BackTable Urology
Ep. 206 Biochemical Recurrence: Insights from AUA/ASTRO/SUO Guidelines with Dr. Todd Morgan
Tue, 17 Dec 2024
Have you checked out the AUA/ASTRO/SUO’s recently released guidelines for salvage therapy in prostate cancer biochemical recurrence? In this episode of the BackTable Urology Podcast, guest Dr. Todd Morgan from the University of Michigan and host Dr. Aditya Bagrodia continue with part two of our series on prostate cancer biochemical recurrence management. --- This podcast is supported by: Veracyte https://www.veracyte.com/decipher --- SYNPOSIS The doctors focus on the difficulty in declaring a patient 'cured' and the implications of biochemical recurrence after treatment. Dr. Morgan highlights the importance of PSA in the postoperative setting and explores the role of the Decipher Prostate Genomic Classifier in personalizing treatment. He talks through the latest AUA/ASTRO/SUO consensus on biochemical recurrence guidelines, including the significance of early salvage therapy and the integration of advanced imaging techniques like PSMA PET scans. Further, Dr. Morgan emphasizes the role for multidisciplinary evaluation, patient counseling, and future directions of research to refine treatment options. This discussion underscores the transition from adjuvant to early salvage radiation as a standard practice and considers emerging biomarker strategies to inform treatment decisions. --- TIMESTAMPS 00:00 - Introduction 03:41 - Consensus Biochemical Recurrence Guidelines 08:56 - Evolution of Post-Prostatectomy Biochemical Recurrence Management 13:24 - Patient Counseling and Risk of Recurrence 17:42 - PSMA PET Scans 20:44 - Postoperative PSA Monitoring 28:35 - The Role of Radiation 31:56 - Hormone Therapy 39:00 - Salvage Lymphadenectomy 46:30 - Future Directions and Concluding Thoughts --- RESOURCES Veracyte https://www.veracyte.com/ Salvage Therapy for Prostate Cancer: AUA/ASTRO/SUO Guideline (2024) https://www.auanet.org/guidelines-and-quality/guidelines/salvage-therapy-for-prostate-cancer
This week on the Backtable Podcast.
Cure is a term that we just like all of us oncologists just really have a hard time saying because pretty much everybody with a history of cancer, of any kind of cancer, has some risk of that cancer coming back. And that risk may be really, really, really low so that we kind of in lay terms use words like cure, but
Really, we tend to rely on a little bit more technical things, which sound awkward, like no evidence of disease. And basically, if we're getting two years, three years, four years out, and no evidence of recurrence, no evidence of disease, we're feeling really, really good, really optimistic.
And often, even times after surgery, when the pathology looks really encouraging, we're feeling really optimistic. And by the way, good news, we have this test, PSA, which is... despite all of its flaws in the screening setting, is an unbelievable biomarker in the post-operative setting.
Hello, everyone, and welcome back to the Backtable podcast, your source for all things urology. You can find all previous episodes of our podcast on Apple, Spotify, and at backtable.com. Now, a quick word from our sponsor. This discussion is brought to you by VeriCyte, provider of the Decipher Prostate Genomic Classifier.
Decipher Prostate is a test for patients with localized prostate cancer that can help personalize treatment. Every patient and their prostate cancer is unique, and Decipher Prostate can provide meaningful insight into the aggressiveness of each individual patient's tumor.
Because the Decipher score is derived solely from the genomic characteristics of the tumor, it provides information not available through already known clinical and pathologic factors. Decipher high-risk patients generally benefit from earlier or intensified treatment, while Decipher low-risk patients may be ideal candidates for monitoring or less overall treatment.
Decipher Prostate is the most validated gene expression test in localized prostate cancer with level one evidence in national clinical practice guidelines and more than 70 peer reviewed publications, including more than 65,000 patients. Visit Verisight.com slash Decipher to learn more. Now back to the show.
This is Aditya Bagrodia as your host this week, and I'm very excited to introduce back to the show Todd Morgan from University of Michigan, where he heads up the urologic oncology section. Todd, how's it going today?
Hey, Aditya. So awesome to be here. Thank you. Thank you. Thank you.
Well, thank you, Todd. Your previous episode on germline testing is still one of my favorites. We actually just published a paper on ordering TENS in men with high-risk prostate cancer. Much of that was inspired by our conversation.
Oh, wait, wait. So tell me about that. I missed it. Where is it published?
So it's in urologic oncology. And, you know, long and short of it, we got our hands on the Invitae database and indication, who's ordering tests, med-onics, radonics, medical geneticists, and, you know, kind of looked at things over the last... five or seven years. And as maybe would be expected, urologists are getting more familiar with testing.
And especially as, you know, the NCCN guidelines has advised for high-risk localized prostate cancer patients to get tested. We're doing more of it, helping out our colleagues kind of down the pike, so to speak. So check it out if you haven't got a chance.
That's awesome. That's a great idea for a study. Really, really good. I can't wait to see it.
Perfect. So today, you know, it really is an honor, Todd. You had the distinct pleasure, I would imagine, of kind of spearheading the AUA-ASTRO consensus, SUO consensus on biochemical recurrence guidelines. And maybe just talk a little bit about that process. I mean, it's a big deal, right? We're like, we want to get in the guidelines, we want to get it paid for. And here's the guidelines.
Yeah, it's awesome. I mean, pretty amazingly early in my career, I think, thanks to some phenomenal mentors that I've had, I had the opportunity to participate in some different AUA and ASCO guideline panels and NCCN. And I, you know, surprised how much I enjoy that process, you know. It is meaningful.
It's like the ultimate, in some ways, of implementation of all the different things that we think about and write about. It's just being part of these multidisciplinary teams, thinking about everybody's different expertise that they bring to the table and learning from them, and then trying to distill
all the science that's produced in some really high-level science and some of the, you know, retrospective work that we all do to, you know, make the best data out of, you know, out of problems where we don't have those RCTs. And so distilling that down to something that's meaningful in the clinic, it's a great process and it's really interesting and fun to be a part of that.
And so when I got the opportunity, you know, AOA reached out and said, hey, we're planning on this project. This guideline, we think the time is right for this. And would you be interested in leaving it? That's, you know, you jump at that opportunity. It was that that was one of those that took me 30 seconds to respond to.
Well, that's super cool. And this is the first BCR salvage therapy guideline, right? This is not a iteration or update. This is this is a tabula rasa.
It totally, yep. So there was a prior adjuvant radiation guideline from about 10 years ago. And that was a great guideline. And we can talk more about, you know, where the field was and where it's gone. But this was intended to be totally different, started from scratch.
And, you know, when you would ask kind of about the, just the process, it's funny because it's an AUA guideline, but really the urologists make up a minority of the members on this committee, and that's for a good reason. I mean, it's AUA plus Astro and SUO, but, you know, who has expertise in this space? Sure, we do as urologists, but also radiation oncologists.
And so my co-chair was Ron Chen, who's just phenomenal, you know, just an amazing radiation oncologist and just such a clear thinker and so knowledgeable. And we had, you know, medical oncologists and patient advocate, nuclear medicine experts. So again, really, really multidisciplinary, and that's fundamental to this space because this is our space, but... is not only our space.
Radiation oncologists have such a huge leadership role in this space, medical oncologists, and all of those collaborations, radiologists are really important. And we really, as we went through the process, we really tried to listen to each other, learn from each other. And I think that that led to a guideline that I'm really proud of.
It's awesome. It's super helpful. And, you know, I kind of half the time feel like guidelines are so vague, they're just like completely useless. But this one I thought was really, really tremendous, Todd. And I'm not just saying that. I've been fortunate to sit on a couple guidelines committee, and I feel like I'm the lucky guy that gets to fine tooth comb like an already like amazing document.
And my contributions are usually fairly incremental, I would say.
I'm sure that's laughable, but okay, fine. No chance of that. No chance of that.
Did you put the pen to the paper? I mean, like, here's the draft, send it out.
We started with a number of us really honing in on what are the key questions that we want to address, kind of the pie in the sky. And the AUA has a really great process, and it's unique to the AUA, different from, you know, NCCN, for example, where the AUA has a methodologist. And it's really intended to lock us in on the best evidence that supports the questions we're trying to answer.
And so when the methodology review happens out of OHSU, when the methodology review happens, that we kind of end up with some of those questions that we want to address. We just don't have data for. And we have to be realistic about that and say, OK, well, there are some things we're going to have to put a pin in for, you know, future revision or update to the guideline.
But we can't actually, with evidence, comment on that. So that actually happens really before we get started. We develop the questions. There's the methodology review. Then we start to get together as a group and start meeting. And then we divvy up basically subcommittees with questions.
sets of questions, key areas that we say, okay, let's propose some initial guidelines to, you know, answering those questions based on the evidence that we're looking at. And so, you know, it's really iterative on that. So the committees meet, propose guidelines. We meet again as a group.
We keep hammering away until we have this, you know, set of 30 or so statements that we feel really comfortable with. And then we all do the writing. And so that's divvied up by everybody. And the AUA is a huge, huge help behind the scenes. You know, helping keep us on track, helping with writing, you know, parts of the methodology. And so it's a team game, big time.
Awesome, man. Well, let's jump into it. And before we started recording, I'd asked when you kind of came through and finished up, and I think we're roughly in the same vintage. And my opinion is it's been a very exciting time with, you know, tremendous advancements in our understanding, diagnostics, et cetera. And maybe I'll ask you, Todd, to take a walk down memory lane and
Even back to trainee, you know, how you thought about post-prostatectomy, biochemical recurrence to now. And that's a huge question. So, you know, don't overthink it.
It was really hammered into us early on based on multiple different trials, including the Key Swag trial, that adjuvant radiation was really important for patients at high risk of local recurrence. You know, that was like, you find that on board exams, on early OCAD exams, I'm sure, patients with, you know, to repeat the PT3 disease or patients with positive margin, right?
These are patients who were guidelines said strongly consider, I forget the exact statement, but really like these are patients that should see radiation oncology for consideration of adjuvant radiation, of course, meaning in the absence of any evidence of biochemical recurrence. And that was hammered into us for years based on, again, very, very reasonable, excellent, high-level data.
And yet, when you look at the utilization of adjuvant radiation for those patients over the years, and there are lots of different studies that have looked at that, including we've looked at this in MUSIC, the Michigan Urological Surgery Improvement Collaborative, and said, okay, of those patients,
who are recommended according to guidelines to strongly consider adjuvant radiation, how many actually get it? And the answer in every study is like 5% to 10%. So basically, nobody was actually getting adjuvant radiation. I'm sure more patients than that were seeing radiation oncology. Patients were opting against it. Docs were opting not to refer or docs were opting not to recommend.
So we had this recommendation that really ultimately wasn't being followed. And Bring that forward to the present day where we have new key trials we've been talking about for years. When's Radical's going to report? When's Rave's going to report?
Asking the question that we all want to know, I've always wanted to know, which is, okay, like, we know adjuvant works better than, you know, waiting a million years to actually give the salvage radiation. We're never giving salvage radiation, but it's adjuvant radiation better than early salvage radiation for patients who are at high risk of recurrence. And
And the answer is no, as far as we can tell. Now, you know, we can talk about, you know, maybe carve-outs for patients at really high risk of recurrence who maybe were undersampled in these studies. But really, you know, waiting until biochemical recurrence is totally appropriate, saves a ton of patients from unnecessary salvage treatment. And so that's where the field has moved, right?
Totally. And, you know, if I may, like early on, like as like a resident, like seeing somebody in clinic who had like a biochemical recurrence, I was like so freaked out. I was like, this is like nothing could be worse. Like it dreaded the conversation. It was just like, so you felt like the patients are just... living and dying by those PSAs. And, you know, I imagine it was somewhat similar.
This is in an era to sound like a dinosaur where, you know, certainly everybody with grade group two disease got treated, still plenty of prostatectomies for grade group one disease. So there's probably been a shift in biology. But, you know, Bogrodia circa 2010 was freaked out. Then Bogrodia was more like, okay, everything's going to be okay.
And now, 10 years into practice-ish, the people that we're operating on are such higher risk, generally speaking, that I might be coming full circle to...
semi not freaked out but you know biochemical occurrences aren't just like oh this is nothing don't sweat so and yes you know of course adjuvant for all practical purposes outside of like you know maybe young node positive particularly offensive scenarios as as fallen by the wayside So I think a lot of this, this kind of resonates what you're saying and well, let's, let's jump into it.
I mean, first things first, when you're sitting down talking about surgery with the patient, did you bring this up or, or what's your kind of style on this Todd?
Yeah, stylistically, I think it comes up a lot pre-op. It should come up a lot during that initial consultation, but certainly not every time. I think we talk about risk of recurrence, right? So we get to go through the whole discussion, surgery versus radiation for the patient who's thinking about surgery. We talk about all the usual quality of life risks, surgical expectations.
And then we do really try to address what I think is a common misunderstanding that Once the prostate is out, the patient is guaranteed to never recur. And patients, I think, are often surprised. What do you mean? I thought if the prostate's gone, how can I get it again? And why are you checking my PSA? Or why would you check my PSA after surgery?
And so it's much easier to address that beforehand than after the fact. Of course, not every single thing that we talk about at that initial visit is retained. That's impossible. But floating that is really helpful. I think I'd at least get to that point for every patient. Do I talk about, okay, now what happens if we hit that fork in the road?
I think I really make sure I address that with the higher risk patients, right? Patients with higher risk disease, where really that initial discussion is about
You know, we have option A, which is surgery with a distinct possibility, oftentimes greater than 50% possibility of undergoing additional treatment, likely to include radiation plus hormone therapy, or option B, which is radiation hormone therapy from the get-go.
And we talk about the pros and cons of each approach, but really ensuring that patients do understand that surgery is not a guaranteed one and done is important.
And when you talk to patients on the front end and you're talking about the efficacy, do you use words like cure just out of curiosity or, you know, what do you actually say to the patient?
Yeah, like never. And so patients, I'm sure you have this experience too, or say, well, so then will I be cured or am I cured? And I just, I always say, and I say, you know, cure is a term that we just like all of us oncologists just really have a hard time saying, because pretty much everybody with a history of cancer has, of any kind of cancer, has some risk of that cancer coming back.
And that risk may be really, really, really low so that we kind of in lay terms use words like cure, but Really, we tend to rely on a little bit more technical things, which sound awkward, like no evidence of disease. And basically, if we're getting two years, three years, four years out, and no evidence of recurrence, no evidence of disease, we're feeling really, really good, really optimistic.
And often, even times after surgery, when the pathology looks really encouraging, we're feeling really optimistic. And by the way, good news, we have this test PSA, which is despite all of its flaws in the screening setting, is an unbelievable biomarker in the post-operative setting.
Yeah, no, spot on. I mean, like for one of the areas that I have some interest in is testis cancer, and it's kind of nice. You can tell a patient, you know, two years into a pretty good deep sigh of relief and, you know, 95% of recurrences will come in.
And, you know, I think once you get to that four or five-year mark, as you alluded to, that conditional risk of relapse decreases, the risk of dangerous relapse decreases. But I always feel it's tough, right? Because they want to hear it. They want to hear that they're cured or in a deep remission or however you want to phrase it.
I also am reluctant to use that type of terminology because, you know, when something pops up in seven, eight years, that's extra not fun.
Yeah. Do you ever, do you use it? Do you say, I think we've carried you or it seems, sure seems like we've carried you?
No, I just feel like it's setting somebody up for a deep disappointment. I mean, you know, internally I'll feel pretty good. They don't come across, you know, if it's like organ confined, negative margins, negative nose, and they're a couple of years out, they can see it in my body language and the way I'm interacting that I feel pretty good. I would like to think. All right.
So you kind of counsel them, the high risk patients, your higher risk. And when do you practically first get, well, let me back up staging wise, who all is getting kind of contemporary PSMA PET scans and so forth in your practice?
So all high risk and most, but not all unfavorable intermediate risk. Okay, no issues with coverage, that's all kind of... No, yeah, it seems like we're doing just fine there. So it's certainly replaced CT and bone scan for all these patients. You know, an unfavorable intermediate risk can be reasonably heterogeneous, right?
You have one core at 4 plus 3 and a PSA at 5, or you have higher volume, higher PSA. I tend not to get it on all unfavorable intermediate risk.
Okay, maybe just to dig in a little bit, like 8 out of 12 cores, 3 plus 4 equals 7, 5% pattern 4, MRI is not offensive. No, no. Okay.
And I think radiation oncologists have a little bit of an earlier trigger to get a PSMA PET, which makes good sense. It's going to maybe impact their treatment plan. And so let's say there's a 3% chance of a positive finding in some of these settings. But maybe that 3% is worth it in the setting of a patient undergoing radiation.
In the setting of a patient who's planning on undergoing surgery, it's hard to justify, I think. There's a lot of scans for not a lot of gain.
Well, let me kind of flesh this out a bit. So I guess what I'm getting at ultimately is when we get that PSA and if it is an unfavorable endometrial risk patient and it's persistently elevated or pops up, like, I'm like, man, I think I wish I'd gotten that on the front end.
And literally I got a text message from a referring provider the other day saying I'm sending you a guy for a prostatectomy, high volume, 3 plus 4 equals 71, a PSMA PET scan. I said, no.
So they come back and they have a PSA, you know, recur within a year, PSA is 0.2, and you get that PET. And at that point, they've got one positive external iliac lymph node. Okay, well, you know what to do.
Right, right.
Should we have not done surgery if, you know, if they actually did have that, if you could see that? Certainly, it really gets into this important controversial area where we have no data, which is for those patients with small volume pelvic nodal disease visible only on a PSMA PET, are they appropriate surgical candidates? And I would argue that they
Understanding with all these conversations and likely need for salvage treatment, that's a small volume disease with the nodes in the region where we perform a node dissection. I think it's totally, totally very, you know, add whatever other word you want to put there that's appropriate to do to offer surgery.
A thousand percent that I mean, I guess if it was an extramedial lymph node that popped up after surgery, I would be really disappointed because I'd like to think that at least did a somewhat of a limited lymph node dissection. All right, I don't want to veer off too far off course, but the short answer is the same thing over here.
If it's like MRI was kind of nasty, higher volume, four plus equals seven, PSAs are getting up there. I think it's nice and to have that PSMA PET scan. Okay, so first post-op PSA, roughly,
We get it at six weeks. I know some people get it at three months, sometime in there. I don't think it really matters when you get that post-op PSA. You need to wait a certain amount of time, right, for the PSA to be able to decrease to an undetectable level. Our pathway is a six-week PSA. That's how it's been everywhere that I've trained. What do you guys do?
Yeah, same, six to eight weeks. I mean, usually I get a cath removal and they have a visit with us in six to eight weeks. And, you know, Pat's been discussed in some form or fashion. Ultrasensitive, standard sensitive?
Typically standard sensitive, except for those patients at really high risk of recurrence, where maybe we want to keep a little bit closer eye on it. But I don't love ultrasensitive because of all the anxiety that it causes for the typical patient where it's going from 0.02 to 0.03. How would anybody understand that to be anything other than it's something that's worrisome?
Whereas we know that that's fine. So I really like that less than 0.1. But there are some patients where, yeah, they're at really high risk of recurrence. And I'd like to have a sense of the trend. And yeah, if I see it's 0.06, 0.08, we know probably it's coming and we can start to lay the groundwork for potential salvage treatment.
So what about like six, eight weeks out, 0.02, 0.03? What does that conversation look like?
Looks great. I think we're fine. We're keeping an eye on this.
Yeah. We're fine. Nothing kind of like starting to...
No, I don't go there for that because it just, yeah.
Okay.
0.1?
Yeah, I'm worried, especially in a high-risk patient. And even, I mean, once we start getting above 0.05 with a trend, and that's a Godland statement, by the way, is if we're using ultrasensitive PSA, we need to confirm a rising ultrasensitive PSA. that we're not treating somebody because their PSA is 0.05 a couple of times in a row. Let's make sure that it's meaningful.
But yeah, once I see 0.1, it's notable. Again, it depends on patient's baseline risk. And so that's really an important fact to keep in mind. This is a study that we published using the CAPTURE database probably 10 years ago now, showing that your disease risk informs the meaning of a post-op PSA.
So the high-risk patient with a PSA of 0.1 is a whole lot more likely to have further progression than a low-risk patient with a PSA of 0.1. And so, you know, that's kind of intuitive, but we just exhaustively, I think, showed that using the CAPTURE database.
Yeah. I mean, so when, when you have a lower risk patient and you're hugging the bladder neck and you're hugging the nerves and you're hugging the apex, I mean, obviously you're not trying to leave any prostate cells behind. You're not trying to leave any gross volume of prostate behind, but what's your opinion on that? Like what is actually taking place?
I think that's it. It's two things. It's one, sometimes there are some benign glands that we leave behind, right? You're right. If we have a patient who's got more favorable risk disease, especially they're young and we're doing everything possible to preserve potency, we are cutting it close. And so could we leave some glands, benign glands behind? Yeah.
Could we leave some lower risk prostate cancer cells behind too? Yeah. Yeah, even in margin negative patients. I mean, you've looked at those slides. Thankfully, it's a negative margin with like two cells between the cancer cell and in the margin. And so, yeah, I mean, those recurrences in that setting are lower risk. And that informs how we manage those patients, right?
These patients, if they ultimately do continue to have a PSA rise and they get radiation, they can get away with just radiation to the pelvis. Whereas the high-risk patients, again, they need more. They need radiation right to the prostate bed, probably nodal radiation, ADT. And so they're really different entities.
So maybe let's just kind of parse out persistently elevated PSA. I hate that clinical state. It's so disappointing for everybody. I had a guy the other day who T3A, grade group three, negative margins, PSA wasn't particularly offensive. His six weeks was 0.2 and six weeks later is 0.4. And I'm just like, oh my gosh, this is... You know, this is super real.
So let's say that guy walks into your office and he's a consult for me. You got a second opinion from San Diego coming out to Michigan. What are the critical bits, pathology, PSA, history, et cetera? And what are additional tests that you want to get at that point?
Yeah, well, so first I just want to speak to what you mentioned, which is like, I think we all take it personally. Actually deeply soul crushed when we see that, especially, I mean, sometimes we're kind of expecting it in really high risk patients, but patients with lower risk disease where we see that it's really, it hurts. And I remember in the last year or so speaking at a conference,
And I think I was addressing like, you know, why does not every patient in that scenario get referred to a radiation oncologist? Because if you look nationally, they don't. And I kind of hazarded a guess of like, there's a little bit is urologists, we actually, that feeling of like, oh my God, we kind of like are embarrassed.
and somehow we dropped the ball, even if the margins are negative and things are okay, but also the margins are positive, but we did something bad and we're just gonna push it off a little bit. I think most people can kind of, hopefully, maybe hopefully not, but I think most people can relate to that.
And Mac Roach, who's an amazing radiation oncologist, gets up and says, yeah, you guys, like you surgeons, you just have it all wrong. But the thought is, wow, we've gotten 98% of your cancer. We did this. And we made a huge dent in this disease. And our colleagues from Radiation Oncology are going to help, hopefully, with the last couple percent.
And I have really thought that was such a good comment. And we need to internalize that. And that was memorable for me. And I really have tried to internalize that. I actually use that terminology more now. That's mindset. Second is, you know, we see these patients and that, right, we're going to, your PSA is elevated. Yeah, that does suggest there's some cancer cells probably there.
Well, you know, a given PSA can be inaccurate for lots of reasons. We're going to check it again. And, you know, yes, I know there's like there feels like there's got to be urgency to do something. But believe it or not, prostate cancer is still relatively slow, slow growing. We look at all the disease features for that person's cancer, just like you mentioned, what do you factor in?
Of course, age overall. health and comorbidities brought, like hopefully if they're a surgical patient, they've got a life expectancy greater than 10 years and all that. And then the cancer features, right? What stage, grade, pre-op PSA, did you have a PSMA PET pre-op or not? And what did it show? So those things are really important. What is their PSA at the time of recurrence?
0.2 is a whole lot better than 2.0. And then the timing that like the, what is the distance between the surgery and that time of recurrence? And so that six-week mark, that persistently elevated PSA is a much worse prognostic feature than somebody who has a recurrence five years after surgery, which does happen.
Those patients that have a really late recurrence are at much lower risk of progression. So all those things are important considerations. There is a table in the guideline that lists those key considerations that I just mentioned. I think PSA doubling time is in there too. Genomics can be in there for folks who find genomics to be helpful in their practice. That's kind of the initial framework.
And then we've got to think about, okay, this is a patient who is likely going to need radiation. We're going to confirm their PSA. And then we've got to think about timing because, yeah, radiation does have side effects. And one of the important acts that we think about is kind of as good as a patient's continence gets before radiation is as good as it's going to get.
We really want to hold off time. on salvage radiation until ideally the patient has regained continence and it had a chance to fully heal. And hopefully that really reduces the risk of significant urinary complications. Yeah, there are some adverse effects of post-op pelvic radiation. It can cause urinary frequency. It can cause bowel irritation and cause stricture.
But if you look at the data, they're probably not as bad as we think in our heads as urologists that There's a pretty robust set of data, including from University of Chicago, who's looked at there's a series of patients undergoing salvage radiation. And a lot of the side effects are relatively short-term, and late effects are pretty mild. So I think we think about all those things.
And then so on top of all that, these days, we're going to get a PSMA PET at some point. And maybe we're going to get it at the six-week mark. We're going to confirm the PSA and then get it probably typically, but we're certainly going to get a PSMA PET sometime in the vicinity of when we confirm that PSA recurrence.
Perfect. Spot on. So just a couple of thoughts. You mentioned the Gleason score, the margins, the time. Those are all kind of makes really good sense. If this patient were to use them as a case example. I also typically would still order MRIs of the pelvis post prostatectomy. Is there something that might not be quite as PSMA PET visible? Any opinions on that?
So that's a great comment. It's something that was not on my radar prior to the guideline process. And it was Brian Chapin who said just what you said. He said, oh, I find MRI really useful in this setting. And we looked at the data and we had, you know, discussed it with our radiology colleague on the guidelines.
And at the end of the day, that is included as a, forget the exact language, but you may consider an MRI as well in this setting. And so I've been, I've started using it in some patients and it is interesting. Certainly, MRI can pick up some local recurrences that just get washed out by the tracer in the bladder, in the urine.
Yeah. Okay. So then, I mean, hopefully they've met with a radiation oncologist somewhere along the way to kind of run through all their options. I mean, obviously some patients are like, I want surgery and they get surgery and they may have had an opportunity to take advantage of the multidisciplinary team.
A lot of times we try to get them in to see our pelvic floor physical therapists, even before the operation, just to kind of get all that optimized and everything.
whatever maneuvers you can to get their functional status tip top ship shape if they're super high risk i'd like to float the idea on the front end that we're not gonna do anything for six months it's generalization but that way they're not like oh my god my psa is undetectable this dude honest to god he's dried you know it's he's ahead of hood sparing and it was all kind of favorable anatomy and
But I get it that, you know, they want to start doing something like day before yesterday and they're still healing, recovering, so on. Can you just comment on the timing conversation and how you're like, this is something that needs to be addressed, but we may not be addressing it for some time?
Well, that's where hormones really saves the day, I think. Because these patients who have high-risk disease, who have earlier recurrence, shorter doubling time, they're going to need ADT with their RT. And so that really can provide a bridge. And we absolutely use that. Just very broadly, we usually say, okay, we're going to think about radiation around the six-month mark. Yeah, some patients...
have a really quick recovery. We feel comfortable with radiation at three or four months. But in principle, we're kind of thinking the six month mark is the right timing for most patients. But we can start ADT at three months. We can start it at four months. We can start it at two months. If we were at this patient, if they have a PSA of
one or two, and they're really at higher risk of recurrence. So that helps. Because then we get started ADT, that lowers anxiety quite a bit. PSA goes down to zero. And I think that buys time to give safe radiation that balances the oncological benefit with toxicity.
So Todd, when you're thinking about Doing something salvage, let's say now the patient's recovered, whether they're persisting, elevated or a post prostatectomy, undetectable to detectable. And you think about salvage treatment, what are the kind of modifiable elements to that?
So it's really sort of the radiation field. Is it just prostate bed or prostate bed plus nodes? And then I guess even prostate bed plus nodes plus or minus metastasis directed therapy if there are a couple other sites of disease seen on PSMA PET. So that's really, that's the radiation piece. And then there's ADT and there's timing of or length of ADT.
Time that we give ADT, minimum of four to six months for patients who are getting ADT, but 18 to 24 months recommended for patients with high-risk features who are undergoing RT. And then on top of that, there's ongoing research into intensification. And so meaning intensified hormone therapy, like adding enzalutamide or apalutamide.
And so that data is still basically immature in TBD, but clinical trials evaluating whether that might also be beneficial. And then there's the timing of when do we actually start initiating these steps.
Based on a PSA.
Yeah.
Yeah. So that's exactly how I think about it. And, you know, it seems like on the one end of the spectrum, it's like, let's just sit tight and we're not overly concerned.
The other end of the spectrum is, you know, maybe even extrapolate from some of the stampede data where it's radiation, hormones, Abby, and, you know, you can make a case in a young, healthy person, aggressive disease that, that, and even doing an advent setting is not totally off the wall. I think again, extrapolating,
So we recently reviewed in one of our journal clubs, how do we kind of personalize this beyond PSA, doubling time, leasing score margins and so forth. And there seems to be some emerging data on biomarkers. Are you guys using that at all to inform timing, PSA levels, ADT, yes, no? Or do you think that's still kind of early phase?
You're thinking like Decipher or Terra or something else?
Exactly. Deciphering Arteria. You got it.
Presented some data at the AUA this year on using Arteria classifier. I think not everybody, probably not everybody knows what it is. Although just I think today, yesterday, it was named in Time Magazine as the medical invention of the year. So that's kind of huge props to that team led by Andrea Esteva and Felix Fang.
What it is is basically digital pathology-driven AI multimodal learning to input patients' clinical features and the images from their histology can be biopsy, can be prostatectomy, and then output, just like the cipher, prognostic information like risk of metastasis. So Otero's model uses the digital pathology images along with the clinical information.
And of course, folks who listen to you, in addition to getting their information, maybe elsewhere too, I don't know, but mostly here know all about Decipher and that it's a gene expression classifier that can be used also, tons of data to support that it's prognostic. And possibly even can help with decisions around RT versus RT and ADT in the newly diagnosed setting.
So these are both classifiers or models that can be used in the post-operative setting. It's still relatively early days for those, but lots of reason to think that they could be used to help, especially around these decisions around intensification, use of ADT or not. And then we did have a little bit of data that we presented using our Tera
Suggesting that maybe it could, in addition to being prognostic in this setting, maybe it can help inform who benefits from hormone therapy and who doesn't.
So clinical trial through music coming to you, coming soon to a site near you, probably?
Yeah, yeah, exactly. We can hope. We can hope.
That's awesome. That's awesome. So you mentioned timing, and I think, you know, I take that to mean PSA level, you know, so functionally they're there. Talk a little bit about who, when.
The principle is that earlier is better. And, you know, it's hard. It's like, it's really hard to get at specific cut points. 0.5, PSA 0.5 is probably the best big picture cut point, but still earlier is probably better. And there's some data from Derek Tilkey and her team at the Martini Clinic
published in JCO that suggested, now it's retrospective data, but suggested, ah, you know, 0.5 is good, but 0.25 maybe is even better. And it's really hard to tease this out because when you're looking at these questions retrospectively, you're saying, okay, patients who get radiation
earlier seem to do better, but also patients with lower PSAs may have a slower doubling time and they may actually just be lower risk patients. And that makes it a little more challenging as always to tease out cause and effect. But guidelines, we feel very, very confident in that 0.5 threshold. We want to give salvage treatment. We want to initiate it before PSA 0.5.
And look, if you have that patient who's got a high risk disease and their PSA is 0.1 and you know it's going up and they've healed up and all that, There's no reason to delay. And in fact, the patient is going to be better off if we don't delay. And so one thing that we just fall short of as urologists is getting those patients to radiation oncology quickly.
And it really does make a big difference.
So I don't know if this comes across your desk periodically, post-prostatectomy, let's say maybe three, four years ago, biochemical recurrence, they've been staged and they've got a pelvic lymph node and they really, for whatever reason, are averse to radiation. Can you talk a little bit about salvage and lymphadenectomy, what your thoughts, opinions are? Oof sounds about right.
So I I've done maybe about 10 of these. Have you done some?
Yeah, yeah. I would say more early on in my career.
Yeah. There was about a three-year period where I was doing them. I mean, it's doable. There's some challenging ones. I mean, like Mayo and Jeff Carnes have published their experience. They have a vast experience with this. And so I talked to Jeff and learned from them. I also talked to Dan Lin at UW a number of times back when I was doing these because he also had a lot of experience with these.
And they're doable. Pretty, like, you know, you learn a lot. It's super interesting. At the time, we were mostly basing our information from patients who went elsewhere for, say, choline PET or maybe a little, like, Axmin 2 back when that was being used.
And, you know, you'd go and you'd do a full dissection, and of course you'd find that node that was positive and about seven other positive nodes. And sometimes the PSA went down to zero, and most of the time it didn't. And sometimes it was a really difficult case.
I mean, I've only tackled one that's very memorable of when the node was in that kind of perirectal fat and just trying to, you know, so we've learned based on PET imaging that maybe about 10% of lymph node metastases go that direction. Different nodal chain and like finding that little pea-sized thing in there was unpleasant. We got it out, but we're like, by the grace of God, we got it out.
Did the patient benefit from it? That's the question. Well, when you look at published series, really, it does not look like it. All of these patients recur. This was, you know, really, I think, nice study published in European Urology four or so years ago, I think. Bravi was the lead author. It just shows that all these patients recur.
And so in the absence of better data, data was convinced that it wasn't making a difference based on data like that and stopped doing it. And in the guidelines, we do include it as something to have on the table in, you know, select circumstances. But I'm actually looking at the text here. It's right.
However, these patients should be counseled regarding the uncertain oncologic benefit from surgery in this setting. And I'd say to put that mildly, conditional recommendation evidence level grade C. Yeah. I don't know many folks are still doing it.
No, I agree. I mean, I think when I was a young hotshot straight out, I was pretty excited. And the data that's kind of seared in my head is that Swarty's eight year biochemical recurrence free rates of about 8%. That kind of killed my enthusiasm. The cases are, are not terrible, not super, you know, you can get some surprise that your orders are tethered in after surgery. And, um,
Anyways, but I mean, I think there's might be, if I was going to do it in a highly select motivated patient who's just feels like this is it for them, or maybe radiation is a contraindication. It's really gonna be like we're kicking ADT down the road. And maybe in some post prostatectomy, BCR, radiation. second biochemical recurrence, pelvic node only.
I think you can like have that conversation again to like kick it down the road, but I'm not like very enthusiastic about this anymore. So does that sound okay?
I totally agree. Yeah. It was worth a try, I think. And again, people, I mean, there were people who did a lot of these and I'm sure did an amazing job and they published their data, which is awesome.
Okay. So we've talked a little bit about when to do it, getting them optimized, PSA levels, earlier is better, that this is a generalization. You're taking into these decisions, the preoperative risk of kind of a bad actor, ADT, nodes, metastasis, directed therapy. I mean, these are going to be multidisciplinary conversations, right? Where you want to have the whole gang in and
So is there anything about the current kind of state of affairs? And we'll keep it to post-prostatectomy. I mean, I think focal therapy, post-radiation, those are whole separate conversations. I actually did a recent podcast with Amar Kishan on post-radiation, and it was mind-blowing, as always, such a bright guy.
But how about just, you know, for us as good country urologists, urologic oncologists, is there anything that I'm missing here?
I don't think so. I mean, the most important thing that we can do is talk to our patients, help them understand what's going on, and get them to a radiation oncologist. Like, it's still something that we don't do enough of, and we just, we got to do it. There's really strong data now to support getting a PSMA PET in the setting. I think the coverage is not an issue.
Around here, it's happening throughout the state, and so I'm really encouraged by that. I suspect in California, it's the same. Radiation or salvage treatment informed by PET scans is well supported now. And that's the EMPIRE study, EMPIRE-1 study, where patients were randomized to either a PET-informed or non-PET-informed strategy. And the PET-informed strategy worked better.
And so that's a great study. And that really justifies the role of PSMA PET in this setting. And so, right, so we need to recognize these patients. We need to keep track of them because this is another like piece of tantalizing music data that I've seen unpublished and I haven't seen the real details yet. So I can only give like a small headline and hopefully Tudor Borza doesn't kill me.
But like a lot of patients are lost to follow up after prostatectomy. And so we, you know, we don't necessarily always have great mechanisms.
for keeping track of patients and we have to in primary care docs are managing a million different things and putting this on PCPs is really challenging when the report from you know PSA test reports back less than four or three years normal and not every patient understands the nuances and not every primary care doc understands those nuances and it's totally understandable so we have to be able to just keep track of our patients to be able to entertain any of this guideline-based care.
Yeah, I appreciate it. Thanks for kind of hammering the PSMA pet part. I feel like I maybe took that as a foregone conclusion, but it's important to specifically mention that. And I also think it's worth mentioning that if a PSMA pet is negative, that doesn't mean you shouldn't receive treatment necessarily.
Ah, bingo. Thank you. Yes. That's a, it's really, really important. And so that's, so that's like the, the clinical scenario, I think that people understandably struggle with, which is like patient has a PSA of 0.2 and then maybe it's 0.3 and then you get the PSMA PET and it's negative.
And so some people might reasonably say, well, let's just hold off and let's, you know, we'll wait till the PET's positive. And then, well then, well, now we got metastatic disease that we're waiting for.
Right.
And, you know, until we have, Studies that have answered that question, like negative PSMA PET, we have tons of data to support the role of salvage radiation in this setting. PSMA PET's only a handful of years old. So we need to fall back on where we really do have level one evidence.
Yeah. It's always like a bit of a interesting thing when I read like a report or I hear that we're in a wait for the PSA rises a bit to get the PSMA pet. I'm like, right now we're just doing our due diligence, like box check. You don't have any obvious mess. Let's let's go. Okay, perfect, Todd.
And then maybe, you know, we kind of talked about some of the things that are coming to the pike that are going to allow us to personalize these intriguing, fascinating, complicated decisions, which are nearly certainly only to get more complicated, which is a good thing in the future.
What makes you excited about the future of management of patients with the biochemical recurrence after prostatectomy?
Yeah, I mean, we're getting better, right? The surgeries are getting better, without a doubt. It's a difficult surgery, but we're getting better at it. And we really finally understand this debate of adjuvant versus salvage radiation. And so we know what to do. And when I look at these guidelines, I mean, a lot of it is really well supported by high-level studies.
So we have a good handle on how to improve outcomes in the setting. And then, yeah, there's a ton of research to be done. All the questions that we can ask around PSMA PET and how we should change management based on PSMA PET, incredibly important. And then incorporating new therapies.
I mean, you know, androgen intensification is now a couple decades old, but we're still just understanding how to incorporate those medications into this setting. And then TBD about PARP inhibitors and other precision-based therapies. I mean, it's all out there for us to eventually do the studies and change management.
Yeah, I mean, it's things like they're moving at such an exciting and breakneck speed. And sometimes I think it's a little bit hard not to get super excited about the newest and the latest and the greatest. And, you know, one of the things that always strikes me with the Music Michigan group is how you all are thoughtful and the cart doesn't seem to get ahead of the horse very often.
You know, we've got the Indicate study, which I think is a great study, you know, in this exact clinical space over here, because I think we start doing things because it makes sense. It seems like that's where the data is heading.
And maybe even to the, you know, the folks out here that are interested, you know, some of these questions about how do we responsibly bring in new tests, new elements are still super ripe for research. And And with the higher grade stage cancer that we're treating, I think we're going to see more biochemical recurrence would be my sentiment.
Any comments on that, Todd? No doubt. I mean, I think that's bearing out in various data sets. Thankfully, we're not treating Gleason 6 hardly anymore. Understanding better the role of surgery versus upfront radiation and virus disease is still an important question. But yeah, I mean, we're doing lots of surgeries on patients with high-risk cancers, understanding better.
from the get-go in transparent conversations with patients that this is, it's multimodal care. And so that's what, that's what we're planning. We're planning surgery followed eventually by radiation or homeotherapy.
Well, Todd, you know, appreciate your time, appreciate your efforts. You know, it really is a tremendous guideline. I encourage everybody to take a look at it. And always a pleasure to pick your brain. Thank you so much.
Hey, thank you so much for having me. I love being on this podcast. Love, love what you're doing. Love listening to it. So great to see you.
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