Nicolas Mottet: So let me remind everyone, I'm just a surgeon. So a little bit simple minded, and I try to convince you that we are not ready yet to change management just based on PET PSMA. So, I have no disclosure with the topic. What are we discussing here? The everyday use of upfront PET PSMA outside trials. You realized how many ongoing trials are there with PET PSMA. What does it mean? Very simple. We don't have the real outcome data yet, so it's experimental. I could stop there. If we have data, they must lead to treatment change that must finally lead to recommendation change based on data and facts, not what's assumptions. Back to basics, why are we imaging? To better characterize a disease extent, we all agree on that. Because the disease extent will define an individualized stratification and treatment decision. The goal at the end of the day, it will improve the outcome.

We image only for that. To finally improve the outcome. There's no discussion, PET PSMA is more accurate compared to any other methods, especially the old fashioned conventional bone scan and CD scan. We all agree on that. Don't need to spend hours on that. It also improved with stratification that from a surgeon cohort showing that based on the PET results, the outcome is different. So you might try to find the risk of your patient based on the pet results. Nice to know.

So we have an increased accuracy. We have better risk gratification, but the increased accuracy clearly means an earlier diagnostic, which leads at the end of the day of a major lead time bias, probably several years. We increase the risk gratification, that's nice. What's the practical impact of that outside being able to explain to the man facing you? Well, sir, "the situation is not as good as we expected." Practically speaking outside that, there's absolutely nothing to change based on risk gratification, evidence based. And finally, does this lead to treatment modification and outcome? Treatment modification, yes, we have data just showed you two things that lead to treatment change. So, clearly in [inaudible], you clearly show that it cleared to treatment change so far. So, what does it lead to any outcome benefit?

Absolutely no data is available yet. Just seeing a delayed math through survival is of interest, but does this lead, at the end of the day, of a symptomatic improved survival or of overall survival benefit? Absolutely nobody knows. It's only based on assumptions. Back to my first slide, we are dealing here with everyday practice outside clinical trial. And there are risk to be used by PET PSMA standard of care that is outside a trial. If it's done that way, as apparently it's already there, we will never ever know if it has real added value. Just let remind every physician in this room, pelvic nodal dissection. Do we need to remove all the nodes when we're doing a radical prostatectomy? It has never ever been associated with overall survival benefit. It adds staging informations. It adds side effects, but has never been shown to add survival benefit.

Even worse, whatever the PET PSMA result is, if a lymph node dissection has to be considered initially based on risk factors, it's still needed. Whatever the results of the PET, just have a look at the sensitivity. Sensitivity is definitely not enough to avoid doing a lymph node, dissection, whatever the PET PSMA results, if you plan to go for radical prostatectomy. You might also say, "well, if we find spots in the bones or in the retroperitoneale, we will eradiate the metastasis to directed therapy." Fine. That's based on nothing. These are the four trials that have been published so far. Most of them are focused on relapsing men. None of them, except one, has some patients that were newly diagnosed. And if you have a look at the number there, 20 patients altogether in a phase one cohort from Memorial. Are we serious? Is this enough to become standard of care practice? Not so sure.

Even worse, while we happen with this. That's a summary that the guideline panel published two years ago for a high risk localized disease. Have a look. Based on the extent of the spots, you might completely change what you are doing leading to either both over or undertreatment decision. That's not so nice because you add side effects. And even among us, the APCC panel, APCC 2021, there was no consensus regarding when to use upfront PET PSMA for newly diagnosed high risk patients, 23% were against. I know it's a long time ago, 2021, but still at that time, that was what we had. Treatment change based on PET PSMA, not so disappointing, I would say, but have a look at the very last part of the slide. N0M0 conventional imaging, you'll find more than four spots with a PET PSMA. 29% of the voting member voted for conventional therapy for metastatic androgen sensitive prostate cancer omitting the local therapy on the N0M0 despite the level one evidence for that. We're supposed to be experts.

Finally, it's not only me, the old fashioned surgeon guy. You have the names of the people who published twice in the JCO two years ago, and few days ago. A controversial tutorial, both claiming exactly the same thing. I highlighted the table on the bottom right, N0M0 PET positive priority is clinical trial. What does it mean for a simple minded man? It means that it's far away from being standard of care. So PET PSMA is of major interest, no question with this. The outcome data are absolutely based on treatment change are absolutely nonexistent. Therefore, it should only be used either in randomized controlled try and multiple trials underway, or at least in very well defined perspective cohorts. If we don't know that way, we will never know at the end of the day, if we are just playing with a fancy tool or if we are really improving the patient's outcome. Thank you.