Stefano Fanti: Good morning, good afternoon everybody. We are here with another opportunity to discuss about PSMA in this academy event. And in particular, my name is Stefano Fanti. I'm a nuclear management physician in Bologna, Italy. And the topic is really controversial. It's about what to do when you have bone findings at PSMA PET with no CT counterpart. It's really a hot topic and I'm delighted to be here and discuss it with two great clinical colleagues that most likely will raise up the most important question. Because, I'm just a poor imager, so I just have one perspective. What I will rapidly go with some example is the many components that you have to take into account when you face a case with a hotspot at PSMA PET and no CT counterpart that say, consider the tracer that you're using, the medical history. Carefully understanding what it could imply. The number and location of the lesion. So what we call the semiotic of the PET exam. And finally, the degree of uptake. So how hot is the finding?

I will start with some examples that I already presented at the APCCC in Lugano, but I guess that not everybody was there. And I will go very rapidly because it's not really about the individual history and finding, but rather the entire concept. Again, great to discuss that with my colleagues. So for example, here is a patient treated with radical prostatectomy. He has a BCR. And as you can see, there are some hotspots, so some findings for example in the scapula, in the spine and here. And there is absolutely no counterpart in the CT.

So how would you regard those findings? Well, in this case, as mentioned before, you have one clue, there are many findings. So of course, the probability that they are all false positives is very low. In this case, it was not considered a biopsy, it was just changed the therapy. And unfortunately, as you can see at follow up, there is a rapid progression, which is unfortunately confirming that there were [inaudible 00:02:13]. And despite the therapy you see that the spot gets hotter and larger. So it's a confirmation. So the numbers makes the difference.

Another point that I emphasize is the degree of uptake. So in this gentleman, it's again BCR, and you see just one hotspot. But you see how focal, how intense is the hotspot. It has in history, no recent trauma, no other reason for such an avid uptake. So again, the patient was regarded as positive. And take into account how intense is the uptake in this situation. But it's not always like that. So this is a gentleman studied for staging. As you can see, there is the hotspot in the primary cancer in the prostate. There are several lymph nodes here. And of course, that's a high risk patient.

But I want to draw your attention to another finding that's a faint uptake. It's clearly very faint as you can see compared to the other lesion. It's in the rib. It is no counterpart in the CT. And the degree of uptake is very important. It's very low. It's really similar to the degree of the uptake here in the [inaudible 00:03:22] lung, which is frequently seen for example in smokers or in patients with some chronical [inaudible 00:03:29]. And it was regarded as M zero. So it's important to take into account the degree of the uptake, what we call the semiotic, the distribution. Again, there was no biopsy, no correlative imaging, just a follow up that the patient was regarded as M zero. And you see, after some months, there's absolutely no longer any uptake. And luckily enough it was treated. There's no uptake also in the pelvis. So in the follow up it was confirmed to be not a malignant lesion.

But it's not always the case. Again, a single lesion, a single hotspot here. And again, in a rib. It's not by chance that I'm showing many cases in the rib, because rib probably is one of the most questionable sites of uptake that could be regarded as false positive. And here you see again, no CT counterpart, a single hotspot. The patient in this case was considered as positive and was treated with metastasis directed therapy, that was successful. The PSA dropped to 0.01. After three years, there was a recurrence. And in this case, what you find is that there are different areas of uptake and the lesion in the rib was completely resolved by the PSMA point of view. But now you see the sclerosis, which is essentially the evolution of the disease in the CT.

So again, very rapidly, and now I'm very happy to have probably a fruitful discussion. In my view, what's important in this situation is first of all, [inaudible 00:05:07] your information that you have available. Some traces could be more keen to give you false positive findings. So be aware of that. That's probably our due as nuclear medicine physicians to take that into serious account, to use the best tracer. The degree of uptake is very important. The history of the patients has always to be carefully collected and taken into account. Correlative imaging could be useful. The point is that you cannot always pretend to have a demonstrative correlative imaging. I mean MRI is useful but cannot be carried out and required to take some [inaudible 00:05:48] change in therapy in every single patient. And again, that's a matter of discussion.

And finally, always get advantage of the multidisciplinary team because the complex cases are always there. You cannot pretend that the word is black and white. It's always a very, very much green matter. So it's been a rush. Chris, Neal, any question? I'm sure that you have a number of questions.

Christopher Sweeney: No questions per se, but a lot of principles that I think we can talk about that addresses patients in general now, with the PSMA PET amongst it. What I would first of all say is I think the top left portion, all the information is key. Nothing is in isolation. It's like baking a cake. If you don't put eggs in or sugar, it doesn't taste like a cake. So the history is key, as you point out. What is the pretest probability that a lesion that you can see is actually real? And I'll just go back to where we were with bone technician bone scan and CAT scans. Years ago, we realized that we caused more discomfort, more risks for patients who were staged for Gleason 6 cancers by doing technician and bone scans, bone scans and CT scans because the false positive rate was so high because the pretest probability was so low.

Sure, that's a little less with PSMA PET CT imaging, but it's still not zero. So we still have to work out the cut point where the pretest probability is high enough that any lesions that we see overcome the noise of false positives to warrant doing the imaging. So that's a very clear principle that we haven't really talked about is, what is the cut point of pretest probability defining what image to do and when? Now, all the patients you presented, their pretest probability, those lesions may be real was significantly high because they all, it seems like, had a rising PSA. So we know that there was some cancer somewhere in the body. So those pretest probabilities are much higher than a patient who's presenting with a Gleason 6 with the a faint uptake in their rib, for example. [inaudible 00:08:04] see how Neal would respond to that.

I fully agree. And thank you Stefano, those are great cases. And I think we're all grappling now. You mentioned the absolute importance of the multidisciplinary team. And historically, it's been in medical oncology, urology, radiation oncology, but now it's ever important to have the nuclear medicine radiologists on board and make sure they have a really good skillset. And making the interpretation so that we limit the false positives. But as you and Chris both very, very accurately stayed, nonetheless, we are going to have false positives. So what is that cut point? And of course, for the clinician sitting knew to knee with the patient, or at least in the pre COVID era, now we're six feet apart, you still have to make a decision about therapy. And we're at this really interesting inflection point where we're getting obviously better imaging, more accurate imaging with PSMA PET.

It's not perfect, there's heterogeneity. But at the same time, we have this burgeoning mantra, intensify, intensify for mCSPC. Arguably even intensify for mCRPC. And yet at the same point, we're saying, when based upon some early findings, especially with a positive PSMA PET and negative conventional imaging, CT scan, technician bone scan, de-intensify perhaps. Don't start systemic therapy. Maybe there's a role for focal SBRT. So I think this is a good problem to have, but it's a complicated problem. And I think that we're at a point where change is good, but it's creating consternation amongst many of our colleagues. And then the downstream effect is for patients and their families, what do they do?

Stefano Fanti: Yeah, absolutely. Great comments. Let me come back to Chris regarding the pretest probability, the bias [inaudible 00:10:21]. I have to say, I'm strictly following the need of being very careful in the appropriate use of PSMA PET. That's to say, when a patient is referred to me, I always ask which is the extra reason and which is going to be the consequence of my report. That's to say, I'm never scanning patients with the intermediate risk at staging. I'm not scanning patients if the PSA is not with a doubling time shorter than one year or if there's no burning reason. Of course, I'm talking about BCR. And I think it's very important that it's the same impression that I got from you both. You refer patients only when you feel that the PSMA may really add something to change properly the management of the patient, not just showing a hotspot. This is something that none should really be interested in.

Chris Sweeney: And I'll pick up on that, Stefano. I just wrote down three points that I was going to make, piggybacking off of their comments already is exactly that. When I see a patient and I have to make a decision, knee to knee or eye to eye through Zoom with a patient now [inaudible 00:11:34] in virtual as well, is, I ask the question, "What potentially curative scenario or major life-prolonging scenario do I not want to miss? What major mistake do I not want to go down and hurt the patient by missing a major therapeutic benefit?" Then I also think about, "If I order this test, is it going to change management?" And that's exactly what you were saying, Stefano. A lot of people will just click the PSMA PET CT scan button and deal with the consequences, not thinking about the consequences before ordering it. And so I think that's the other question I ask. So what is the clinical scenario treatment option that I don't want to miss? If I order the test, is it going to change my management in a meaningful manner? And part of that question is, what's the treatment burden of the potential treatments that you're thinking about?

So let's take the example of a patient who presents with locally advanced disease, possibly the patient you showed with the no positive local disease in the prostate and maybe some scant disease outside of the pelvis. I would definitely push on with the potentially curative option of pelvic node and prostate radiation with long course hormones. Definitely like the stamped [inaudible 00:12:55] scenario where many of those men are much more likely to be alive 5, 10, 15 years later because you intensified with radiation and hormones. Far greater than would've been with the systemic therapy alone from the data that we have. So that's just an example where I would not do a PSMA PET CT scan if it wasn't going to change my management because I've got to just treat based on the nodal disease. I wouldn't overreact in this case because we see the result. I wouldn't overreact to the likely false positive lesion in the rib.

Stefano Fanti: Yep. Yeah, great point. And Neal, let me further comment about what you mentioned [inaudible 00:13:37], which is quite common after PSMA. Because usually, using the more sensitive methods, of course you see more and you are required to do more. But I guess, the point that you raised up about, sometimes you can also de-intensify, that's also very important to me. It's not common to have a PSMA test required with the aim, let's say, of not using the heaviest weapon immediately. But that's a very interesting approach. I like it. It's really smart in my, again, humble imager point of view.

Neal Shore: Well, I think that what we all tend to experience regularly in our clinics when we treat patients with advanced malignancies, particularly prostate cancer is, as it's said, there's no free lunch for many of these therapies. And the fatigue, which is the bane of virtually every one of the therapies that we offer and how that affects quality of life, not to mention all the other adverse events keyed to the different novel mechanisms of action really do come into play. But at the same time, I really fully agree with what Chris said is, our charges to prolong survival, preserve quality of life, prevent complication of therapy, understand patient preference value. How risk seeking or risk intolerant are they? And sometimes I think getting the PSMA PET, it can be remarkably helpful, especially in that presumed localized, high risk, newly diagnosed patient or the BCR population.

The case that Chris cited, I thought was a good one, that it might not have really given us much additional information but only some complexity. There's that nice paper by [inaudible 00:15:40] that looked at the nm CRPC group of roughly 200 patients who were nm CRPC classic for SPARTAN, PROSPER and ARAMIS. And at the end of the day, did it really change the fact that they would all still be good candidates for an AR pathway inhibitor drug Apa, Enza, Daro, despite the fact that PSMA PET clearly in 98% of the patients showed lesions that were not picked up on conventional imaging.

So I think we're continuing to learn. One of the areas that's really interesting, if I could segue a little bit is just understanding follow up PSMA PET based upon lines of therapy and you showed some examples of that, but I think we're still really in our nascency, certainly in the US as we just in the last year are starting to get accessibility throughout, regarding PSMA PET. And what to do with it based upon subsequent lines of therapy

Stefano Fanti: Yeah, that's absolutely in line with my opinion. I personally would never be the guy denying a patient to have a therapy potentially curative just because I've been reporting a hotspot that I'm not absolutely a hundred percent sure that corresponds to a lesion. That's a big responsibility. And again, it emphasizes the need for MDT because you can probably discuss that only within a team. I have a last curiosity. Well, you are based in the US so you are probably using the two most accurate tracers, which are PyL and Gallium 11. But nonetheless, also this very accurate tracer may suffer some false positive findings. So our frequent is in your practice to ask, for example, an MRI to confirm something that is seen at PSMA. Is that very infrequent? Is that common? How frequently it comes?

Neal Shore: Yeah, I think it depends upon the stage and the anatomy that you're interrogating. I think for us as surgeons as well as my radiation colleagues, still like getting MR of the prostate for anatomical understanding for staging, for planning surgery radiation, and also for the pelvic field. Regarding bone lesions, I do get follow up, depending upon the size and location, and it's an evolving aspect. Part of it is just being able to make sure that there's not... We talked about clinical utility. I think we were talking about the economic utility and/or avoiding the economic toxicity. Unfortunately, in the US, MR is still a very expensive imaging technology to order.

Chris Sweeney: And I'll pick up on that a little bit and say, it really depends on the clinical context, whether I need to know that information. I'll just take a step back and say, I will sometimes order a PSMA PET CT scan in a patient with a high risk localized disease that's already bone scan technician positive... Negative CT and technician negative, if a patient's thinking about a prostatectomy. But if you see disease on the PSMA PET beyond the prostate, maybe that would steer them towards systemic therapy and radiation. So would an MRI help change that situation? Probably not of any lesions that prop up on the PSMA PET, because the pretest probability is real and I'm not going to chase it down with an MRI. The other scenario though is, in the patient with a biochemical relapse, if they have one isolated lesion and it's CT negative and the PSA's gone up, does knowing if that's a cancer spot really change anything? Like you did with some of those patients, you can just say, "Okay, this is a PSMA positive lesion, biochemical relapse, CAT scan negative." We often for years have been just watching those patients with serial PSA's and an occasional image. I don't see the need to change that paradigm and just repeat the imaging to see the dynamic of it, and is it something that's getting more problematic? And then commence hormonal therapy.

The other way I think a PSMA PET may help in the biochemical relapse setting is, if they're PSMA PET negative, CAT scan negative and their PSA's going up, you can say, "We just watched these. We don't really need to intervene." But then if you start to see lesions on the PSMA PET and not the CT scan, the question is whether to do the SBRT with or without performance. And I think that's a very open field. And I just draw attention to the paper that just came out in [inaudible 00:20:41] with our Twitter [inaudible 00:20:43] colleagues of [inaudible 00:20:45] and team and the [inaudible 00:20:48] team where they have the [inaudible 00:20:49] data. But [inaudible 00:20:51] some patients with the SBRT alone in that setting have a delayed time to radiographic progression.

But we're not curing anyone. All of those patients seem to progress at some stage. So the question is really, I don't think we miss a curative option with SBRT just because we see the lesion. I don't think we're hurting the patients by delaying and seeing if that lesion gets more prominent without having to have to do an MRI, and just watching them closely. So I think it again, comes back to, what's the dynamics of the change? What's the history around the pretest probability? To really make a decision rather than this ever escalating image intensification if you were chasing down lesions and then still being left going, "Well, I don't know." How many times do we shrug our shoulders after an MRI and a PSMA PET? I find that way too often. So I think we need all the data and not just rely on the imaging alone. Stefano Fanti: Yeah, absolutely. I guess that's probably a good way to summarize it all. That's to say, as an imager, I have to admit that no imaging method is perfect at all. Don't expect it, never expect it. There's never been a hundred percent accurate method. And definitely, these are not MRI or PSMA PET. Most of all, in my view, and I guess at all the discussion we had was about, never miss the stronger weapon that you have available, which is your clinical expertise. The discussion with the colleagues, the capability to take into account the biology of the disease, the evolution. There's so many data, there's so many therapies that now you have available. So never treat a hotspot, never underestimate a hotspot, not never get crazy for that. That's in my view, the very important message. So having thorough consideration and evaluation of the patients. And I leave to you the last conclusion, Chris and Neal.

Neal Shore: Well, I would just say I love your conclusion because you're basically championing that the art of medicine is still alive and well. We get biomarkers, imaging markers, which are fantastic and they inform us. And of course, we look at the patient most importantly, the clinical parameters. But yes, that is the joy and the real honor for what we do. It is that art of medicine and getting that clinical expertise to sometimes say, "You know what? I'm going to act on this information or maybe I'm going to hold on this information," or, "You know what, maybe I don't need to get this information right now." So I applaud what your conclusion was.

Chris Sweeney:  I'll double down on that and I'll say in a slightly different way, I love cake, but you need eggs, you need sugar, you need flour, cocoa if it's chocolate cake. You need the other ingredients to make a cake. And it's the same with managing the patients. We just need to have all the ingredients to put it all together to make the best cake for the patient.

Stefano Fanti: Fantastic. The sweetest conclusion ever, I guess. Thank you very much for sharing those does very, very instructive and nice discussion. And thank you for your attention. Thank you very much.

Chris Sweeney:  Thank you, Stefano and Neal.

Neal Shore: Pleasure. Thank you.

Chris Sweeney: Well, Stefano and Neal, that was a really interesting conversation where we were talking about the clinical implications of PSMA PET CT. And just as we were completing the talk we started to talk about biology and the biological implications. Thanks for sticking in for the bonus scenes from our news reel. Because, what I think I'd love to do is just get your thoughts on this slide set. So here is my proposed framework to understand the different information from technician bone scan and CT imaging, versus PSMA PET and even whole body MRI without CT correlates. So in the left panel we've got a CT abdomen and pelvis technician bone scan. And [inaudible 00:24:56] criteria, which we've all grown up with, we call a cancer spot in the lymph nodes, or even in an organ if it's greater than a centimeter in the short axis. And that's a fairly bulky size of cancer in billions of cells. The greater the number of clones are probably seen with the greater burden of disease that we see in any given spot. And probably more resistance has developed, is an item that I'd like to propose.

And it's very clear, CAT scans and bone scans do not measure cancer directly, but they tell us that the cancer is doing something to the bone. So is that telling us that the cancer has got a foothold in the bone micro environment and is being supported by the bone? And is this a more resistant cancer? Is it more adaptable, is it more aggressive? And we know that once we see a conventional scan positive disease in the locally advanced setting, we scan them, we screen them, we see boney metastases. They're probably not curable with systemic adjuvant therapy. But the same patient that has the same three lesions, we actually are probably seeing that they get eradicated with intense hormonal therapy in the adjuvant setting. So I think we just need to possibly delve into the biology a little bit.

Whereas on the other side, the flip side is, if the PET is positive without the CT or CAT scan finding, sure, we're evaluating the cancer more directly. It's a smaller bulk of cancer and possibly less clones and less resistance. It doesn't have a foothold in the bone to be protected by the bone micro environment, and we can possibly eradicate with intense systemic therapy in the adjuvant setting. And that I think we even know something from a prognostic and a predictive benefit, in terms of what we know about hormonal therapy for metastatic hormone sensitive disease. It's very clear that patients who have three or less boney metastases, with or without nodal disease and no liver metastases have a very good prognosis with ADT alone. Oh sorry, I should say a better prognosis. If the prostate is intact, we know that these patients benefit from radiation and we know they have no benefit from docetaxel in the metachronous low volume setting. The STOPCAP IPD presented at [inaudible 00:27:20] confirmed that metachronous low volume has no benefit with docetaxel. But we do know that these patients benefit from radiation.

Whereas on the flip side, patients with high volume disease have a poorer prognosis by four more boney metastases or liver metastases, but they have a benefit from docetaxel. We just don't know this information because we don't know the biology as well, I think for the PSMA PET positive conventional scan, negative disease on the right. Neal and Stefano, how do you respond to this speculative hypothesis generating set of thoughts?

Neal Shore: Well, I think it's really excellent. I mean these two slides that you've put together, Chris, are really great. I mean they're really full of important information, really clearly comparing and contrasting the value proposition that we now have with the novel next generation imaging. Particularly as we see with PSMA PET and countries that have been able to use whole body MR. And you're absolutely right, we all suffer from the development of resistance, clonal selection, whether it's the initiation of testosterone suppression and going on an AR blocker or a PARP inhibitor or an immunotherapeutic or a radiopharmaceutical or taxane.

And so you're, your points are extremely provocative and of course make great sense, especially if you want to be particularly proactive and rigorous in saying, "Hey, my early shots or my first shots are typically my best shots." But we have to get the level one evidence to really go forward with that. And as you aptly demonstrate here, we have two big unknowns. And what to do with that information where we recognize there will be less clonal selection and a better phenotype, a better biology to potentially not only put disease in remission for a longer period of time, but even for some patients arguably even eradicate the disease. So I think this is great. I think this is a really provocative and important summary of a lot of tremendous trial work that has been done over the last decade, if not more.

Stefano Fanti: Yeah, absolutely. I can only echo Neal. It's fantastic. Your proposals are excellent. And by the way, I really like the different perspectives. That's to say, I've heard a lot of discussion regarding the fact that we have to adapt or rescale or reevaluate the categorization in low and high volume, especially in normal sensitive prostate cancer with the next generation imaging. But that's honestly not enough. And what you did is much more. That's to say, just use the different sort of information that we got with those imaging methods, which are completely different by the biological things they're looking at. That's to say, in one case, you have density, you have osteoclast reaction and osteoblast. On the other cases, you're looking at the cloning, at the cancer itself. So it's completely different categories.

Again, it's not just a matter of rescaling or recounting the number of lesion stratifying, it's different. You have to take farther evaluation and conclusion. And the provocative component of our proposal is fantastic. That's to say, let's move farther. Don't stick with adapting an old view with the new methods that we can have. Let's move farther. Let's use more information to adapt the treatment to the patient. Great. Fantastic, Chris.

Chris Sweeney:  Thanks for your support Neal and Stefano. That means a lot.

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