Phillip Koo: Welcome to UroToday. My name is Phillip Koo and I have the pleasure of serving as the moderator for a special program, entitled, Detection and Localization of Prostate Cancer, Case Review of Scans, Pearls, and Pitfalls.

So as we're all aware, the imaging landscape in prostate cancer has rapidly changed. Axumin and fluciclovine was approved in 2016. Gallium 68 PSMA-11 was approved in December of 2020. And we anticipate the approval of PyL PET, hopefully in May or June of 2021. And with that comes a lot of new disease states, new clinical scenarios, and new clinical dilemmas that I think oftentimes, in clinical practice, we have some struggles navigating those uncharted territories.

In order to address that need, we've put together a multidisciplinary program and panel to really provide us with a comprehensive approach and perspective on how to tackle some of these questions. And for the case review and the pearls and pitfalls, I can think of no one better than Dr. Andrei Iagaru who's Professor of Radiology and Chief of Nuclear Medicine at Stanford University, to walk us through that.

And then for our multidisciplinary panel discussion, I'm joined by esteemed colleagues, Dr. Alicia Morgans, GU Medical Oncologist and Associate Professor at Northwestern, and Dr. Neal Shore, Urologic Oncologist and Medical Director of the Carolinas Research Institute in South Carolina.

So, at this point, I'll turn it over to Andrei to get us started and look forward to a very stimulating. So thanks, Andrei, for being with us.

Andrei Iagaru: Okay, so now let's spend some time looking at cases where DCFPyL or PSMA-11 was used. And again, we'll follow the same format with presurgical staging in patients we see with intermediate and high-risk prostate cancer. I will caution the audience, at the time of this presentation, definitely at the time when the images were acquired, these were not FDA approved radiopharmaceuticals so everything was done under research protocols.

Just briefly, the prostate-specific membrane antigen in many ways, it's a great misnomer because it's not prostate-specific. It's a transmembrane protein that's over-expressed in prostate cancer by some orders up to 90% of prostate cancers. It has enzymatic activities and it's over-expressed in other entities as well.

I did a quick PubMed search of PSMA PET and you can see the exponential growth since 2010-2012 to now. And through April in 2021, there were already 277 papers published already on PSMA PET. But if you think that you missed the train, on the same day, the number of FDG for publication it's a lot order higher. So we're in the infancy of PSMA PET research and publications so don't give up if you didn't have access to PSMA until now. There will be plenty, plenty of opportunities to do meaningful and exciting research using PSMA PET going forward.

Some of our protocols in biochemical recurrence, I think it makes perfect sense to use PET CT and the imaging is done as indicated in this schematic. One can also give IV or oral contrast and this is what I was referring to earlier that maybe a one-stop-shop, possibly replacing bone scanning or dedicated CT in some of these patients.

And if access to PET MR is not an issue, I think it makes perfect sense to stage patients prior to prostatectomy for intermediate and high risk with PET MR PSMA imaging where one can start the pelvic multiparametric MR soon after injection of the radiopharmaceutical follow-up with a high-quality PET of the pelvis and then do a quick whole-body MR and PET just to survey for the presence of possible distant metastasis.

This is the normal biodistribution on the left, Gallium 68 PSMA-11 on the right DCFPyL. So very similar. Some may argue that labeling anything with F18 will lead to higher image quality than Gallium 68 just by the physics of fluoro 19 which has lower energy, shorter pathway in tissue before producing the photos by manipulating with electron.

That being said, lacrimal gland, salivary glands uptake as well as clearance through the kidneys. Some uptake in the bowel, low-grade liver, and spleen optics. So this is pretty typical of this class of agents. There are others that are not discussed here like PSMA1007 which supposedly has less clearance through the kidneys. But somehow anything introduced in the body in this form has to be eliminated. In that case, there's higher liver uptake and reportedly higher rate of nonspecific findings.

These are different patterns of PSMA PET and biochemical recurrence. Several lymph nodes on the patient, on the left. More lymph nodes on the patient in the middle, extending all the way up to the retroperitoneum. And then a combination of multiple nodal and bony metastasis in the patient on the right.

So now let's talk just a few cases. This case, a man presented with clinical stage T2c, Gleason 4+5, PSA of 9.4. and as I said, we do an imaging of the pelvis that is higher quality, as well as the whole-body PET. And these images, for the most part, are not difficult to interpret. This is what we see here. Two foci of uptake on whole body as well as dedicated pelvic PET. And in this case, they correlate very nicely with the location of the prostate cancer on histopathology.

Our Urologists are using S3V mold of the prostate based on the pre-prostatic from EMR. And then the prostate is [inaudible] to that mold section. These sections are marked for the presence of cancer and then these slides are scanned back into PETs so you can then correlate PET MR and pathology for this finding, which I find really neat.

Alicia mentioned artificial intelligence and machine learning. I want to mention that my colleagues are working on co-registration of the pathology MR and PET data, which again I think will find very interesting applications going forward.

So that was a straightforward case. Now the second case, another man, clinical stage T2c, Gleason 4+3, PSA 4.2. In this case, already, we can appreciate that on the whole body version of the PSMA PET there are some areas of uptake that probably shouldn't be there, like this one in the sternum. And so let's see what they are.

In the prostate gland, there is the malignancy and it's confirmed on the delayed imaging as well. But we will appreciate the presence of diffuse uptake in the sternum, low grade, diffuse uptake in the sternum. The subsequent staging is demonstrated on the bone scan to have intense uptake. And the CT is not the optimal way for imaging the sternum, but in this case, it demonstrates the presence of the uptake area there.

Phillip Koo: Great. So thank you, Andrei. You know, it's interesting. With the approval of Gallium 68 PSMA-11, it did include that indication for patients at initial diagnosis. Maybe one question I'll start off with is, do you think, maybe looking into the future, do you think there will be a role for conventional imaging at initial diagnosis for patients who are high risk? And, I guess maybe, putting it another way, is it even necessary to get conventional imaging upfront if you're going to go... or would you consider going straight to a PSMA PET on someone with high-risk disease?

Andrei Iagaru: I think that PET, including PSMA, is conventional. And so it's upon us to convince everyone else that it is conventional. So, I think that for staging these patients pre-surgery, intermediate and high risk, I would say definitely a pelvic MR because it's very useful and then, as I advocated for, if you have access to PET MR, PET MR is great for initial staging. If not, pelvic MR plus PSMA PET CT would give you all the information for accurate staging.

This being said, that sternal area of diffuse, low-grade uptake was not metastasis. It turns out that patient had a water skiing accident a few months ago and that was nonspecific uptake on PSMA in that region. So not all glitter is gold. Not everything that lights up on PSMA is prostate cancer. Most of what we see is prostate cancer but we need rigorous training for our colleagues interpreting these images so that we avoid making false-positive calls as these are introduced widely in the community.

Phillip Koo: Great. Thank you. So Neal, what are your thoughts on the imaging that you would acquire, now that you have that approved indication for PSMA-11 in initial diagnosis? And if it becomes more widely available, will your approach to imaging change?

Neal Shore: I think it absolutely will. I really enjoyed Andrei's comment that this is now conventional. Conventional is the best imaging that you can get. Our, what we used to call conventional or standard imaging of CT and Technetium bone scan, is clearly relegated now to inferiority when you look at the broad, published data on PET PSMA and 18FPyL PSMA. It's a very exciting time.

That first case really fascinating, right, because you had a 78-year-old man who had a Grade group 5, who went and... if I interpreted it correctly, had a prostatectomy. And had a prostatectomy probably because he was very fit and the PET PSMA said, we think you have confined disease so we're going to subject you to the rigors of a prostatectomy.

So, I think, historically, many of us would have said, you know you probably almost invariably have micrometastatic disease, even if the older conventional imaging, conventional 1.0. And so, frankly, radiation in two years of ADT would be better for you.

So I really appreciate that case that you presented there. So I think yes, Phil. I'm super excited about this. I said earlier, it's a long time coming and I'm so enthusiastic to hear any day now that the FDA will approve 18FPyL.

And then the other question is, how do we go through the process of making sure it's accessible to us. And maybe we'll talk a little bit about that later on, cyclotron accessibility and the timing for getting it, and the transportation. Hopefully, that won't be much of an issue. I think that it's going to be.

Phillip Koo: I agree. I agree. So, Alicia, how are we going to navigate this transition? Clearly, we're hearing the sentiment that we are going to be moving to PSMA, and PSMA will become conventional. But now, in the setting of clinical trial data that we've accumulated over the past decades, how do we reconcile that and how do we make a smooth transition to this new reality?

Alicia Morgans: I think we need to do it with enthusiasm but with caution. And caution, I think from my perspective, does not mean that we stop moving forward. It just means that we try and move forward in a way that is consistent with our old data.

And that's why for that second patient that you showed, I think that, again, this is multidisciplinary. I would either want a biopsy or I would want to know if there was something specific that happened to that sternum, just as you said, a water skiing accident, that could explain it. Because that was very much out of proportion with what I expected in terms of the PSA, and the rest of the imaging. There was nothing else going on but something very odd happening up here.

So this is a way in which we can move forward with caution. There would have probably been a biopsy or a long discussion about that. But in terms of applying the data that we already have, I think that we need to try to integrate PET imaging into our prospective studies so that we can try to get, as I mentioned, this sort of understanding of a crosswalk.

For example, we have the beautiful study that was presented where we saw that SPARTAN-like patients, who met criteria for not having metastatic disease by technetium bone scan by CT's or MR's, still had these multiple areas of metastatic disease by PSMA PET in 98% of patients.

And so that helps me understand, as a clinician, that if I see a very small burden of PSMA avid disease in a patient who has conventional imaging negative, I can still treat them with a medication that not only will prolong their metastasis-free survival but if I'm able to intensify in that setting I can improve their overall survival, as well as their quality of life.

I don't want to lose the ability to do that. And so, what I hope that we do with our more advanced, more accurate imaging, is learn how we can convert what we had, the data that we had, into usable data despite and with our PET imaging, so that I can still use the drugs that I want to use, as appropriate, to still get the benefits for patients and have some understanding of what to expect and some rationale for why it's so reasonable for me to apply the data, even though the stage that I see is actually different when I have a more sensitive imaging strategy.

Phillip Koo: Great. Thank you. So to switch gears a little and to talk about that biopsy issue that you brought up, Andrei what's your approach to the solitary rib activity on a PSMA PET, and then what happens when you see two or maybe three... there's no trauma, there's no reported history of trauma, and biopsy of these lesions isn't feasible?

Andrei Iagaru: So I think it depends on the clinical scenario, right? If it's the initial staging and having one lesion with slight uptake doesn't fit the criteria and I would not suggest going for a biopsy. I would just use clinical judgment.

If it's a biochemical recurrence, and that's the only finding and the PSA is rising, I would be more suspicious, especially if no history of trauma, etc. And I would consider it true positive, even in the absence of biopsy. So I think that... and there is data to support this approach. There is data showing that a single lesion in the presurgical setting, it's very unlikely to be metastatic disease versus in the biochemical recurrence, solitary lesions are likely to be biochemical recurrent prostate cancer in the setting of rising PSA.

I would also bring back to what Alicia said about how we implement this, that there will be places that our earlier doctors of technology. I want to give a big shout-out to our colleagues in Urology who we started using PSMA-11 in 2015 and my colleagues Geof Sonn, Alan Thong, and Ben Chang, they did not hesitate to send us patients for these research trials. So I look at them as early adopters.

And then, it's upon us to show that this is useful so that others will transition it to widespread clinical use. And the same goes for biochemical recurrence. Our colleagues in medical oncology, Sandy Srinivas, Sally [inaudible], or in radiation oncology, Steven Hancock and Hilary Bagshaw, they did not hesitate for a moment to send us these patients for early clinical studies.

So I think having, again, partnership goes to the tumor board but partnership also goes to the research entity where you have to have the buy-in from your colleagues. You have to get their trust. And I will say that, in the beginning, all of the findings were biopsied. And as the results started to come in more and more of our cases were [inaudible].

As we learn how to interpret these images, after seeing more and more of them, the rate of biopsying these lesions is very low. Which tells me that the treating physicians now believe in the value of this imaging, and hopefully how we interpret them as well.

Phillip Koo: And I'd like to emphasize your mention of clinical scenario. And I think imaging specialists, at this point, are not just interpreting images. I think we need to interpret images in the context of the clinical state. Now that we have access to the EMR and access to our colleagues, I think that is something that falls on the responsibility of the person interpreting, as well as we can't just throw it on the ordering physician and say, hey, you guys figure it out.

And this is another reason why I think, when it comes to cancer imaging especially, performing that in that integrated type of environment really makes a big difference. Any final words about PSMA at initial diagnosis? Maybe we'll start with you, Alicia, and then Neal?

Alicia Morgans: So I think at initial diagnosis it's going to be a very important and very exciting part of our understanding. I do know that, even without the imaging to show me exactly what to do next in terms of the older imaging strategies versus PET imaging strategies, I want to know if the patient has distant metastatic disease. And so I am going to want to understand that, using a PSMA, whether it's PyL or whatever it is strategy as soon as it's available.

And having the information doesn't mean that we necessarily need to change our behavior. It just means we have the information, we can have the conversation, we can inform our decision-making more effectively. And that, to me, is a win in itself.

Neal Shore: I would echo that because the extra information could alter decision making from no treatment to directed localized therapy to combination and systemic therapy. So it'll be very important. We certainly can learn from institutions such as Andrei's that's had the technology from some time, our colleagues in Australia and Germany.

So we don't have to necessarily reinvent the wheel but I think that, to Andrei's earlier point, those slides showing the escalation in studies, there's a great opportunity now to do investigator-initiated trials.

We do need to taste, and touch, and feel, and work with our radiation oncologists, our radiologists, our nuclear medicine radiologists, especially in the United States. I think this is really great for the nuclear medicine field to really go into a marked improvement in the multidisciplinary function, not just in academia but certainly within the community. So I just echo everything that Alicia just said. It's a wonderful time. This is going to be very transformational in 2021.

Andrei Iagaru: Case three is pretty straightforward. It's also presurgery but it's typical of what we see with the presence of a primary as well as some pelvic lymph nodes. So we're not going to spend a lot of time here other than to illustrate the findings. So we have the primary cancer in the prostate, both on whole-body imaging and dedicated pelvic, as well as pelvic lymphadenopathy which was confirmed at the time of surgery as well.

So now let's move to the biochemical recurrence. This is a patient with a history of clinical T3a, Gleason 4+3, received prostatectomy and radiation therapy, now with rising PSA. A PSA of 0.89. So let's see what the findings are here.

So here we have left supraclavicular lymph node as well as retroperitoneal lymph node. And this patient happened to have an Axumin scan prior to the PyL. The reason for that is, all our research scans are offered at no charge to patients and, of course, that being said, we cannot have huge numbers of these scans.

So we use PSMA PyL in this research access program after the Axumin is negative or equivocal, or non-concordant with the PSA values. So maybe if we can stop here for a second and knowing what we discussed in the other case, what are your thoughts about that left supraclavicular lymph node?

Alicia Morgans: I mean, it's impressive. I think that the demonstration in differences between these tracers is always something that is striking to me. And we see that or have seen that, for example, in the TheraP trial with FDG demonstrating differences from a PSMA approach. But I think it's also really important and interesting for us to see this with Axumin and with the PyL PSMA.

I guess my question, that PSA was around ).89 and so, do you think, Andrei, that the reason is because the PSA was so low that the Axumin was really not sensitive enough to pick it up? Or what do you think the issue was? Was there a difference in expression of the target, because that doesn't seem to make as much sense.

Andrei Iagaru: Well, so this case in our experience, it's definitely biased by our selection, right? We don't image patients with positive Axumin unless the positivity is not correlating with the PSA value, meaning a very high PSA and very few Axumin lesions. That patient will get PET PSMA. But otherwise, all the patients who come for PyL have had a negative Axumin.

So I think it's a combination of this selection bias, as well as biology, right? PSMA is over-expressed in up to 90% of prostate cancer, not 90% of prostate cancer will have increased amino acid transporters so that is probably the bulk of the explanation here.

In turning back to you, we use the AUA criteria, post-prostatectomy, and the Astro-Phoenix criteria post-radiation therapy as initial treatment to select these patients. Do you think that going forward, this criteria will need to be changed because we will have patients with positive PSMA and PSA values that are below the current criteria for recurrence.

Alicia Morgans: I think, particularly in the radiation population this is going to be an issue. And I have tried to... I'm in the process of talking to multiple collaborators about how do we make a trial that's really intelligent for biochemical recurrent patients and particularly when we have to apply the Phoenix criteria I struggle because we do not adhere to the Phoenix criteria in many clinical scenarios and so doing so in a research strategy also then doesn't make sense because patients won't be eligible because people are not able to wait for that rise that's required by Phoenix.

I think, from a prostatectomy perspective, I have less difficulty with the AUA criteria, although even they, for some institutions, they don't wait to reach that threshold after prostatectomy to really say that someone's recurred. I'd be curious to hear what Neal thinks though.

Neal Shore: I agree. I think that our colleagues at Astro, in combination with SNMMI and other appropriate nuclear medicine expertise in societies really have to have a consensus agreement on re-establishing thresholds. I think the old Astro-Phoenix definition is no longer appropriate given where we are. And that's going to require a lot of effort, consensus, and then education in Urology and Medical Oncologists, and Radiation Oncologists in the community have to really start thinking a little bit more clearly as to when to test and then when to treat. I'm in full agreement.

One quick comment I had to make about case one. I love the fact that your prostatectomy patient went from 78 and then to 81. I think, at Stanford, you all are redefining that 80 is the new 60 and really pushing the comfort in doing prostatectomy in the octogenarian group. Of course, it's been done but I couldn't miss the opportunity to appreciate that.

I'm just wondering if... and maybe that's really an interesting aspect, again, to this improved accuracy of these scans and opening up opportunity for patients to make this decision based upon what they think is in their best interest in terms of an interventional treatment.

Phillip Koo: I agree with that. I think this idea of individualized, personalized treatment, I think age is just a number and we all recognize that. So interesting discussions about the PSA levels. So at what level would you recommend a PSMA PET in your patients at biochemical recurrence?

Neal Shore: That's a great question. I'm still learning. Obviously, I'm just scouring the literature and publications from Andrei and other colleagues. It seems to have clearly enhanced, positive predictive value over fluciclovine. That seems to be the consensus at levels of less than 0.5 and certainly at 0.5 to 1.0.

But, nonetheless, its accuracy improves once PSA goes above 1.0. So I think this is important to continue to understand the timing of the PSA elevation from a surgical intervention, the doubling time, as well as the histopathology. But I would continue to need to learn from Andrei and others as to what those thresholds should be because there's nothing more disheartening to ordering a test and getting a negative finding and then thinking, well, it just wasn't accurate and therefore it hasn't changed the clinical utility.

Alicia Morgans: I would agree. I think usually I'm looking for a PSA of around 0.5 but we have done it with PSA's that are lower and they have been positive. So, like Neal said, really that doubling time is important, which is hard to calculate when they are as low as they sometimes are.

But I think that as we continue to learn, and of course we've seen that it's a continuous scale. So maybe patients who have higher risk factors at baseline, even at these lower PSA's, will have more likely positive scans. But this is something I think we're still evolving into understanding.

But patients know that the technology exists and so as soon as they see their PSA rising there's definitely a wish that they can get the imaging completed and really help to understand and move forward in whatever treatment is necessary at that time. So this is definitely something that I think, as we continue to understand the imaging better and really define which patients, at which point, and which PSA can be imaged, will be helpful for the field.

Phillip Koo: Great. Andrei?

Andrei Iagaru: Not much to add. All those thoughts are very insightful and it makes sense to track and correlate not just the actual PSA value but this doubling time and also the aggressiveness of the initial presentation of disease.

Phillip Koo: So, it's interesting though. I think some of the data on doubling time hasn't really panned out the way... I mean, granted they aren't large studies, the way that I think we would have expected. I think there's some small studies with fluciclovine that looked at this. So you're right. I think that it just needs to maybe be studied better.

Can I ask a question about the value of a negative scan? Oftentimes we get these scans and we think all right, we're looking for something positive that we can treat but isn't there value in getting a PSMA and it being negative and then that informing your next decisions?

Alicia Morgans: Absolutely. Absolutely. So in the biochemical recurrent setting, of course, we're thinking about pelvic radiation to salvage this patient and when we have a negative scan we're all very, very excited. And I think that any time, this is probably oversimplification, but I do tell patients when we don't have enough cancer in you to even see it with this more sensitive imaging strategy, that's not a bad thing either.

Now when we start thinking about FDG versus PSMA positivity and perhaps there's different expression patterns, we can get into... that's what I mean, it is a little bit more nuanced. But I would rather have a patient not have radiographic evidence of cancer if that is for reasons of just having so little disease that it's undetectable at that time.

Neal Shore: I would completely agree with Alicia on that. And we see this, right? Patients have their anxiety. We, as clinicians, have an anxiety of the recurrent and rising PSA after an active interventional treatment. And then I say, look, we're just getting through COVID now, you've got your vaccines hopefully, and yeah, your PSA 15 years, 12 years after your prostatectomy, five years afterward, we don't know where the disease is but it's going up.

So you have micrometastatic disease but it's okay. We don't have to start systemic therapy. If there's a clinical trial I enroll them into that. Lowering T, testosterone, as we all know, is no free lunch. And even radiating sometimes, focal radiation, albeit markedly well-tolerated universally but there are potential risks to that and costs as well. Or even potentially the idea of going in and removing a node laparoscopically.

So I really think that's very spot on what Alicia says. It's up to us, as clinicians, we have to tap down that anxiety of the PSA and say, look, the cellular volume causing that level of PSA rise is so low right now and we can just relax. We'll get back and we'll give you a few more months.

And my experience is patients, once you explain it to them in maybe more articulate ways than I just did, they say, you know what? That's great. I'll see you in several months and we'll repeat the PSA and maybe we'll repeat the imaging as well.

Andrei Iagaru: And I would add, perhaps, that it gives us a reason to continue research for other targets than PSMA because, again, cancer biology is so complex maybe those patients are the 10% that don't express PSMA and we need another to find the cancer.

And there is experience, including in our own center, where patients with PSA-driven five have negative PSMA scans. So you don't get necessarily a PSMA scan negative of very low value. You can have PSMA negative scans with a high PSA value and I've seen the warranty there is not very high after a negative PSMA scan.

Neal Shore: Patients with poorly differentiated neuroendocrine prostate cancer with relatively low PSA's, they often are PSMA PET negative. And so, we can't get lulled into that false sense of security that the scan was negative but they may, indeed, have aggressive disease. So what's the guidance for those patients, and particularly if we know on histopathology that they have small cell features and neuroendocrine features?

Alicia Morgans: Those are the patients I usually get an FDG panel on. If I'm concerned for small cell I will absolutely get an FDG PET because in my understanding of the literature, those patients, hopefully, are going to be able to be visualized that way because of just the high turnover of glucose utilization. But I should not have jumped in. We have two nuclear medicine physicians who can tell us what their thoughts are there.

Andrei Iagaru: Your answer is excellent. I only have to add that perhaps research going forward will help us identify other targets as well. But FDG in that scenario makes perfect sense and thank you for saying that. It carries more weight coming from the Oncologist than from us.

All right. So a couple of interesting cases of recurrence. This is a patient who is a clinical-stage T3a, Gleason 4+4, received prostatectomy and radiation. Now with rising PSA of 0.3.

And in this case, the area of focal uptake is in the abdominal wall at a side that was previously treated with radiation therapy for local recurrence, for recurrence in the abdominal wall. So this was considered highly suspicious for recurrence adjacent to the treated area.

And, again, because this patient had a negative Axumin they were referred to the research access program for PyL and these are the two scans, side-by-side. There was really no uptake on the Axumin and focal uptake recurrence, expected recurrence at the treated side in the abdominal wall on the PyL scan.

And then the last scan in the biochemical recurrence case series is a clinical history, clinical-stage T2a, Gleason 3+4, received radiation therapy, and now with a rising PSA of 0.36. And I will point you to the area in the shoulder where we have abnormal uptake. And this turned out to be a solitary lesion in the left scapula.

And this is the comparison between the Axumin and the PyL with a solitary lesion in two fields, point about lesions that are in the ribs. Very faint uptake in this right rib. That was actually fibrodysplasia. So there are known false positives that should be known when discussing these cases. So let's see if there are any concluding thoughts perhaps before we move into the potential for coupling therapy with these diagnostic tools.

Phillip Koo: Great. So PSMA PET CT both of these patients PSA less than 0.5, PSMA detached recurrent disease. Thoughts on next steps? And maybe Neal, we'll start with you.

Neal Shore: I think these are really good cases because of what we were showing earlier that a lack of finding oftentimes in our earlier experiences with the Axumin and fluciclovine and here you do two cases with comparative findings showing the added value of the 18FPyL. So I think it's great because it can clearly inform local therapy versus systemic therapy or no therapy. So I think this is a perfect example of how this is going to change our diagnostic evaluation and then subsequently our therapeutic choices.

Alicia Morgans: I would completely agree. And I think to Phil's earlier points about nuclear medicine doctors really joining the team, understanding the clinical history, having all of us participate in multidisciplinary management discussions is so important. If we look at that first case that this small area of previously treated abdominal wall area, that's not typically what we would expect. That's not where I would expect prostate cancer to necessarily be.

So knowing that clinical history, I think, is really helpful in understanding this is not a false positive. This is a truly positive area. I also want to commend our nuclear medicine doctors just for having such clear vision because the scapular lesion was so faint. I love multi-D clinics because you can show me where these abnormalities are. I can see it clear as day when you point it out. And thank you for that and for the arrow signs that you leave sometimes in all the imaging that we have. So, very impressive.

Phillip Koo: You know, it's interesting. There's a new learning curve with these new technologies because what we think is typical versus atypical is different in these. And we're seeing things in patterns and places that we've never seen before. And though we call them atypical, they are becoming typical. And I think exactly that abdominal wall lesion without also knowing the history, you might try to find another reason to explain it. So with PF-

Andrei Iagaru: I don't think that the audience should get the idea that that's what you see most commonly, right? Most commonly you do see the recurrences in lymph nodes and in the skeleton. But I wanted to point out that with this more accurate that makes you find things that were considered very rare. And they're not that infrequent.

Another one is liver capsule implants, where liver metastasis as solitary sites of disease. Those before the age of PSMA were exceedingly rare as far as I know. Now they're not that infrequent so that's another point that I wanted to make.

And also, as we move to therapy, we'll talk more about it. But I have to give huge congratulations and acknowledgment to our colleagues in Germany who studied the PMSA-11 program and who then generously allowed a worldwide audience to use it and who provided us when we filed an IMB with the FDA, the talks and safety data to be able to do that.

And conversely to Martin Pomper and his group at Johns Hopkins who developed PyL and who were very helpful at every step of the way when we wanted access to it, as well as the company behind it.

Phillip Koo: So, PSMA PET has really brought renewed attention to the idea of all of the metastatic disease and that's clearly become very controversial. And I don't think we're going to be able to tackle the whole topic right now but just, if Alicia and Neal, you could just share your approach to patients with oligometastatic disease in this biochemical setting.

Alicia Morgans: I think, increasingly, we are hoping to use things like SBRT to try to change the disease trajectory without necessarily adding androgen deprivation therapy. Although, of course, there are settings where we want to use a combination of radiation and androgen deprivation therapy or intensified therapy strategy too. So it really depends on the patient, the extent of oligometastatic, and what else is going on in terms of comorbidities and patient preferences.

But this is an area of active investigation and imaging is absolutely critical in our identification of these patients as we try to define how we should best move forward for any individual. Neal, I'm sure you're involved in this work on the front lines.

Neal Shore: I agree with your comments. We need more trials. We certainly are all familiar with STOMP and ORIOLE and others that are being conducted now. And they're still, it's a bit of a moving target of what defines oligometastatic. Three for two, is it 1:3, is it 1:5? What's the imaging that's being performed.

Right now, as Alicia alluded to, the value is perhaps delaying a requirement for ADT, which is in and of itself important. So I think this is a very exciting area. I think it still is important for all of our colleagues to enroll patients in clinical trials so that we can better stratify who benefits from what therapy and what level of oligometastatic disease that they indeed have.

Can I just ask one question to you, Phil, and to Andrei? And that's, I think you mentioned maybe we're going to talk a little bit about artificial intelligence and the interpretation for PSMA PET, next-generation imaging going forward.

I think it's really exciting, especially in research, where oftentimes our local radiology teams are still prone to say too numerous to count, which is something I hate to see. And so, will artificial intelligence help us avoid too numerous to count, and then also help us with therapeutic responses?

Phillip Koo: I think artificial intelligence is something we need to embrace. And, you're right, I think at that point it really broadens the ability to do higher-level image analysis. This idea of too numerous to count disappears. Volume approaches, volume assessments, our ability to assess treatment response, using PSMA, is a better biomarker. There are just tons of things.

The biggest challenge, I think, is the logistics, the IT piece. Getting all these incorporated into the workflow. Reimbursement's another issue. So, I think as an imaging specialty, whether it's nuclear medicine radiology, there's an embracement of AI. Clearly, we know it's going to help PET patients but it's just sort of those incremental steps in between to actually make it part of our workflow and process is still yet to be determined.

Andrei Iagaru: My initials are AI so clearly I'm in favor of embracing AI. But jokes aside, I look forward to clinically useful software because the growth that we expect with the introduction of new examinations cannot be matched by growth in space for faculty or enough faculty to interpret these images. So, I look at artificial intelligence and machine learning as optimizing our workflows and, hopefully, creating better reporting for our referring physicians. So I'm totally in favor of its use going forward.