PSMA PET for Primary Staging (high risk localized, N1, M1) - Thomas Hope, Bertrand Tombal, Nicola Fossati, and Robert Reiter

August 2, 2022

In this educational initiative, focusing on the knowledge of PSMA PET imaging and PSMA theranostics, Drs Thomas Hope, Nicola Fossati, Robert Reiter, and Bertrand Tombal discuss a series of five cases focusing on how PSMA-PET impacts the management of prostate cancer patients.

Independent Medical Education Initiative Supported by Novartis/Adacap and Point Biopharma


Thomas Hope, MD, Associate Professor, Vice Chair of Clinical Operations and Strategy in the Department of Radiology, Director of Molecular Therapy, Chief of Nuclear Medicine at the San Francisco VA Medical Center and chair of the Cancer Center’s Molecular Imaging & Radionuclide Therapy Site Committee.

Dr. med. Nicola Fossati, FEBU, Dept. of Urology, EOC - Ente Ospedaliero Cantonale, USI - Università della Svizzera Italiana, Lugano, Switzerland

Robert E. Reiter, MD, The Bing Professor of Urologic Oncology, Chief of the Division of Urologic Oncology, and Director of UCLA's prostate cancer program, Professor, Urology, Molecular Biology, Director of Urologic Research, and Co-Director of the Genitourinary Oncology Program in UCLA's Jonsson Cancer Center

Bertrand Tombal, MD, PhD, Bertrand Tombal is Chairman of the Department of Surgery and Professor of Urology at the Université catholique de Louvain (UCL), Cliniques universitaires Saint-Luc, Brussels, Belgium

Read the Full Video Transcript

Thomas Hope: Welcome. My name is Thomas Hope. I'm a nuclear medicine physician and radiologist at the University of California, San Francisco. This is the PSMA-PET Academy educational program. This session is the first in a series of case discussions about how PSMA-PET impacts the management of prostate cancer patients. Today, I'm joined with Nicola Fossati, Robert Reiter, and Bertrand Tombal, if you want to introduce yourselves briefly?

Nicola Fossati: Okay. Thank you for the introduction. My name is Nicola Fossati. I'm a urologist working in Lugano, Switzerland, at [inaudible 00:00:32]. We have our PSMA-PET CT available since approximately five years, and we are now running some studies comparing different traces combined with PSMA for the detection of nodal, bone and visceral metastases, and I'm happy to be here to join this discussion. Thank you.

Rob Reiter: I'm Rob Reiter. I'm a professor of urology and molecular biology at UCLA in Los Angeles, and I have about seven years of experience with PSMA imaging as part of a collaborative project between UCSF, led by Tom, as well as nuclear medicine and neurology at UCLA, that led to the first FDA approval of a PSMA-PET tracer in the US.

Bertrand Tombal: I'm Bertrand Tombal. I'm a urologist from Brussels, Belgium, and we have also a five year experience with at PET-PSMA when we transited from PET choline, and more recently from whole body MRI.

Thomas Hope: Okay. Let's get started with our cases here. Our first case is fairly straightforward. It's an inpatient at initial staging. He is clinical T1C, Gleason three plus three, six out of 12 cores with a PSA of 10.9. First I'll start with Dr. Fossati. How do you decide which patients at initial staging do or don't get PSMA-PETs?

Nicola Fossati: This is not the typical patient who would receive a PSMA-PET because this is not a high risk patient, according to the EAU and the NCCN guidelines. He's in favorable intermediate risk, so maybe in this case, as a first step, we, according to the guidance, we do not consider a PET CT with PSMA.

Thomas Hope: Great, so this patient actually ended up not getting a PSMA-PET and underwent a repeat biopsy under active surveillance, and his repeat biopsy ended up showing one core having Gleason four plus five equals nine, and another core with a three plus four equals seven. Dr. Reiter, how does this impact your decision for getting a PSMA-PET?

Rob Reiter: Yeah, this basically is one of the sweet spots for PSMA-PET, and it's in the guidelines, the NCCN guidelines that were recent recently released. A patient with high risk prostate cancer obviously has a significant risk of either nodal or distant metastasis, and so PSMA-PET would typically be ordered. At least, we'd try to get it ordered. We'd still have some issues with insurance payment in the US, but nevertheless, he is a good candidate for PSMA-PET.

Thomas Hope: Okay, great, so he undergoes a PSMA-PET after that repeat biopsy, and you can see here, this ended up being a PSMA-PET MRI, and it's actually interesting. You can see on the DCE, the dynamic contrast enhanced image, an enhancing mass that correlates with the PSMA-PET uptake, but you don't see much actually on the diffusion wave imaging. This would probably be a PI-RADS four, but upgraded from a three based on a positive DCE. Not the most impressive MRI images. The whole body image on the left there, the MIP, the anterior maximum intensity projection images, showed no evidence of nodal or distant metastases, so this was localized disease at initial staging. Maybe, Dr. Tombal, I'll move to you. How do these results change the way you would manage this patient?

Bertrand Tombal: By the time it's negative, it wouldn't change the management. I think that that's what we recommend to people. I mean, typically for that guy, we would discuss either a radical prostatectomy and an extended lymph node dissection, or radiotherapy on the prostate and lymph node, and, let's say, one and a half to three years of hormone therapy, and we do insist that, because it's negative, the sensitivity is not enough at this point in time, I believe, to rule out treating the lymph node. Today we can say that we would recommend PET-PSMA certainly, but a negative PET-PSMA don't change the management. Just of note, in Europe, we do less and less DCE with MRI or PET-MRI. We usually, because we can gain time and no injection. I mean, one injection, at least, so, but for that guy, I wouldn't change anything. I would stay on the same therapeutic plan.

Thomas Hope: Any comments from Nicola or Rob about the, particularly pelvic node dissection? I think there's a lot of debate about this, do you or do you not need a pelvic node dissection in a patient who's PSMA-PET negative? Do you both agree with Dr. Tombal?

Rob Reiter: Yeah, I mean, I'd say the standard of care still for surgeons is to do an extended pelvic lymph node dissection, but there are people talking about omitting it at the time of initial radical prostatectomy, and then consider going back and doing a salvage lymphadenectomy, if and when the patient progresses in lymph nodes, but as a standard of care I still do it, and we can debate the extent of it, but basically the standard extended pelvic lymph node dissection, and that's based on, as Bertrand said, the fact that about 20 to 30% of men with a negative PSMA-PET will still have positive nodes, and that of course can impact subsequent management.

Nicola Fossati: Yeah, and I would like also to add that lymphadenectomy is still considered a diagnostic procedure, not a therapeutic procedure, but on the other hand, the indication to perform or not perform lymphadenectomy should not be based only on PET-PSMA. This data should be integrated with the other clinical and pathological variables. There are nomograms and predictive tools available to integrate the lesion, PSA stage, and of course the result from PSMA, and based on this, we can decide whether performing or not, with lymphadenectomy. In this case, I would go for performing it, based on the high risk and the high Gleason of the patient.

Thomas Hope: Awesome. Okay, perfect. Let's move on to our next case. This is a patient, again, very similar initial staging. T2A, PSA 4.3, Gleason four plus four in a single core, out of the template biopsy. Then maybe, let's start again. Dr. Tombal, would you get a PSMA-PET in a patient who has these risk factors?

Bertrand Tombal: In Belgium, we are lucky enough to get reimbursement in high risk, so to be honest, we say high risk, and high risk, no. If we look at what we've done with all-body MRI before, the likelihood in of finding metastasis significantly increases when you have double criteria, so either one of PSA and Gleason, or T, but so for while we would limit to these two criteria. Now, to be honest, since it's being reimbursed in the very high risk, we usually take any high risk criteria, because I think that it makes things easier.

Thomas Hope: Sort of building on that, it's interesting. If you look at all of the prospective trials of PSMA-PET, primarily OSPREY, CONDOR, and then the UCSF-UCLA data, the UCSF-UCLA data did allow intermediate risk, but it was 90 plus percent high risk, and the DCFPYL papers are all high risk. They didn't even allow intermediate risk. Yet, the NCCN guidelines include unfavorable, intermediate risk into that. Rob, do you have any thoughts on that? How do you think about these intermediate patients in PSMA-PET?

Rob Reiter: Yeah, I mean, we do have nomograms that predict for lymph node positivity, so you certainly can resort to those, but I think if you look at most of the data out there, I think Bertrand's right. There's high risk, and then there's very high risk, and although we call four plus three unfavorable intermediate risk, it's clear that a significant percentage of those really probably have higher risk disease. If you look at even outcomes of radical prostatectomy, those patients behave more like Gleason eight than they do Gleason three plus four. As you know, in our study, we did allow for Gleason four plus three, but usually they had two criteria, four plus three with presence of intraductal or cribriform, or PSA greater than 10, or T3 disease, T3 appearing disease on MRI. Those would be the things that would lead me to order a PSMA-PET in those patients, but I agree with Bertrand. To make it simple, Gleason eight, even in a single core, we haven't seen the MRI yet. I'd probably order one if I could.

Thomas Hope: Great. All right, well, let's look at the PSMA-PET here. Now, this is a PSMA-PET MRI. What you can see on the top row here is a slice through the prostate, significant BPH, and there's a focal lesion here with actually what appears to be a little bit of extracapsular extension and focal PSMA avidity. Then there's also one left pelvic side wall lymph node with focal uptake as well, so you can see this patient ends up being N1 and has a very, very small primary tumor within the prostate gland. Okay. Now let's go back to the same old questions. Dr. Fossati, what do you do with a patient like this now? N1 disease, low volume in the primary tumor. How do you manage someone like this?

Nicola Fossati: Well, according to the guidance, this case is still suitable for a local treatment with, for example, surgery, radical prostatectomy, plus extended pelvic lymph node dissection, or radiation therapy with a field focused not only on the prostatic fossa, but extended also to the pelvic area, combined with ADT. What I would like to underline is that it could be a big mistake to focalize only on the positive spot in the nodes. This is true especially for the radiation treatment, because there is an increasing use of stereotactic body radiation therapy, SBRT, and we could think that there probably is only there, and stereotactic treatment could solve the problem. It's not like that, because we have evidence from extended lymph node dissections that the PSMA-PET is underestimating the tumor burden of the disease, so there is a high chance that if you do an extended lymphadenectomy there, you remove, for example, 30 nodes, and you find three or four positive, even if the PET-PSMA was positive only in one single spot. PET-PSMA could be very important for staging in a patient like this, but we also have to know exactly what to do then with these results, so I would consider, if fit for surgery, this patient suitable for radical prostatectomy and extended lymph node dissection.

Thomas Hope: Now, I will say, I'm on a call here with three urologists, and maybe I'll go to Dr. Tombal to try to address this, but how does nodal positivity on PSMA-PET impact your decision of radical prostatectomy versus radiation therapy, whether or not you do SBRT or whole pelvic node radiation, but does this impact that choice or does it not change anything?

Bertrand Tombal: No, not, and we are known to be a center that use a lot radiotherapy as well. In this specific patient, it wouldn't change. We would treat the prostate and the lymph node, probably, but as mentioned, as Nicola mentioned, radiation oncologists wouldn't be in favor of radiating just the lymph node, and I mean, surgically speaking, we are back to the previous discussion where standard of care would be an extended lymph node dissection. What would be more interesting is that, if there was no lymph node, because then maybe it would change the plan. We could go for brachy boost and radiotherapy to save some hormone therapy. We could think about more deviant approach, but here it still remains very standard.

Rob Reiter: Yeah, I guess I would add to that, there are two standard approaches and we don't really yet know how we should change management in the face of a positive PSMA-PET in a single lymph node or two lymph nodes. It clearly changes one's thinking, and I think we would probably all agree that the more lymph node positivity, the more likely we would be to not do surgery and recommend radiation and ADT, including to the lymph nodes. In a case like this with a single lymph node, I think surgery is reasonable. If one has available the opportunity to do radio-guided surgery such as they're doing in Germany and we've been doing here now for a while, that certainly can probably help to detect the positive lymph node during surgery to make sure you got it, but again, the long term outcomes of that are simply not known.

Bertrand Tombal: You want to be sure at least that you get that lymph node, because it's quite posterior already. You want to be sure that you don't end up not having the lymph node in your lymph node dissection, which happens from time to time. This is where here really this technique of radio-guided surgery may help, because at least you're sure that you took it out.

Thomas Hope: That's a good point.

Rob Reiter: It can actually detect more nodes that are not positive by PSMA-PET, probably smaller than the size limit that's detectable by PET. We've had a number of patients where radio-guided surgery has detected additional lymph nodes, and in one case we actually aborted the surgery, because it was clear the lymph nodes were extending up into the retroperitoneum.

Thomas Hope: I mean, I'm assuming that once you start having PSMA ... Getting smaller and smaller nodes with radio-guided surgery, do you think you're changing the outcome in those patients by seeing these PSMA negative disease, by going after them in that way, or what's the goal of doing that?

Rob Reiter: Yeah. I mean, I think it's ... Oh, sorry about that. It's the same as with radiation with SBRT to oligometastatic disease. One goal is to delay ADT. That's certainly been an endpoint for some trials. One is to just delay progression in general. Probably about 20% really get a very, very good response or even a permanent response, but I think that's yet to be answered.

Bertrand Tombal: When we started discussing, when I was a resident, I mean, a single lymph node like this, we would have aborted surgery. We would have said, "That guy is metastatic, we don't do surgery at all." Think where we are 20 years later, where we recommend local treatment in a metastatic patient, low volume. Basically, there are two questions. Is it enough to omit local treatment? Certainly not. Second, is there a reason to change our practice on the lymph node dissection? As Nicola mentioned, with all the trials we've been doing, we've shown that it's diagnostic. It's not yet proven to be absolutely curative, so still we would get it and decide on what next based on the extent of the pathology.

Thomas Hope: There's one other thing about this case which is interesting, which is that this patient has bilateral hip implants, right? If this patient, if I were to have shown you the diffusion weight imaging, it would've been non-diagnostic and not helpful, and I'm sure, hopefully you're all familiar with the results of the PRIMARY trial, a really beautifully done study out of Australia comparing multi-parametric MRI to PSMA-PET. I want to see what your thoughts are on PSMA-PET in place of MRI, particularly maybe in patients like this who have bilateral hip implants. Obviously not in the NCCN guidelines, but maybe Dr. Fossati, if you had any thoughts on that. Have you ever started considering using it prior to biopsy or even to stage patients at risk?

Nicola Fossati: Well, this is an interesting topic and I think in the future will become even more important. I think that so far, it's not part of the standard of care and we will see how many centers will be able to combine MRI and PET, maybe for biopsy. I think that for the next two, three years, this will be only experimental in some studies, and then we will see what happens in the future.

Rob Reiter: Yeah, Tom, yeah, the PRIMARY trial's great. We just published a paper correlating MRI with whole mounts compared to whole mounts and PSMA, and basically, at least in higher risk disease, didn't really show that PSMA-PET added much, that MRI was probably a little bit better for spatial localization, at least of the main index tumor, and that PSMA didn't add a whole lot to it, but there are anecdotes, of course, when MRI is negative and PSMA-PET is positive, and you can do a PSMA targeted biopsy, and there are anecdotes visa versa. I think right now, I don't think it adds too much for the average patient.

Bertrand Tombal: This guy is a very illustrative because he's got a very large BPH, and he's got very heterogeneous BPH. What we started to see is that, here I have one of my colleagues from the hospital with a prostate of 264 CC, huge BPH, elevated PSA. We did several MRIs, all considered negative. Then we did a PET-PSMA, because a spot just in the middle of the BPH. I think that this is a typical case where we may have missed something, because he's got that kind of absolutely typical chaotic BPH in the center, so I think that once again, it's not going to replace everything, but there's going to be an indication where it's going to be really helpful when MRI has not really contributed. As to replace it upfront, it will be a cost issue, at least in Europe.

Thomas Hope: Yeah, no, I wanted to bring it up as a discussion point. Clearly we're not ready for it yet, but I think it'll be interesting to see if PSMA pet has a role to move up a little bit, but in a patient like this with hip implants, MRI is going to struggle, so maybe this type of weird case, that it might be helpful, but right now we're still in the anecdote realm. Hopefully the PRIMARY-2 trial will maybe give us some more information on that. Okay, let's move on to our next case. This is another patient, similar history, T3B, Gleason four plus four, PSA 9.3, I think a little more classic patient you'd definitely order PSMA-PET on. Here is the conventional imaging, so MRI was done initially. You can see low signal intensity on the ADC, high signal intensity on the calculated B-1600, PI-RADS five lesion. Bone scan was negative, CT chest and and pelvis negative. First question is, this conventional imaging issue. Do we use conventional imaging still? What patients do you get them in? What's the role of bone scan in patients with prostate cancer? Maybe, Bertrand, do you want to go with that first?

Bertrand Tombal: I mean, to be honest, there's no role of bone scan, unless you've got a patient which has multiple bone metastases and you want to have more information on, who needs local treatment, but to be honest, it was asked at the APCCC, and most people who did PSMA did PSMA as a primary, because you've got your CT. If you've got any doubt on anything, you can ask the CT to be injected as well, and then the bone scan, it's an exam from the past. Why would you still use bone scan? I mean, now we have to fill a special request if we want a bone scan in a patient who had a PET-PSMA, so honestly, I think that for this high risk patient, my personal opinion is that at first stage, it can be skipped, and we only do PET-PSMA and then we see. If the PET-PSMA showed multiple bone metastases, which is unlikely in a patient like this, we still believe in the low-high volume to decide on local treatment. Then we're going to order a bone scan, but not for everybody.

Thomas Hope: Rob, do you have a follow-up on that?

Rob Reiter: Yeah, I mean, I agree. I haven't ordered a bone scan in years and years and years, and I think the data out of Australia and some of our retrospective data and others basically does not support the use of conventional imaging. You get a CT scan, and CTs have never been terribly useful, but you get a CT when you get a PSMA-PET scan anyway, so.

Thomas Hope: Okay, so conventional imaging is gone, at least in the castration sensitive setting. I think in the CRPC setting, it's a little more of a difficult conversation, but we'll skip that for today's conversation. Okay, so this patient went on and got a PSMA-PET, and you can see here, the patient has ... Down in the prostate, he's got definitely uptake in the prostate, and then there's two lesions in the bones, one in the right sacrum here, and then one in the upper thoracic spine, consistent with two small osseous metastases. Remember, this is a patient who hasn't had any definitive therapy with what looks appears to be two small osseous metastases. Bertrand, or actually, Nicola, do you have ... How would you handle this, if this patient came through after getting a PSMA-PET?

Bertrand Tombal: First, at the present time, we are lucky to be working with very good musculoskeletal radiologists, and we want to be sure it's really metastasis, okay, because we had some ... It would not be rare that we would order a simple spine MRI, which in Europe is very clear, to be sure it's metastasis. Now, to be honest, in the beginning ... I mean, our nuclear medicine, nuclear physicians are getting better and better at adjudicating this upfront, so I guess when you work with training people, with well-trained people, the need decreases, but it still may be a false positive. Assuming we come forth with another technique, that these two small bones are indeed bone metastasis, then we would probably, at least in Europe now, treat this as a low volume metastatic prostate cancer. We would not operate, usually, we would recommend surgery. We would probably go for two years of combined hormone therapy and recommend stereotactic radiotherapy on the ... I don't know the age of the patient, but he looks fit, so we would go for a triplet treatment recommending ADT or a pathway inhibitor for two years, local treatment of the primary, and metastatic targeted therapy, recognizing that the level of evidence is low, but we have indirect evidence and we would speak with the patient and recommend that.

Nicola Fossati: This is the typical case where we CM0 conventional imaging, CM1 molecular imaging, so I think that here, we are in a gray area where we will need to solve this issue in the future, because we have lot of new drugs tested and approved in the setting of newly diagnosed metastatic disease, but with the conventional imaging, not with the molecular imaging. We are in a field where we are not so allowed to use these new drugs, and on the other hand, we don't know if we are really speaking about, talking about metastatic patients. There are a lot of colleagues also discussing and asking for bone biopsy in these cases, without any evidence supporting the use of bone biopsy, but in case of conventional imaging and MRI negative on the bones and PSMA positive, we are really in a difficult situation. I think this is a typical case that a few years ago, everyone would have treated with the surgery or radiation therapy without any problems, because it is considered non-metastatic. Now we are improving our diagnostic tools with imaging like PSMA, and I think that the solution in the future would be to integrate the PET-PSMA in the TNM staging, considering so the results of the PET CT for the C and the M staging of these patients. I don't know what to think about this.

Rob Reiter: I would honestly argue against doing a bone biopsy. We got pretty good at doing them, but in all honesty, these lesions are in typical places for prostate cancer. I'd imagine the SUVs on these are actually fairly high, that there's probably not a lot ... There's probably almost no chance that these are actually false positives. I would probably omit that and assume that they are real. If you had something in the rib or if you had very low SUVs, I think that's where there's increasing difficulty as more radiologists are reading these and not kind of expert nuclear medicine docs. I would probably, honestly, like Bertrand, I would manage this as a low volume metastatic castration sensitive prostate cancer, and the only difference is we would probably do SBRT to those two lesions in addition to kind of standard radiation of your choice and two years of abi or enza or one of those. We generally can get that approved because we can kind of call it metastatic, so we've been successful doing that. Surgery would be rare. Somebody who had really terrible lower urinary tract symptoms and was not a great candidate for primary radiation, one could imagine radiating those two sites in bone plus ADT and surgery for the primary, but that would be the exception.

Bertrand Tombal: I think that the combination therapy discussion, M-plus versus M0, has really taken a different twist with the STAMPEDE M0 arm. Maybe that's why I'm biased, because I've been the chair of the IDMC of that trial for more than 10 years, and see, actually, there was a lot of advertisement about abiraterone in metastatic, because it was driven by the market authorization, but from scratch already, three, four years ago, if you look at the benefit you have with two years of ADT plus abiraterone, in very high risk patients for which I guess 30% would show similar PSMA result, you've got a 50% improvement. You double the improvement from the [inaudible 00:27:42] trial, and that's why I think that the rational ... To me, the only thing that we have to be honest has not been demonstrated yet is the SBRT, that we would recommend, but for the combined ADT, we have enough argument, I guess, from the STAMPEDE M0, and soon we're going to get ATLAS, we're going to get ENZARAD, so I think that the day the standard management of high risk M0 becomes ADT plus two years of any of the pathway inhibitors, then the discussion will be super simplified, and the only remaining discussion will be, do you give SBRT to these lesions or not?

Rob Reiter: Totally agree.

Thomas Hope: That was a great discussion. Okay, let's move on to our fourth case. We're going to move from initial staging to biochemical recurrence. This is a patient who was treated 10 years ago with HDR breaking therapy to the prostate, and he had biochemical recurrence. He nadired actually at a PSA of 4.2 seven years ago, and you can tell, so over seven years it's slowly been rising and now it's at 8.3, and he has the following PSMA-PET. In essence, he has a little bit, on the right one, right column here, you can see some local recurrence right at the apex anterior, and then he has two other pelvic nodes, one in the obturator foramen, which is a place we're seeing more of these recurrences now that we have PSMA-PET, and then a left pelvic side wall node here that's fairly juicy. How would we go about treating this? Maybe Nicola, if you wanted to go first, and what's your thought process on what to do with this patient?

Nicola Fossati: Well, I think that a lot of variables need to be integrated in this case. First of all, age of the patient, and then comorbidities, to understand whether we would like to consider a local salvage treatment, a yes or no. In that case, I think we need to perform a biopsy to the prostate to confirm the local recurrence and to also justify a local salvage treatment that we know is associated with a lot of comorbidities. Then, in case we consider a local salvage treatment, I think that surgery plus lymphadenectomy is the only option, because this was already radiated with brachy therapy. Well, a second irradiation is not impossible, but of course, it's associated with a certain amount of morbidities. On the other hand, I think that we can also consider systemic treatment, and in this case, the association of ADT with other drugs is based also on other variables such as PSA doubling time. That is another important prognostic factor. So I think it's a case that need to be integrated with a lot of variables and depends patient by patient. What do you think also, on this case?

Rob Reiter: Yeah, no, I would agree with Nicola. I think there are a lot of variables. I mean, he's got at least nodal disease, metastatic disease. He never really nadired, even after his HDR brachy therapy, but his age, comorbidities, local salvage plus treatment of the oligometastatic disease, I mean, there's not a whole lot of data for it. What local salvage you would use, surgery of course we all know has its ... It's certainly technically doable. We do plenty of them, but risk of incontinence is quite significant. One could do HIFU or cryo, but it would need to be whole gland for this type of recurrence. It doesn't have negligible side effects to that, either, and given the fact that there are two nodes, what benefit there would be to that local salvage is pretty unclear to me.

I mean, I would start with the inclination really to manage this patient as a patient who's got more advanced disease with systemic therapy. One could do SBRT to the nodes, but without treating the primary, it doesn't make a whole lot of sense. I agree with Nicole, it's a bit of a complicated case in terms of what's the correct way to manage, and how aggressive one wants to be, but we have great systemic therapies. If he's a bit older, 75, let's say, or something like that, his PSA doubling time appears to be quite slow. I would be try to be less aggressive, not more.

Bertrand Tombal: I would say, first, he's a slow progressor, okay, because he doubled his PSA in seven years. Second, it's an HDR 10 years ago, so there is a high likelihood that he was not irradiated well at the apex, which is one of the problems of HDR. Probably, so I would like to see the MRI on the apex to see if we see where is the recurrence, although we know that it may be imprecise, but honestly for a guy like this, assuming the guy is young and fit, we would probably recommend the stereotactic radiation therapy on the apex and the lymph nodes and the bone. If we cannot treat the primary, then we would not do that because it has no meaning, but once again, it's a discussion with the patient to one extent, but at least, the big difference between now and five years ago is that we know where it is, so we can discuss with the patient the option of being maximized.

If we are maximum, that's going to do a lot of side effects, but it's up to the patient to decide. On top of that, I think that if you remove the prostate, you can do a cystectomy, because look at this. It doesn't seem to have a very nice bladder function, so I know some centers in Germany, they would get for a cystectomy, an extensive lymph node dissection, and a radiotherapy on the bone. Everything is possible in that guy, and of note, it shows clearly the benefit of the MRI. That's what I was mentioning earlier on that. The MRI is a good semantic for the bone. That's clearly a big metastasis.

Thomas Hope: Great. Okay. Well, I think the take-home from that is, there's a lot of ways to treat this patient and we don't yet know the right way to do it, but it's interesting to me, the last patient versus this patient, the difference in terms of ADT-abi, adding into this versus just doing SBRT, and how that varies as we go between what's M versus N across these patients. Let's go to our last case and we'll wrap it up. This is a patient who had a radical prostatectomy two years ago, and his PSA has risen to 10. I can't remember. He had biochemical persistence, which I think was about a four after radical prostatectomy, and actually was lost to follow-up, so came back after radical prostatectomy. Two years later, PSA is now 10, and you can see on his PSMA-PET, he has a couple of findings.

First, on the middle column, you can see he has a left external iliac lymph node that's PSMA positive. He also has a small sub-centimeter retroperitoneal lymphadenopathy that's PSMA avid, so low volume disease, but then also, if you note up in the chest, he has some very low avidity PSMA disease just around the aortic arch, right there, very difficult. You're not going to be able to put a needle in that, so I think to a certain extent, you just have to trust the imaging. How would you think about treating this patient in the setting of what now is M1 disease? Maybe we'll start with Dr. Reiter this time.

Rob Reiter: I think this is probably one of the simpler cases you've given us. I treat him systemically with some type of LHRH agonist or antagonist together with some type of second generation anti-androgen or abiraterone. I don't think I would be going after any of these nodes. I know we've got radiation therapists who will kind of go after everything, but I think that there's very likely to be no benefit to that. I'm sure he has more disease than we're seeing, as we discussed earlier. I would manage him as somebody who has got metastatic castration sensitive disease, even though it's, I guess you could ... I'm not even sure you'd call that oligometastatic, because he's got at least three or four positive sites.

Thomas Hope: Dr. Fossati, let's say that the chest disease wasn't there and it was just retroperitoneal, aortic, and left pelvic side. Does that change the way you would manage the patient or are they still M1, therefore ADT plus androgen targeted therapy?

Nicola Fossati: Well, we have evidence from the largest series of patients treated with the salvage lymph node dissection that when you take out the nodes, especially when there are positive spots in the retroperitoneum, you find more positive node probably for micro-metastasis that we are still not able to detect, even with PSMA. Yeah, even without the chest metastasis, I would consider this patient as an M1, and I would not consider this patient for a salvage treatment because of the involvement of the retroperitoneum. We have some studies evaluating the optimal candidates for salvage treatments, such as salvage lymph node dissection, or salvage radiation therapy, extended to the lymph node area. These patients are those with positive uptakes in the pelvis, not in the retroperitoneum. Yeah, again, I would consider this patient as metastatic as well.

Thomas Hope: Great. Okay, Dr. Tombal, do you have any closing comments on this case before we wrap it up? I think [inaudible 00:38:19].

Bertrand Tombal: No, we're just waiting for the result of the EMBARK trial for this patient, to know exactly if we can use anti-androgen monotherapy, ADT monotherapy, or combined treatment, so that's going to be very exciting.

Thomas Hope: Yeah. Do you know when that's supposed to read out?

Bertrand Tombal: No.

Thomas Hope: No. Okay. Sometimes soon, hopefully. Okay, great. Well, I think that is all the cases I had. I thank the three of you for participating. I thought it was educational for myself and hopefully the people who watch this enjoy it, and that's a wrap.