18F-Fluciclovine in Biochemical Recurrent Prostate Cancer - Andrei H. Iagaru

May 10, 2021

Detection and Localization  of Prostate Cancer: Case-based Scan Reading Review 

18F-Fluciclovine Cases  - Part One of Three - Scan Reader Training and Discussions Presenter: Andrei Iagaru. 

Independent Medical Education Initiative Supported by Advanced Accelerator Applications, A Novartis Company

Biographies:

Program Presenter: 
Andrei H. Iagaru, MD, FACNM, Professor of Radiology - Nuclear Medicine, Chief, Division of Nuclear Medicine and Molecular Imaging, Director, Nuclear Medicine Residency Program, Co-Director, PET-MRI Research Program, Stanford University, Stanford, California.

Program Discussants: 
Neal Shore, MD, FACS, is the Medical Director of the Carolina Urologic Research Center. He practices with Atlantic Urology Clinics in Myrtle Beach, South Carolina.

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Program Moderator:
Phillip J. Koo, MD, FACS Division Chief of Diagnostic Imaging at the Banner MD Anderson Cancer Center in Arizona.

 

Read the Full Video Transcript

Phillip Koo: Welcome to UroToday. My name is Phillip Koo and I have the pleasure of serving as a moderator for a special program, titled 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 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.

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 my esteemed colleagues, Dr. Alicia Morgans, GU Medical Oncologist and Associate Professor at Northwestern, and Dr. Neal Shore, Urologic Oncologist and Medical Director of the Carolina Research Institute in South Carolina.

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

Andrei Iagaru: Good morning. Thank you Phil for the very kind introduction and good to see Dr. Morgans and Shore again. It's a pleasure to join you on this educational program. And as you said, the landscape is changing dramatically. We look forward to these new tools and we look forward to learning more about how they're used in day-to-day practice, not just in research scenarios. And we can spend a lot of time, but I focused on a few interesting cases, as you will see highlighted in the next slides.

Okay, so today we will discuss some fluciclovine as well as PyL PSMA cases and I hope we will touch upon the radioligand therapy. Of course, this is all tied in together in the concept of theragnostics.

So what is fluciclovine? This is a synthetic amino acid that is transported across cell membranes by amino acid transporters. And these amino acid transporters are upregulated in several entities, including prostate cancer. It's important to recognize that the highest concentration, the highest lesion-to-regular tissue is at 4 to 10 minutes after injection, so that has an impact on how we scan this patient.

Afterward, this redistributes to other organs, including liver, pancreas, lung, bone marrow, myocardium, and skeletal muscle. The longer you wait, the more [inaudible] ends up in skeletal muscle, hence, again, the need to image [inaudible] injection. And with that in mind, this is the imaging protocol. We actually inject these patients in the scanner room while they're positioned on the table. And then at 3 to 5 minutes post-injection, we start image acquisition for PET/CT, with a quick CT, and then afterward, the PET parts, starting from the pelvis and going towards the head.

This is the normal biodistribution for fluciclovine, as indicated a little bit earlier. Salivary gland, skeletal muscle, liver, pancreas, spleen, bowel, and bone marrow have normal uptake. There is little genitourinary clearance, so we see small amounts cleared by the kidneys and small amounts occasionally into the bladder, but much less than say, other tracers, such as FDG or PSMA, which has a major component of renal excretion. It's important to recognize the uptake in normal bone marrow because that is used as a criteria for image interpretation. So when you interpret these images, first, you need to keep in mind that this is not specific only to prostate cancer. So you can have a non-specific uptakes say in inflammatory lymph nodes. So knowing the pattern of spread of prostate cancer is critical in differentiating between true malignant lesions and false positives.

For lesions that are small, so under a centimeter, focal uptake in something that is a putative site of disease for prostate cancer, can and should be interpreted as a probable disease. For lesions that are larger than that, uptake that is greater than normal in bone marrow is highly indicative of a recurrent disease or malignancy.

So now let's go through a few examples. This slide illustrates various patterns of prostate cancer presenting on Axumin scans. These are all biochemical recurrence. So you can have, the case on the left with bilateral pelvic lymph nodes creeping up into the retroperitoneum. The case in the middle has the same pattern of recurrence in pelvic retroperitoneal lymph nodes, but also some bony disease, including in the right femoral head. And then the patient on the right has multiple sites of bony metastasis, in addition to some nodal sites of disease.

And with that in mind, we'll go through a few cases. Case number one, he's a patient with newly diagnosed Gleason score 4+3 prostate cancer, PSA of 42.3, because it was considered high risk, a CT and a bone scan were done, and they did not identify metastatic disease. Their clinical stage was T1c and grade 3. So this is the maximum intensity projection image and I see that even from here, one can appreciate some focal uptake in the prostate gland, but let's look as we go through.

This is the MRI, again, indicating the lesion and on the PET/CT, correlates very nicely with the area where there's overexpression of these amino acid transporters and therefore, you have a high uptake of Axumin fluciclovine. But, is there anything else other than that? In this case, yes, there was. There were right pelvic lymph nodes, retroperitoneal lymph nodes, as well as retrocrura lymph nodes, and that is indeed the pattern of spread for metastatic disease. So in this case, a patient is high-risk, but negative staging with CT and bone scan, Axumin indicates the presence of possible nodal metastasis all the way into the retrocrural space. And interestingly, lymph nodes that lit up in the supraclavicular [inaudible], mediastinal and supraclavicular space.

So turns out that this patient received the COVID vaccine within two weeks of the Axumin scan and that was in the left deltoid. So maybe we can break here and discuss a little bit of what do we do because this scan changes the initial thoughts about how extensive the disease was.

Phillip Koo: So Andrei, that's a great case and I could already sort of imagine what the reports might look like in various scenarios. In some cases, someone might say those supraclavicular nodes and mediastinal nodes might be related to COVID. However, oftentimes the radiologist or nuclear medicine physician might not know they received the COVID vaccination. In which case, they'll say, "Hey, these are suspicious for metastatic disease." Really puts the ordering physician in a bind. So would love to hear Alicia and Neal's perspective on this.

Alicia Morgans: I don't yet know, at this point, how frequently COVID vaccine is going to affect these PET scan results. If I learned that from my patient, I would probably call my nuc-med team member and say, have you been seeing a lot of this? Because I'm not sure what the likelihood is. And then what I would also want to talk with you about, the likelihood that these could be false-positive nodes. I mean, how commonly does that happen? Do I need to think about a biopsy? The ones that are supraclavic and really above the diaphragm, particularly.

If I was going to move forward with treatment, which ultimately, obviously this patient's going to need, I would probably think about a biopsy if it's possible. Though those were very, very small and I'm not really sure that one could actually access them. If I couldn't biopsy them, I would probably steer this patient in the direction of radiation to the primary and then intensified systemic therapy. Sort of a STAMPEDE-type approach and consider two years of intensified ADT and abiraterone, for example, with radiation to the primary, and then the cessation of treatment with the close monitoring and follow-up. To assume that perhaps this patient is localized, but if this patient is very low volume metastatic, we could restart our androgen deprivation therapy after that two year initial therapeutic approach. But this would definitely be a tumor board conversation in my institution because again, I'm just not sure about the false positive rate and would love to hear about that from our nuclear medicine team. I don't know from a urologist's perspective, Neal, what your thoughts might be.

Neal Shore: I think you summarized it very nicely. I think it's a bit of a data-free zone in terms of the significance of fluciclovine or for that matter, many other scans regarding the timing of receiving a COVID vaccination. So I would certainly defer to my radiology colleagues on that. I would do exactly what you're suggesting.

But nonetheless, this patient with a PSA of 43, unusual for a Gleason 7, but certainly based upon the classic D'Amico, or stratification, highly likely that this patient would have nodal disease or bone and nodal disease, despite the lack of finding on standard conventional imaging. I think that's one of the beauties of the CONDOR trial and Andrei, you've educated us all on that, I'd love to hear your thoughts on it. But how that getting a more advanced pet imaging, in this case, the fluciclovine scan would certainly change the decision. Historically, where a surgeon might just say, "Look, your CT and bone scan's negative. I know your PSA is high, but let's go in and operate, and maybe I'll do a more extended lymph node dissection because of the PSA." Now we're left with positive findings on fluciclovine, which were certainly concerning, they're following the nodal ascendancy of what we would expect with prostate cancer, but here's this additional confounding controversy over the timing of the COVID vaccine, which really makes this a very great case, really contemporaneous to what we're all struggling with.

Andrei Iagaru: Right, then there are plenty reports and we see it on a daily basis, the FDG uptake in axillary lymph nodes and at the site of injection, but this is not FDG. So we truly could not offer a very educated answer to our colleagues in urology, medical oncology, and radiation oncology when this case was presented indeed at a tumor board, other than to say that we know there are nonspecific uptake reasons from Axumin as well. And so the question from me to you was, would it make a difference if you only have disease in the abdomen and pelvis, maybe it's oligometastatic disease versus disease in the mediastinum and supraclavicular regions? And I think there's a big difference between those as far as treatment. And so the decision was made to biopsy these lymph nodes, and this was successfully done under ultrasound guidance and the results of the biopsy was adenocarcinoma. So this was a true positive finding and one that changed how this patient was managed. And again, if you just use what's considered standard of care now, it would have been a very different outcome, probably in the long-term as well.

So to address Neal's comment about the CONDOR trial and all of that I've seen that, I can foresee, with more and more data emerging, where probably the PSMA scans, be it PyL or PSMA-11 or whatever will be available to clinicians, will largely replace the CT and bone scans done on their own at the initial staging for these patients with intermediate and high-risk prostate cancer. With the caveat that we know already of anecdotal cases where, on a bone scan done with high quality SPECT/CT or with sodium fluoride PET, you will find additional bone lesions. Not sure that those will change the management or what you will know from PSMA.

Neal Shore: As Alicia said, these were very small lymph nodes, they weren't seen on CT scans. So kudos to your interventional radiology team at Stanford to be able to successfully accomplish this, especially with ultrasound, as opposed to CT imaging. I'm doing a lot more metastasis-directed biopsies these days, especially for genomic profiling. But my question for you, Andrei, is help our audience understand the involvement now of your interventional radiology team and how you present cases to them in a time-efficient way. I think in the community, this is something that's actually pretty new, busy community, your medical oncologist gaining the expertise of their interventional radiologists and sort of demystifying this notion that to do a biopsy is not necessarily that problematic of an undertaking.

Andrei Iagaru: That's a great question and thank you for the kind comment about my colleagues, we're also very appreciative of them, as we are about our urology team, who also does biopsies when many others probably wouldn't go there. I think it's really an example of the power of multidisciplinary approach and presenting difficult cases in tumor boards. We participate, from nuclear medicine, in more than 10 tumor boards every week and so is every division in our department. So that brings together people who know their field, from medical oncology, surgical oncology, radiation oncology, radiology, including intervention radiology, nuclear medicine, thoracic imaging, if it's a malignancy in the chest. So I don't see that there's a one size fits all approach. I think that having access to a multidisciplinary tumor board allows cases to be triaged into who is best suited to help.

Phillip Koo: Yeah, just to speak on that. For our tumor boards, it's correct, having IR present for each of our tumor boards has become even more critical. And I know that's logistically a challenge, but I think it's just something that really elevates a level of care. So I'll turn it back to you, Andrei, to continue your cases.

Andrei Iagaru: So now, case number two, this is a 78-year-old man with a 4+4 Gleason score newly diagnosed prostate cancer, PSA of 12. Again, high risk, standard of care CT and bone scan were negative for metastasis. This was again a clinical T1cN0M0 and grade 4. As you can appreciate from here, the results from the Axumin probably will be a little bit different than what is known at this point, prior to doing the fluciclovine. And I will say that at our institution, pretty much everyone considered for prostatectomy undergoes a dedicated prostate MR. And here on the top, we have the diffusion-weighted imaging indicating diffuse involvement in the top left panel, as well as involvement in the left prostate on the top right panel. In addition to that, there are bony lesions noted on all of these images, and those are the areas that have abnormal patterns on MR imaging.

So already from doing the prostate MR, we know that this is a very extensive cancer in the prostate gland, but also that there are local bone metastasis. And let's see if the Axumin adds anything to that. So in this slide here, we show the intense uptakes throughout the prostate gland, as well as in the left prostate, and at other levels through their pelvis. And we already see on this soft tissue window that there's focal uptake that correlates to bony structures. And in addition to that, there is a lymph node that is suspicious in the right external iliac/inguinal region, as well as the multiple sites of bony metastases that were highlighted from the pelvic MR. So you can appreciate them here on these three different levels through the pelvis, bilateral pelvic [inaudible] structures. So maybe here we take a moment to discuss what treatment options are available for this patient.

Alicia Morgans: So I would say that this patient with some lymph node involvement and some bone involvement certainly is still the patient that I would want to use local radiation on. I did not see staging of the rest of the chest. Obviously, we were just focused down there, but I would want to make sure that we had complete staging of the chest to make sure that there were no other visceral metastases or other bone metastases or areas of concern that would really put that patient into a high volume status. But with those couple of bone lesions, just within the pelvis and those lymph nodes, this patient seems like a low-volume metastatic patient to me, and therefore, would be a good candidate for local radiation to the prostate.

In many cases, we do intensified systemic therapy in addition to that local radiation, even though the data does not yet support that approach, just given the lack of data, not that there's evidence of detriment there. So we would probably do a combination of an androgen deprivation therapy approach plus abiraterone in this case, plus radiation to the prostate, assuming that this patient does not have any evidence of having a high volume status. I would also say that just, in the interest of being complete, we would always want to make sure we had genetic testing on this patient as well as the last patient to make sure that we understood future options and implications for family members. 

Neal Shore: I might also add the discussion with the patient to absolutely combine ADT with an AR pathway inhibitor, whether it be abiraterone or enzalutamide, or apalutamide just for complete discussion of approved NCCN recommended therapies. I think ADT and docetaxel because this is low volume and because of the ease and convenience of oral therapy is the way that most of us have been going. What's interesting to me is what ... and Alicia nailed the concept here. This is arguably now a next-generation imaging, low volume disease, but it's not low volume disease as historically we saw in CHAARTED and STAMPEDE and TITAN and ARCHES.

So, what if there were now four or more bone lesions on the fluciclovine scan? So therefore now by number criteria, met high volume. Would that change your decision Alicia regarding radiating the prostate? I think I know where you're going to go with it, but I just think and this is a sort of ... not to misuse the word charted, but unchartered territory now, as to how we make decisions. So yeah, we're now low volume next-generation imaging to high volume next-generation imaging, and what are those implications?

Alicia Morgans: So that's such a great point and I always really try to stick to the data as the data exists, and the way that I would probably use the next-gen imaging in this setting, would be to talk with my radiology team, the nuc med team, and of course the team that's reading body, whoever's doing CTs and say, "look, in retrospect, if you're looking at those CTs, if you're looking at the bone scans, are there any subtle things there that you can see when you know what you see on your next-gen imaging that might upstage your conventional imaging?" And that I think is my attempt to make a crosswalk between our next generation or PET imaging and the conventional imaging where all the data was really defined.

That crosswalk is just my way of trying to make sure that I'm doing evidence-based care. And I would say it's interesting in many cases my radiology team will say, "Hey, when I look back, there are subtle things that I wouldn't necessarily call on a first pass, but yeah, I can see something there." And that would make me more comfortable, sort of making that patient high volume. If there was absolutely nothing there, I would have a frank conversation with the patient and say that we don't have perfect data. But in the breakdown on conventional imaging, there was a benefit to radiating low volume but not high volume disease in the STAMPEDE trial.

This is of course an area of active investigation with the ongoing SWOG study. So we may have more information, particularly if the investigators on that study are able to give us that crosswalk in a prospective study, maybe some of those patients will have PET imaging that we can really make those conclusions more clear in that study. But if that patient is high volume on a PSMA or Axumin scan, but low volume on conventional, I think that will be a discussion with the patient. And some patients might choose to radiate the prostate anyway, given the little morbidity in many cases.

And some patients may say no, for whatever those reasons might be. But I also then, of course, would use intensified systemic therapy no matter what. I'm usually more hesitant to use docetaxel unless that patient has clearly high volume on conventional imaging Neal.

Phillip Koo: Great, so Neal, I have a question for you, so we're talking about the scenario in which you actually get next-generation imaging. In this scenario at initial diagnosis, the Axumin label actually does ... It's a little generic, it's elevated PSA following prior therapy. Oftentimes the question these patients may not even get this type of scan. Would you even recommend it in your patients who come in with high-risk disease and negative conventional imaging?

Alicia Morgans: We have been. And many patients are getting them. Now, if they're high volume on conventional imaging, no, if they're very clearly low volume, that's a conversation with the patient, but it's interesting in our tumor boards more frequently, our urologists are encouraging us to push and to get that additional imaging. And I think sometimes in our group, the urologists are the cutting edge folks in terms of technology, and they're always thinking about it and they're always encouraging us. So I would say we as medical oncologists, at least in my little group, tend to be a little less aggressive in terms of that.

But we have been getting them more and more and they are coming into play. But again, if it's high volume on conventional, I wouldn't see a real need.

Neal Shore: Yeah. No, I would agree with the use of fluciclovine in a case like this absolutely. But honestly, Phil, I do think that if I was to have access to the market data, I would think that still the most common utilization for fluciclovine is in the biochemical relapse population, and less so on these arguably high-risk localized on conventional imaging, but I would agree that this is a very good use for it. It's interesting, right? Because, again this patient is at very high risk for having extraprostatic disease, and I guess one of the things I was thinking in Andrei's presentation is, what if there was two different variations of this case?

Where there was just extensive nodal disease, no bone disease, but just within the pelvis? Would that change the treatment consideration to just ... or maybe radiation and two years of ADT and not considering this necessarily, metastatic by some of the criteria that we had in the mCSPC trials and maybe not using combination therapy? Versus if that same patient, rather than having just intrapelvic nodal disease, had a few concerning nodes above the bifurcation, and maybe you try to biopsy them and they were negative, but they seemed to be consistent with extra pelvic nodal disease.

And so that puts you into the sort of ... again, classification conundrum is this low volume, but of course the just nodal only intra versus extra pelvic. So I think I would add that as a question for everyone's consideration.

Alicia Morgans:  These are the questions that we wrestle with in real clinical care. I think we tend in our group, to use more systemic treatment intensification adding that extra AR targeted agent in addition to radiation, even if it is only local pelvic metastatic disease. And there are those patients, we extrapolate a lot from the heterogeneous population that was enrolled in STAMPEDE. And because there were those patients who had some nodal involvement, at least clinical nodal involvement in STAMPEDE, we say to ourselves, "Hey, we can just do this intensification for a two-year period with radiation to the prostate and see if we can still get benefit."

But this is all a gray zone. And clearly, if it's outside of the pelvis, then that would be metastatic. And one other comment, and then of course, want to open to the floor that I would say is that, to Phil's question where I said we've been trying to get more of these PET images. We are sometimes denied getting those images because this is not a clear indication for insurance purposes and for coverage. And if we have conventional imaging showing metastatic disease, it is not uncommon for the insurance company to say, "I'm sorry, but no." And so that does come back at least 50% of the time, we're not able to get it. We think about it, but we can't always do it.

Andrei Iagaru: But we've shown the MR, the pelvic MR. And I know we're a MR-heavy institution, how frequently do you use prostate MR for these patients? And one can make the argument that in this case, sure, fluciclovine show that there's no disease beyond the pelvis, but why not do it as a PET-MR for example? And Phil, I know you're PET-MR friendly as well. So I'm bringing up PET-MR as one of the underutilized technologies, particularly in prostate cancer, which is very, very helpful and ...

Phillip Koo: My perspective on PET-MR is, access is very limited. And I still think ... obviously you're a leader in this space and we look forward to seeing more of that data. It's just challenging for us to even purchase that equipment, build a business case to operationalize it. But I agree, in many ways, it is the holy grail of PET imaging in prostate cancer, but just hard to make it work at the moment.

Alicia Morgans: I would agree, I would say it's of interest, but it's been challenging for us. As far as I know, we do not routinely have that. Although I think there is some interest in the research domain at my institution to do that.

Neal Shore: Similarly, we don't have access to PET-MR per se, but I've noticed that the very clear increasing trend Andrei of both our surgical preparation to almost invariably get MR for understanding anatomy and making attempts at neurovascular bundle sparing, et cetera, and how wide our margins are going to be. And then our radiation oncology colleagues in any high-risk to very high-risk cases, really wanting to understand what the anatomy looks like to better provide their planning as well. But I think, PET-MR is very exciting, but we currently don't have access.

Alicia Shore: MR is definitely being used though for surgical and radiation planning, just without the PET.

Andrei Iagaru: Okay. Now we are moving towards biochemical recurrence, which is the most common use of fluciclovine or Axumin. And this first case has a history of T3aN0M0, Gleason 3+4 initially treated with prostatectomy now with rising PSA. Currently 1.24. As we look at this projection image, we can already appreciate that there are some areas of abnormal uptake in the pelvis, which ones are prostate cancer recurrence versus something else. Let's see first by going through the slides. So, in this particular case, it turns out that there are pelvic lymph nodes in the right perirectal as well as the perirectal space.

These tiny lymph nodes that had focal uptake. So by location, by interpretation criteria, they're highly suspicious. And in addition to that, there is a bony metastasis as well as shown on the images on the bottom. So, Axumin being useful in this case in a patient with a relatively low PSA value by identifying nodal as well as bone metastasis. This case also illustrates a non-specific uptake of Axumin. In this case in the right inguinal lymph nodes, this uptake it's less intense. The lymph node has a fatty hilum and is not the most common site of recurrence for prostate cancer.

So, we need to be cautious in what we call a recurrent prostate cancer versus some other etiologies such as inflammation, which can have mild uptake on Axumin. The next case is pretty straightforward I would say. And you will see why I chose to show it. This patient has a history of pT2 clinical stage, Gleason 3+4 who receive radiation therapy, and clearly now is presenting with widespread nodal and bony metastasis. I'm using this case to illustrate the fact that one can use Axumin actually to document the response to treatment. In this case, the decision was made to treat the patient with Abiraterone and the patient was referred to see the response to treatment.

We saw PSA decreasing from 790 to 38. And I've seen that the fluciclovine scan on the right demonstrates that there is decrease in conspicuity and number and intensity of uptick in the known bone lesions. So imaging, correlating with the decline in PSA. So, I think that maybe here we can stop and discuss the use of fluciclovine in these biochemical recurrence settings.

Phillip Koo: Great. Thank you very much, Andrei. So just one comment, on case number three, you have that right inguinal lymph node, and you're absolutely right, it's non-specific. Oftentimes what we do see is we see these nodes mentioned, and oftentimes IR or the recommendation for biopsy is of the most easiest accessible node, which in this case probably wouldn't be where the money's at, which I think leads to some discordance between what the truth might be and what was actually sampled. And again, another reason why I think IR in those multi-D tumor boards is so important because that discussion helped the approach be where the money's at as opposed to something that is non-specific.

So, one question I'd like to start off with is, do you have a PSA level, below which you do not recommend fluciclovine, and then Neal from the urologist perspective, do you have a level of which you don't even bother ordering an Axumin?

Andrei Iagaru: I think that we need to be mindful of what's published data, and that shows that very low PSA value. So less than one, even less than 0.5, the chance of the Axumin being positive is actually quite low, by some papers about 30%. I think that we also need to be cognizant of this data coming from older studies, where there was no access to digital PET for example. In our experience looking back at Axumin scans [inaudible] the approval, our positivity rates are a little bit higher. And I've seen that it has to do with access to digital PET scanning technology.

That being said, I would not necessarily jump at the Axumin scan at a low PSA under 0.5 for example. I would go with PSMA, which has really great numbers in this quartile of PSA.

Neal Shore: Yeah, I appreciate the question. And so when the Axumin was first approved in 2016, it was the ... some would say the bright, new, shiny object that was going to give us better accuracy to conventional imaging. Patients were concerned. Why is my PSA going up? You removed my prostate and or you radiated my prostate and you're reaching a criteria, but usually, it was in the post-prostatectomy patients. And I had pretty unsatisfactory experiences overall with any PSA values of less than one. Interestingly I've even had it, some undetectable, negative findings in PSAs as high as eight.

And what's happened over the last year, again to Andrei's point is the excitement that's coming forward regarding PSMA-PET scans. Unfortunately, we don't have it, but I've made it very available at least in my discussion with patients to say, you can get it, there are several sites in the country that have PSMA-PET. And now as you said in the intro Phil, in December, the FDA approved two PSMA-PETs now at UCLA and UCSF. And we're on the cusp of getting the 18 FPYL approved this month. And for the last six months, I've been holding back, ordering Axumin scans, and having this discussion with my patients and saying that a more accurate PSMA-PET scanning is about to become accessible.

So that's the approach that I've been taking. And I know we're going to talk more about that. I think it's great for our ability to make therapeutic decisions. And I think this is really ... it's long overdue for accessibility in the U.S.

Phillip Koo: Yeah, I agree. Great comments. Alicia, in case number four, Andrei presented the use of an Axumin PET-CT in the setting of assessing treatment response. What are your thoughts on imaging and action and specifically in that treatment response setting?

Alicia Morgans: It was really neat and nice as a clinician to see the correlation between the imaging and the PSA. That is not something that we have done routinely or actually, I've never asked for that because I'm pretty certain it will be declined by insurance. And at this point, we still use conventional imaging and things that can be identified and measured on conventional imaging. And so I would do follow-up imaging, but it would be probably CT and bone scan. I do think that in the future, we'll be able to use these approaches and PET approaches, whatever that is, to understand disease response, and then potentially make decisions on that.

But at this point, it's not something we can do routinely. One of the bits of technology that I'm also looking forward to along those lines, when we're looking at response is using some of the AI algorithms that you may already be using to do a subtractive algorithm to understand which lesions precisely are decreasing in size, which ones are staying the same, and which might be growing. Because I think that the heterogeneity in prostate cancer, particularly when it's that widely metastatic, is what will ultimately help us understand which lesions we're not quite capturing with the current therapeutic approach.

And that is something as a person who uses systemic therapies to control disease, is really, really going to be interesting to me, where am I making progress and where am I not?

Phillip Koo: I think that's a great point Alicia, that heterogeneity piece and how imaging can help with that. Clearly, we know from the TheraP trial with FTG and PSMA, there's signal there that there's a lot of heterogeneity. With fluciclovine, I think we'll learn more, but I think it's an area that we need to dive into a little further. One point I'd like to reinforce is Andrei, your point about image quality I think is something that can't be overstated. Oftentimes we really commoditize imaging, which I think is absolutely wrong. The techniques, the protocols, the manner in which you conduct your imaging is just as important as the interpretation of the imaging.

And Andrei I think you really show that the value of having the technological piece, the hardware can make a big difference. Andrei, any last words in this BCR space or Axumin?

Andrei Iagaru: No, I think that everyone else brought up very important points. I will just add that I don't see that Axumin will completely go away, prostate cancer like every cancer is so complex that even an excellent tool like PSMA will have some false negatives. With Axumin there's little to no accumulation in the bladder. So, a recurrence in the prostate, but maybe sometimes easier to identify, and it's a different biological target. And so I hope that PSMA will contribute largely to the management of these patients, much more than Axumin does today, but I don't see that Axumin will completely go away.

We'll see a decline in numbers, but there will still remain a niche for it.

Neal Shore: So in this case that Andrei presented, and I agree with that type of PSA response and the patient presumably doing well clinically, I would not have gotten a repeat fluciclovine. And to Alicia's point, it is cool to see the incredible resolution of positive findings. But what if in that case, the PSA only declined by say 50% and the patient will oftentimes say, "Oh, that's great. I went from 700 to 350. That's a good sign, right doctor?" And we all know that that's not necessarily a good sign at all. And then you did that fluciclovine scan, and then instead of getting the result that you did, half of the lesions were still bright and positive.

How would that change your mind? And I think where I'm going with this is, maybe it's a segue to where the findings of if you ... in that patient and maybe you've had cases like it, you then obtained a PSMA-PET, to see if there were any additional information to guide treatment, specifically potentially theragnostics.

Andrei Iagaru: I see that that's a great point. I would even argue and Phil brought it up in the setting of the TheraP trial. For those cases, FDG may be helpful as well, because we may have really aggressive cancer that we may not be fully aware of. And FDG would be an excellent marker in that scenario.

Phillip Koo: And Neal to your point, it's great when the imaging confirms everything else that you're seeing, and when it doesn't that's what I think a lot of times all bets are off and it creates a lot of problems. And again, I don't think we could say it enough that this whole multi D discussion is critical. And I think in those cases, bringing that back to the tumor board and discussing what that means and what the next steps are, I think are really valuable.