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Alicia Morgans: Hi, and welcome to Clinical Case-Based Learning. We are here for a virtual tumor board in advanced prostate cancer. We're going to start with case number one, Mr. John Roberts, who has a prostate cancer recurrence.

Mr. Roberts is a 71-year-old man with a history of hypertension and locally advanced pT3N1M0 prostate adenocarcinoma. He's a Gleason 3+4 prostate cancer. He was treated initially, with radical prostatectomy and pelvic lymph node dissection in March, of 2018, shortly after his initial diagnosis. He did not opt for adjuvant radiation at the time, despite being pT3b, and his PSA was undetectable postoperatively. In September, of 2021, his PSA was detectable at 0.31, so starting to rise. And he underwent 18F-DCFPyL PSMA PET to inform his decision-making.

Before we get to that, I just want to share with everyone who is thinking about this case, that he is actually a pretty healthy guy. He is active. He spends a lot of time outdoors. He gardens, plays with his grandchildren. He has a couple of comorbidities, including hypertension and hypercholesterolemia. He's taking enalapril, simvastatin, and daily aspirin, and all of these are really well controlled. So he is generally, quite a well individual.

And now I will hand off to Andrei, to share our images.

Andrei Iagaru: Sounds good, Alicia. So we will review now, the PyL images. And for this first case, I will share how I tend to review these scans. So first I look at the projection image, which gives you a roadmap of what's normal body distribution and what's abnormal. So normal with most agents is evaluating PSMAs uptake in lacrimal glands and salivary glands. The thorax should be pretty clean. There is hepatobiliary clearance, as well as [inaudible 00:01:55] uptaking is clean. There is renal excretion, as well as renal binding. And there are some uptakes throughout the GI tract, particularly in the duodenum. The rest is excretions through the ureters into the bladder.

So just by looking here, what stands out to me, are two areas of abnormal uptake in the pelvis. They should not be there. And with this in mind, we can go to other views. I would also just briefly emphasize this low-grade uptake in both axillary regions.

And although we name this prostate-specific membrane antigen, it is well known that this is one of the best misnomers, because this is not prostate-specific. It's overexpressed in up to 90% of prostate cancer, but we do see things that are non-prostate cancer. We do see things that are a benign impact. We do see them. So here we see bilateral axillary normal appearing lymph nodes, with fatty hilar, and not increased in size. These are probably just reactive changes. So keep that in mind, when reviewing these images.

As we scroll down through the pelvis, we evaluate the retrograde duodenum, to make sure there are no abnormal lymph nodes, either by size or by uptake. And as we arrive towards the pelvis, we pay closer attention, making sure that we are not missing lymph nodes. We follow the ureters going toward the bladder. This is still the ureter on the right, but now we see a small area of very intense uptake, which seems to be a nodule, probably a peritoneal implant adjacent to the bowel. We go lower down. This is again, the ureter going into the bladder. However, this area, more anterior, is either a lymph node or another peritoneal implant.

So in this particular case, correlating with a relatively low PSA, we see small volume disease, that was not identified on anatomical imaging. So back to you, Alicia.

Alicia Morgans: Great. Thanks. Those images are incredibly powerful. So thank you for going through those. And thank you also, for pointing out the axillary nodes. Because I do think, knowing that those are reactive, I think is really, really helpful.

I do want to just leave the basic case up while we talk things, through. And just to sort of recap, he is 71, he has a couple of comorbidities, but they are very well controlled, and he is functionally very, very active. And I think, pretty clearly, has a recurrence of his prostate cancer. He is not on any treatments at this time, no systemic therapies. And just as a reminder, he also did not receive any pelvic radiation in the past. So this is the first recurrence, he's hormone-sensitive, and has only had local treatment with a prostatectomy.

From my perspective, usually, I think about pelvic radiation for patients who have this initial recurrence. And I do not think that is a slam dunk answer for this individual, given what we've just seen on this PSMA PET. And I wonder, Hilary if you can talk us through how you think about pelvic radiation, what the benefit normally is, and how you would think about this patient, in the context of what we saw.

Hilary Bagshaw: Great. Thank you. If someone came in with normal conventional imaging, but a rising PSA, to 0.3 for example, especially with his risk factors of pT3 disease and node positivity at the time of prostatectomy, I would definitely recommend pelvic radiation, including nodal irradiation and hormone therapy. Typically, a short course, although there is some controversy in that. But given what we saw on the PET scan, I'm not sure that pelvic radiation would really benefit him. And what could potentially just give him toxicity without benefit, is that those two little peritoneal implants are not in the typical field that we would radiate. We could certainly go after them, but the problem is, one of them is kind of right in around a bunch of bowel loops, and we really can't boost, right adjacent to bowel like that, as high as we would like to. For example, we go to 70 Gy in the foci, but the bowel only tolerates about 60 Gy. I think it's tough. He is relatively young and well, so one approach would be to follow him, and see how the disease kind of declares itself, versus potentially, starting him on hormone treatment now, I guess.

Alicia Morgans: Yeah. I appreciate you talking us through that. And I think, it also makes a difference, was this only identifiable, this disease, on DCFPyL PSMA PET imaging, or was this actually, something we could see on conventional imaging? And I don't think we mentioned it, but Andrei, this patient had conventional imaging as well. Right?

Andrei Iagaru: Right. And we're choosing here, in the interest of time, to focus on the imaging that is contributory, the prior imaging was noncontributory.

Alicia Morgans: Meaning it was negative. Right?

Andrei Iagaru: That is correct.

Alicia Morgans: Thank you. Not contributory, in terms of anything pretty to see, other than normal structures, but important, I think, when we think about contributing to the decision-making process. And I wonder, from a urologic perspective, what do you think?

Geoffrey Sonn: Yeah, this is a tough one. It's something that we are going to run into in the coming years with more PSMA PET being done. What do we do in this setting of a new finding on PSMA PET, that is not seen on conventional imaging? Or that in retrospect, you can go back and find a subset meter lymph node on a CT scan that correlates, but wouldn't have been called on its own. And we just do not have answers to this. The recent trials, looking at PyL PET, really do not address this yet, as to whether these new findings... It's quite clear that we are finding additional lesions we wouldn't have known about before, but whether this is changing the outcome of these patients for the better. Because in this case, this is a patient that quite clearly in the past, would have gone on to get radiation therapy, and may or may not have responded to that.

So from my perspective, here, we are left in a situation, where we don't have a clear-cut answer as to what to do. And I would echo what Hilary had said, that our options would be to continue to monitor without radiation therapy and see what happens. Certainly, if he develops other metastatic sites over time, that makes radiation therapy less appealing. But if not, and we have growth of these local lesions and nowhere else, then you might think about some sort of a surgical and/or radiation consolidation treatment, or hormonal therapy alone, and see what response you'd get.

You would presume that these things would shrink on ADT, and that may give some sense as to whether this is a true positive or a false-positive finding. In the CONDOR trial, the positive predictive value was imperfect for PSMA PET in distant nodal disease, and especially visceral disease. So while these look quite convincing, it is possible that these are not actually prostate cancer metastases.

Hilary Bagshaw: I actually have a follow-up question for Andrei, just thinking about what Geoff said, and maybe I missed this, but can you see a nodule on CT, or is it just PET uptake that we are seeing here?

Andrei Iagaru: There is a tiny, soft tissue nodule associated with both areas of optics. So it is not without the CT correlate. It's just that, it is something that is not increased anatomically, so you will not call it by size criteria, and for some then on a non-contrast CT, you may just scroll by, and not even notice it.

Hilary Bagshaw: Thank you. I just think that kind of changes how I would think about it. Like if it was just PET uptake, maybe I'd say, let's just push forward with radiation, be a little more aggressive, hope that it was a false positive with a soft tissue nodule. I guess it's a little more concerning.

Alicia Morgans: I would agree. And to build on that, and also, what Geoff has mentioned, from a medical oncology perspective, if we can't see it on conventional imaging, we are a little bit in a gray area, in terms of systemic therapy. Because all of our trials for patients who have metastatic hormone-sensitive disease, if that's what we are calling this, are defining that disease using standard CTs with contrast, when possible, bone scans, and potentially MRIs. And so when we have a disease that we can't identify by size criteria on a CT, then it just leaves us in a gray area. And if we say that this is a biochemical recurrence, and it's a hormone-sensitive, never previously treated biochemical recurrence, we're still in a gray area, because we do not have clear data, that starting immediate ADT is definitively better, in terms of survival and outcomes for patients.

So what I'm hearing from everybody is that there is a fair amount of wiggle room here for a shared decision with our patient. That we can consider for some patients who want to avoid intensification of therapy, monitoring with no systemic therapy, no local therapy, no direct metastasis directed therapy, and just see what we see over time.

Alternatively, in the complete opposite direction, we could use ADT and abiraterone, or ADT and apalutamide, or ADT and enzalutamide, whatever AR targeted therapy we would want to partner with our ADT, for low volume metastatic hormone-sensitive prostate cancer. And then also, consider maybe, pelvic radiation, or something that could be targeted, if we find that the patient has stable disease, or improving disease, and we want to consolidate, at some point in the future. But this sounds like a conversation. And I wonder if we chose that approach, if we wanted to follow this patient over time, Andrei, and if we did follow with a PSMA PET scan, how might systemic therapy affect the way that the imaging looked, and how would that maybe, alter our understanding of the disease process, based on what happens when we use these testosterone targeted treatments?

Andrei Iagaru: That's a very good point, Alicia, and the data is emerging. There's a very nice, albeit, small cohort study from Australia, from Louise Emmett, and her colleagues. They randomized patients with hormone naive, versus castrate-resistant prostate cancer, and they repeated the PSMA scan at nine days and subsequently, to see changes in response to ADT. In the hormone naive cohort, there is about a 30% decrease at day nine in the intensity of uptake. And after that, the response kind of plateaus, and stays heterogeneous.

In the cancer-resistant group, there is the opposite. There is an increase of about 40%, 45% by day nine. And then again, a heterogeneous response with those with persistently increased uptake, perhaps progressing. So I'm not sure that we have sufficient data to use this, to monitor response.

And in response to comments from both you and Geoff earlier, it is true. It is on us, in the imaging community, to prove that, not only that we can find more findings, but also that they have an impact on overall survival and quality of life, or whatever other measurements. And maybe then, and this was too easy for me to not mention it back, maybe then, PET will be conventional imaging as well. Because I do not think there is anything unconventional about it.

Alicia Morgans: I agree. And I assume, and hope, that it will be what we call conventional at some point in the very, very near future. Because you are right, there is nothing unconventional about it, and we're excited to have the technology.

So why don't we do a final word of recommendation from each of our specialists here? Starting with Geoff, what would you recommend to this patient?

Geoffrey Sonn: I think that we would all want to have a discussion with the patient because we do not have a clear-cut answer as to the best approach to take. If we decide to monitor this, I would follow it quite carefully, to get some sense as to the rate of rising of his PSA, because we don't have these prior PSAs to get a sense of the trajectory. Was he undetectable two months ago, and then all of a sudden now he's up at 0.3, would suggest perhaps, more aggressive behavior, or was it just the first number that we have? So if we're going to follow it, a repeat PSA in probably, no more than three months, would help to inform whether we are going to go the more conservative route, and just monitor this for a period of time, or the more aggressive route, and consider radiation, or ADT.

Alicia Morgans: Thanks, Geoff. Hilary, what do you think?

Hilary Bagshaw: Yeah, I agree with what Geoff said. And with close monitoring, I think, I would just have a frank discussion with the patient about the risks and benefits of radiation, and that we do not really know if aggressively treating these sites that we see on the PSMA scans is better for his long-term outcome. He may be someone who wants to be aggressive or maybe the opposite. So I think, as you mentioned, shared decision-making is really important here.

Alicia Morgans: Well, that's the approach I would take. I will agree with both of you and agree with that comment from before. And Andrei, it sounds like we are leaning towards, of course, including the patient in this conversation. If he leans towards monitoring, would you use things like CT scans to monitor him? Would you try to continue to use PSMA PET? How would you monitor, optimally, as we wrap things up?

Andrei Iagaru: Very good question. I think, that in the absence of treatment, just on monitoring, and especially, if you have a high PSA doubling time, or any sign of aggressive disease, you want to catch lesions before they become large enough to be seen on standard imaging. So I would follow up with another PyL, or other PSMA available, once we document an aggressive phenotype. If there is treatment being given, which I don't think we agreed, as a group, to go forward with, then I would probably, just use anatomic imaging, such as CT, to see if there is any change in size.

Alicia Morgans: Great. Thank you. Well, it sounds like we are going to have a good conversation with this patient, and we will let him lead the way. I appreciate all of you for your insights, complicated, and you made it much less so. So thank you.