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Alicia Morgans: Hi. I am so excited to be here today with Professor Irene Burger, who is joining me from Switzerland, where she works as a nuclear medicine physician, and is joining me to talk about her EAU 2024 Lecture, a state-of-the-art lecture on understanding how to use PSMA PET in high-risk localized disease, and all of the changes that it has brought about. Thank you so much for being here with me today, Professor Burger.

Irene Burger: Thank you so much, Alicia, for having me.

Alicia Morgans: Wonderful. So, Dr. Burger, can you please share where we are, where do things stand right now with PSMA PET? It's no longer new, it's no longer the new kid on the block. Tell me, what is the state of things right now?

Irene Burger: Well, it's amazing. I mean, it started off in Switzerland in 2016, and within only a few years, it really became the standard for staging high-risk patients. I think since 2020, nearly everybody that has high-risk prostate cancer in Switzerland that needs staging gets a PSMA PET/CT scan, and this is really unbelievable how fast also clinical practice changed. I am excited that this was possible, and I think it's, of course, the work of a lot of people, mostly from Germany, who brought the substance up, but also in Australia. The proPSMA trial, a phase three study that really showed that the sensitivity is higher, and specificity is more or less the same to detect metastasis with PSMA compared to conventional imaging done by Michael Hofman, was tremendously helpful to lead to this change.

Alicia Morgans: Absolutely, and I think we still have come quite a way from even those introductory studies, and as you said, PSMA PET has really rolled around the world and has become a standard, thankfully, for many people. And I wonder, meta-analyses have been done that suggest that this is the way to go, at least in terms of that increased sensitivity. What are your thoughts? Can you share some of the comments you may have on the meta-analyses that have been looking into this?

Irene Burger: Yeah, absolutely. I mean, it is, of course, reassuring that now, more and more data from several studies also regarding the different tracers, not only Gallium PSMA-11, are showing up, and the meta-analyses confirm what this prospective trial in 2020 was showing, that sensitivity is really higher. It is nothing else as good at the moment if you take all the patients, and still, we have to take into consideration that we are not perfect for each and every patient. So some patients are just PSMA-negative. And then, of course, my staging, PSMA PET/CT, is just as good as the CT would be to detect nodal metastases or distant disease. However, this is a very small proportion of the patients. I think for the vast majority of patients, PSMA PET/CT is by far the most sensitive tool, but it's not perfect. And I think this is also something which is always leading to a lot of debate.

I mean, now we have these expensive PSMA PET/CTs, and still we cannot rely on it for nodal disease, for example. No, we are not going to detect micrometastases, and we are not even detecting some macrometastases with PSMA, but we detect about 60% of the metastases and probably the more clinically relevant metastases. So now, I see more and more doctors relying on the PSMA PET, maybe even also in combination with a nomogram, to say, this patient doesn't need to have a nodal dissection, or this patient needs a nodal dissection, and let's not forget that nodal dissection, if you undergo radical prostatectomy, is associated with a comorbidity of 20%. So it is substantial.

Alicia Morgans: Absolutely. And actually, that was some of the other data presented at EAU 2024, that perhaps we'll see a shift again in doing more of these. But if we perhaps don't need to because we have PET information, that could also be helpful. And I wonder, there are different tracers that are now available for these PSMA PET scans. There's not just one tracer, one scan. So, you're a nuclear medicine physician, and you certainly are an expert in all of these. What does the urologist or the medical oncologist need to know about all of the options that are out there?

Irene Burger: Well, that is a conundrum, and it is indeed even sometimes not written on the reports. I mean, I sometimes get external reports where they just write PSMA PET/CT, and I'm like...

Alicia Morgans: What kind?

Irene Burger: It shouldn't be done that way. Let's face it, PSMA is a target, and usually, you should not name the tracer after the target but after the structure of the substance. Now, in this regard, PSMA tracer names are misnomers, but very successful because this is prostate-specific in the word, everybody loves it. Okay, but let's face it, we have more lipophilic and more hydrophilic PSMA PET tracers. They have a different bio-distribution. So it's also not F18 versus gallium tracers. It is really, you can have a Gallium PSMA-11 or an F18 PSMA-1007, which is more hydrophilic. And then you have an F18-PSMA-007, which is more lipophilic. Now this changes really the bio-distribution of the tracer. More lipophilic has the advantage of more hepatic uptake with less renal excretion. So, for local recurrence in the prostate bed, there is an advantage, but you have a lot of unspecific uptake in the bones, and therefore, if you have a bone lesion on a PSMA PET/CT, you always need to know which tracer you've been using to make a proper diagnosis. If you don't know this, you shouldn't say anything about the bone lesion.

Alicia Morgans: And that's so important, I think. As we think about these PET scans and our misnaming of them, I think we also think a lot about the sensitivity and whether there could be false positives in regions. Of course, false negatives. So can you share your thoughts on that and how we, as clinicians, should try to sort through and judge with a little bit of information which may be more likely to be false positives, maybe in ribs or other areas, and where we may miss things, false negatives?

Irene Burger: I mean, at the end, I personally believe that here in nuclear medicine, we still really have to catch up. We need more standardization, and we need to have more standardized wording. There's a huge heterogeneity, and again and again, I mean, you have an F18 PSMA 1007, and people that write down 'bone metastasis cannot be excluded.' You never can really exclude anything if you want, but that's not helpful. So to give something like a grade of suspicion, I think here it is super important to either really stick then to the suggestions to really use myriad more or less for the prostate cancer assessment of PSMA PET scans, or you need to sit down with your nuclear medicine physicians, or what's our wording? What do you write down if you think it is something 75%, 50%, 25%? I think that this is really key to be sure that locally you at least have the same understanding of language, which is sometimes tricky enough.

I believe that this is sorting out a lot of those issues. On the other hand, of course, sometimes it's tricky. The most important thing is, I think, you have to know your anatomy. I mean, you have to know where you have ganglia versus lymph nodes. You have to also know how a hemangioma looks like in a bone or what fibrous dysplasia looks like. So I always say it's not PET, it's PET CT or PET MRI, even. So you really need to know also how to interpret your anatomical imaging component, which I believe is just as important as the PET component. This is something I think also a lot of education still has to happen, but to really improve on those false positive pitfalls, standardized reporting, I think, is an absolute key, and I was very pleased to see at EAU also that here a large effort is also taken, even from the clinician side.

So I think it is sometimes good if I were to say, I mean, in nuclear medicine, let's face it, we are used to everyone doing things a little bit their own way. So now, as we are entering areas where things are very standardized and trying to really break them down to five points, we really have to adapt to this. And I think this is important. Now, talking about the false negatives. Yeah, I mean, prostate cancer can be PSMA-negative. It's not even that uncommon. I think in the primary staging setting, it's around 10%, 15%, maybe even 20%. The later you go, especially, for example, after ADT, the more the tumors tend to express PSMA, so this percentage decreases. That's probably also why you saw in the VISION trial, most of the patients had some PSMA expression. It's very rare that you really have nothing, but sometimes it's also not enough.

So there is not black and white; there's a lot of gray in the middle, and we don't know yet very well how far down we are still okay to do our PET scans, how many percent of the tumor needs to be PSMA positive so that we really have a good chance to see the disease on the PET CT.

Alicia Morgans: Yes. I think just to comment on a couple of your points there, understanding traditional radiology, I think, is so important because, as you mentioned, whether it's the CT component or for those who have the MRI component available, this is also a really important part of the anatomy and really placing where we see the avidity from the PET tracer. And one of the challenges that I have in my practice is that in the US, it is most common that we get a CT scan that does not have contrast, that is then paired with the PET image. And so, particularly in the liver and in other areas, I worry that things are potentially invisible to me because I don't have contrast. My hope is, to your point, that we can standardize around the world how these are actually done and try to come to some consensus. And I really hope that they end up using CTs with contrast so that we can see the anatomy that's there behind the avidity.

Irene Burger: I mean, that is really probably more about regulatory politics than biology and science. Yeah, I mean, at the end, you always have to see in which setting your PSMA PET is done; is a radiologist involved? Yes, no. Usually, if you are not dual-boarded, you are just allowed to do the unenhanced scans. I think there is a tremendous demand to also, I mean, let's be frank, my education to become a radiologist and a nuclear medicine physician took eight years. Now, I also should become at least a third oncologist in treating really sick patients. And I mean, yeah, that's just not feasible anymore to really be able to cover this all. So, we need to train people more dedicated to what they really need on the CT component without having them spend five years doing ultrasounds of baby heads and musculoskeletal exams of the knees. I think this oncology track imaging idea would be super important in this regard.

But then those people also need to be capable of doing contrast-enhanced PET-CT scans. There's a lot of regulation and politics involved. But yeah, I mean, I agree. I think it is often very helpful, especially once you are in the later stage. I mean, for the early stage, I think if you know your anatomy very well, where the ureter is even on an unenhanced CT scan, sometimes it can be tricky, but usually, it's visible. Nevertheless, I have to admit that I now also do contrast-enhanced CT scans for staging in combination with the PSMA on all patients.

Alicia Morgans: Well, even this medical oncologist can usually find the ureter, thankfully, in early-stage disease. So as we wrap up, I would love to hear your thoughts overall on the integration of PSMA PET into that high-risk disease. What is your bottom-line message to clinicians who are increasingly using this to help understand the truth about the stage for their patients with high-risk localized disease?

Irene Burger: I mean, for staging high-risk patients with PSMA PET/CT, I think the most important part is to use it. It's more sensitive than anything else you can have to select your patients for the proper treatment, but don't believe blindly. So, especially if you have a PSMA 1007 and you have bone lesions, if they change treatment, try to at least get a morphological correlate on a dedicated MRI or try to get a biopsy. Don't withhold curative therapy from patients just because you see something in the bones on PSMA PET/CT. I think this is something we also had to learn now and then for the future. I hope that we will maybe one day be able to use biomarkers, liquid biopsies to really preselect the patients for the best tracer because, especially in the earlier stage, a lot of patients have more GRPR expression than PSMA expression. So, we could use another PET-CT scan if we would know beforehand. And I think that is something not for tomorrow, but maybe for the next four or five years.

Alicia Morgans: That is incredibly exciting, and thank you so much for reminding us that we need to make sure we understand which tracer we're using. We need to understand which patient is the right patient. We need to talk with and know our nuclear medicine physician so we can ask questions and don't accept everything at face value. At the end of the day, we need to get the right treatment for patients. Not withholding care is really important, and making sure we understand the truth about the extent of disease is probably the most important of all. So, thank you so much for your time and your expertise, and congratulations on a fantastic lecture at EAU 2024.

Irene Burger: Oh, thank you so much.