear example. You have a residual mass here, which is almost impossible to evaluate with conventional radiology. You have hotspot uptake here. But after treatment, there is still some residual area in the site with no counterpart. So you can consider the patient as cured. And that's the contribution that we have.

And finally, bladder cancer. Again, there are several potential indications of FDG for the evaluation of bladder cancer, are not really something that is done so frequently. And again, this is an example for staging especially. These are again, from the paper that we published together with the friends of San Raffaele.

Identification of distant met is clearly much easier if you have the hotspot on FDG. But also, ruling out the presence of metastasis could be helped by the use. So it's essentially, about the restaging, which is the overall impression that I have. It's that it works. It honestly, FDG-PET has not been designed like an SUV, has not been designed to run among bison. It's just an occasional opportunity that you have with your system to use it in indication which are not really so fundamental, so important, but nonetheless, could be useful.

And let's make a jump in the past because now I'm moving to prostate, to PSMA. But I will start with really, a little bit step back. Because we are talking on something really old. Nuclear medicine indeed, is more than 50 years old in the game of prostate cancer. With bone scanning, all of you knows very well, the good old imaging system for the bone, which is bone scanning. It's been introduced at really 50 years ago, and it's really Stone Age to us. It's something that belongs to the past, but it's still around. And it's not only Stone Age because it's, I mean, 50 years for imaging is really a long period. To me, it's also Stone Age, because of the quality of the images, because they look like cave paintings, honestly. The quality of the spatial resolution and the information are really, really obsolete. So it's something that we keep on doing, but it's not really so interesting to me.

And it's very interesting to note is that, it still mentioned it in every guideline. If you see the high-risk patient at presentation, they're supposed to have a bone scanning. In any guidelines, either EAU or in NCCN, or the other guidelines, it's mentioned, and do a bone scan to the patients. Why? Do we have good randomized trials demonstrating that bone scan as a role? Absolutely not. It's just because of tradition, habit. You use something that you have always been doing. So it's something that I'm telling everybody, "Hey, stop doing that, because we don't have that much of literature." It has been incorporated in every trial, but that's not a good reason. They were therapeutical trial, not trial demonstrating that bone scan has real an impact on patient management. But nonetheless, it's still done.

Next step, little advanced we are moving to. Something like 25 years ago, choline PET has been introduced. Choline PET, a little bit better, not a real revolution. What I used to say that the images were not really so impressive, but rather, impressionist. Because they look better, but not the way that would've liked it. So sometime I say okay, it's a glass which is half empty or half full. The point is very clear, the low sensitivity.

Everybody knows, a lot of papers demonstrating we have been using choline. It was much better than the other methods, but at the same time, was not good enough to really gain widespread use. But what it comes, 10 years ago, and that's one of the very first patients that had imaging on Heidelberg. It was a gallium PSMA introduction. Same patient. Choline, almost negative, just an old year, and a number of nodes seen by PSMA. So that was really a revolution for us, and it's been a revolution for all the field of urology.

The data demonstrated a much, much better sensitivity as compared choline. So it was rapidly incorporated into daily practice. But very correctly, as Alberto said, we didn't have any great Phase III randomized multicentric trial, with major measurable clinical outcomes demonstrating the impact. That's the limit. We may further discuss the reason of this limit.

Nonetheless, it was incorporated into the guideline. It happened in 2019. And PSMA PET was suggested by EAU guideline for biochemical occurrence, either after radiation therapy, or after surgery. And suggested to be performed if available, because another point is that, the degree of approval and availability is very scattered around the world.

It happened that there's been a lot, really an impressive amount of literature, which again, is not outstanding literature. It's good literature coming from different centers, frequently monocentric, frequently not randomized. Essentially, because there was no sponsoring issue behind it. Gallium PSMA-11 is not patentable molecule. So it's not easy to run a trial without someone supporting you.

Which are the indications? So how can we in practice use PSMA-PET, to be honest, and regarding what is available? Is that about diagnosis? Is that about finding prostate cancer? Absolutely not. Forget about that. It's not even mentioned in the guidelines, and it's right to not mention that. Because we have no role, absolutely no role. If you want to find the cancer, you have to use multiparametric MRI. And that's absolutely clear, there is no sufficient data to even debate the point right now, in my impression.

Is that about staging? We have seen some images and some doubt, very properly raised by Alberto. In staging, again, if you refer to the guideline, you will see that there is multiparametric MRI for local staging, as absolutely clear. And then again, the old bone scan, which is still there for some traditional reason. Nonetheless, since some five years and more, the German colleagues have tried to use PSMA-PET for staging, and essentially, for staging the high-risk patient.

And here is a case that I've been stolen from Alberto, that probably was a little bit a believer long ago. I may pretend that. And it was presented at EAU. A young patient, family history of prostate cancer, with a Gleason score of eight, so clearly, a high-risk patient, that is undergoing conventional staging. So bone scintigraphy negative, CT negative. So it should have been treated radically with an ideally, solution for the disease. But as part of a trial, we run multiparametric MRI. It's clear, you see very well the lesion. You confirm the lesion with Gallium PSMA, but you see nodal and bone disease. So it's clear, that this patient cannot be cured by surgery alone. It should undergo something else.

The data are not just anecdotal. Finally, a couple of prospective randomized multicentric trials have been run, in Australia, and then US. And the data are very consistent, regarding the fact that there is a clear superiority over conventional imaging. There's no doubt. The only doubt is the impact on, for example, overall survival. We don't have that, and we don't have that for many reason.

Because it's very expensive. There's no sponsoring. It should be very long, and it should be almost impossible to answer the trial. Because if you propose nowaday this trial in Italy, or in Germany, or in [inaudible 00:10:23], the urologist will not really accept the patient going into the arm without having any PSMA scan. That's very clear.

Recommendation for staging. It's now finally, 2022, been incorporated. Been incorporated, PSMA-PET and all body MRI to increase the sensitivity. But with a warning, be aware of the lack of outcome on treatment change. That's a very appropriate warning just to say, be careful, we don't have any proof that you're really making a benefit in survival. And we come back again.

The point is that, better detection rate, I agree, does not automatically and necessarily mean better clinical outcomes, but the rational is very strong. The more you know, probably, the better you can plan how to treat the patient. So it come back to your expertise. If you have, just shown before, a very faint uptake in one single rib, be careful, that could be a false positive. But if you have several areas of increased uptake, either in the lymph node and in the bone, you cannot pretend to not see them, and not use such information.

And that's a nice review recently done by the colleagues who are in Milan, which confirmed the same. And confirms, for example, that again, the specificity is high, the sensitivity is not really very, very high. Don't forget, that we have a spatial solution of some millimeters, let's say, three to four millimeters. So the micrometastases will always be missed. So if a node is negative, you cannot really pretend that there is absolutely no disease there. You cannot spare lymphadenectomy just because the PSMA-PET is negative.

And now, biochemical recurrence. Well, that's really our bread and butter. It's the main indication for PSMA-PET. And the advantage is clear, you got all the information with one imaging only. So it's clearly easy to report, definitely much easier than an MRI. I'm sorry for my friend from radiology. But reporting path, usually it's almost trivial, because you see the hotspot and you can identify that.

And the data, very strong. The EAU guideline, but also ASCO and the other guidelines, are fully incorporated PSMA-PET for biochemical recurrence with a number of data. We have demonstrated that's very important. We have the higher detection rate, especially in early biochemical recurrence. So when the PSA is very low, that's when you can pretend to treat the patient. In this setting, you still have a curative window, it's not that late. So that's important to be very accurate in this setting.

And in the last version of the guidelines is now recommended, even if there is a weak score, which is again, related to the lack of good randomized trial with main clinical outcomes to measure the effectiveness. But no doubt, that if PSMA-PET is available, it should be done in biochemical recurrence.

And of course, the same apply to PSMA, sorry to PSMA persistence. If you have a gentleman that after treatment has still a high PSMA, it clearly applies the same concept. That's an example that we performed. And again, you see choline, almost negative, and impressive images with Gallium PSMA.

And again the recommendation is mentioned. It is not even mentioned. It is recommended clearly to perform PSMA-PET.

So in biochemical recurrence and PSA persistent, I guess we can conclude that has a clinical role, it's recommended, is widely adopted, and it's been a success.

Are there other indication? Yes. Alberto show to you CRPC. What about, do we really see more with PSMA? We clearly see much, much more with PSMA. Even in patient with, theoretically, non-metastatic CRPC.

Those data are showing that 98% of patients scanned with PSMA will be positive. So almost every gentleman will be positive. But the most impressive is the fact that, more than half of the patient will be M1. So they're not really an mCRPC. So it's even questionable that it really exists. The category of non-metastatic CRPC, it's only about what strategy you can use to study the patient.

And in the APCCC conference, already three years ago, the majority of panelists voted for PSMA PET-CT in CRPC. Even if we don't have any ultimate proof of the outcomes.

SRT planning. It's another indication where again, it's already been incorporated for example in the ASCO guideline, the use of PSMA-PET.

And so, can we come rapidly to some conclusion after this sort of little ride in the nuclear medicine? I guess that, for the indication in genitourinary cancer, we switched from useless nuclear medicine to somewhat useful nuclear medicine. But we still have a lot to do, and I will come with some good news for the renal cancer person like Roberto. But the indication are not comparable to the relevance that we have in prostate cancer.

In prostate cancer, I guess, that in the last decade, we can say that PSMA-PET has been a game changer. It has really changed the way that we, you, manage, that we manage the patients. Even if again, we may discuss regarding the robustness of the existing trial.

And some very short view in the future. Just a couple of slides. Where are we going? What can we expect? Well first, is something that goes beyond imaging, and it's the possibility to use PSMA as a probe to drive your dissection. So essentially, you don't really use the imaging itself, but just like for the lymph node sentinel approach, you see, during the operation where nodes should be in case removed, and are happy that the colleagues here in Milan are driving this, together with the other group in Europe.

And I said, we finally have some good tracer in kidney cancer. It's not PSMA, it's a different fragment. It's essentially based on [inaudible 00:16:41]. So it's labeled with the common, not so easy to produce. But it's just been communication regarding the Phase III trial of the ZIRCON trial, a couple of weeks ago, reporting very promising data on that.

And as you can see, the quality of the image is quite good. And you can either see the primary tumor and the metastasis, and that can clearly, have an impact in the future. So good news, Alberto, for you on coming.

And with that, I thank you for your attention. Thank you.