Episode 128: APCCC – PSA relapse post prostatectomy

Dr. Neha Vapiwala discusses investigations and treatment for these patients.

 

Silky:
Yeah. Thanks, Tom. As everyone knows, I’m in the moment in Italy in vacation. If I’m going out, Chris is going to take over. You never know. Yes. At the APCC, the biochemical relapse chapter was a very complicated one. There was a lot of non-consensus in that chapter, and we are very happy now to hopefully get some clarity about that. The first question is really like… At what PSA level do you think now that we should do an imaging and what kind of imaging obviously?

Neha Vapiwala:
Sure. Absolutely.

Speaker 3:
Neha, before you start. I’ve already messed this up. I’m really sorry. But if you’d like to introduce yourself before you answer the question, that’d be great. I’m terribly sorry. Brian really does that bit, which is…

Neha Vapiwala:
No problem.

Speaker 3:
We need him back. We need him back.

Neha Vapiwala:
Well, for starters, I wish I was traveling with you, [Silky 00:01:16], through the mountains and the tunnels. That would be much more fun.

Silky:
[inaudible 00:01:21].

Neha Vapiwala:
Yes. Well, thank you. Thank you for having me. Yeah. I’m Neha Vapiwala. I’m a professor of radiation oncology at the University of Pennsylvania, specializing in prostate cancer treatment and I’m very happy and honored to be with all of you today. Some of, I think my role in this, stems from the ECOG-ACRIN ’81, ’91 indicate trial that just recently opened that’s going to try and shed some light on these issues. But getting back to your question, Silky. I think just to take a step back. Part of the, I think growing need, and I think the call for some clarity in this space comes from, at least in the US, an increasing number of our prostate cancer patients being diagnosed with higher risk disease due to changes and delays in PSA screening. Then, in turn, an increasing use of radical prostatectomy to treat some of this high risk and potentially locally advanced non-metastatic patients.

Neha Vapiwala:
We’re seeing a population that presents with biochemical recurrence and that means we got to figure out what to do, and they tend to be very, as you can imagine, varied in their presentations. You have folks who had pathological findings that you could have predicted that they would need additional treatment. You have others where they’re really low risk and suddenly they’re presenting with biochemical recurrence. How to manage them, how to even work them up to get to your question and at what PSA level to even start thinking about re-staging is really all over the map. I’ve often said it’s depending on who you ask, when you ask them and who’s in the room at the time, you can get different answers.

Neha Vapiwala:
If you’re talking about PET scans, at least in the US right now, Fluciclovine PET is really the only commercially available, widely available option that we have among the modern agents. All of the data really tell us, including from the LOCATE trial, which was the main trial that provided us the FDA approval, that if your PSA is under 0.5, you’re really not going to see much with this scan. Once you start getting into the range of PSAs above one or above two, that’s when you actually have the chances of actual disease seen on PET of 65% to 75%. When you think about the population we’re often managing in clinic, they come in with this ultra sensitive PSA levels, PSAs below 0.2. They want to know what’s going on. The truth is our current widely available PET imaging is really subpar for our needs.

Chris:
I got to pick up on that. There’s all this new data about PSMA PET being better than Axumin PET. Can we just say now and address the question, how much better is PSMA PET than Axumin PET and what is its lull in their detection [inaudible 00:04:31] seeing something below that, but what if there… Does PSMA PET improve upon that?

Neha Vapiwala:
Yeah. I think that’s exactly right, Chris, there’s a lot of excitement obviously just for Gallium PSMA PET. Now, most recently, the PYL compound, which literally just very recently received FDA approval in the US. But when you look at some of the early data from UCSF, UCLA, and Gallium, the specificity for nodal detection, for example, which really is one of the most important things we’re using the PET for is intra and extra pelvic metastases. Are they there or not? The specificity is excellent, 95%, but sensitivity with Gallium PSMA was still only around 40%. If you’re talking about that’s in the intact setting, I should clarify, that these patients were evaluated, but again, it was clearly correlated with the PSA levels.

Neha Vapiwala:
Even though, yes, it is arguably more sensitive and some of the direct comparisons that have been done, it’s not a home run. It’s not like we’re suddenly able to catch patients at extremely low PSAs the way we often see them in clinic. I still think there’s room for improvement, let’s say, but certainly progress with PSMA agents over Fluciclovine as far as the minimum PSA threshold.

Silky:
Neha, really concretely, what are you doing? Let’s say you would have Gallium PSMA available in the States or something that is very similar, how long would you wait? At what level… Let’s say after radical prostatectomy to start with, because it’s obviously different if you do it after radical radiotherapy. What level would you choose to say this patient needs now an imaging with PET?

Neha Vapiwala:
We usually have been waiting until 0.2 as a minimum. There will be patients where, let’s say the velocity of the PSA rise, the rapidity with which the recurrence occurred, let’s say it’s within a year of surgery together with horrible pathology findings, we might do the imaging sooner because we’re more concerned, but for your typical patient where it’s been more than two years since surgery, it’s a somewhat indolent rise, typically I wait until at least 0.2 before I think about imaging.

Silky:
Okay. Interesting. Then, I think now comes the real big question, right? Let’s say we don’t see anything in the PSMA PET/CT as you have explained very nicely, doesn’t mean that there isn’t anything.

Neha Vapiwala:
Right.

Silky:
What are you doing? Are you now saying you’re doing it like long, long time before salvage radiotherapy? Or are you saying, “No.” Some really very prominent radio therapists do, just wait and do other imaging and then treat when you see something on the PSMA PET/CT? What would be your approach outside of clinical studies?

Neha Vapiwala:
Yeah. No. Excellent question. We do face this quite a bit.

Silky:
Yeah.

Neha Vapiwala:
Part of it is going to depend on the man in front of you and potentially loved ones that are in the room, and what the goals of care are. That’s always number one. What are the expectations in terms of outcome? What’s age and general health status of the patient? What is the actual clinical risk that you think this patient has of having undetected micro mets? Because, as you just said, Silky, the absence of PET defined local involvement is not proof of absence of disease. We’d like to think it is, but the negative predictive value has its limits.

Neha Vapiwala:
Even the EMPIRE-1 study did show that. I think if you have everything lining up in a way where the pathology findings from prostatectomy, the pace of the PSA rise, the absolute value of the PSA and a negative PET, if all of those are concordant for the most part, or most of those are concordant that there is not metastatic disease, I think it makes perfect sense to proceed with standard of care, prostate bed and pelvic radiation therapy with six months of androgen deprivation, and the RTOG 0534 SPPORT Trial is going to be published imminently and presuming that that shows the continued failure free survival benefits to treating lymph nodes in all of these patients, we will, I think adapt that practice widely among radiation oncologists.

Neha Vapiwala:
But then, and conversely, if you have a negative PET, but everything else tells you, including your gut tells you that this patient is likely to explode with metastatic disease, I don’t believe that you should put aside your knowledge and your thoughts on the matter just because there’s a negative PET. I think it’s reasonable in those patients to still start with the same approach I just outlined, but perhaps prepare the patient for the possibility that systemic therapy may change maybe longer and maybe enhanced, if that makes sense?

Chris:
Can I pick up… Yeah. Can I just dissect a couple of those points? I just want to underscore we are 100% focusing on trying to cure patients in this setting. When you use the word metastatic disease, Neha, I think you’re meaning disease that’s outside of where prostate bed was, but that doesn’t mean the patient is not curable without therapy. That’s my impression. Do you and Silky agree with that?

Neha Vapiwala:
Yeah. I think absolutely there is the spectrum that we see. I think all of us have seen the difference in the natural history and of course, oligometastatic, but even some patients who don’t quite fit the oligo title. That, of course, is all conventional imaging defined historically, right? This idea that five is the upper limit, but who’s to say it’s not six or seven or eight in the molecular imaging era? I agree with you. It’s not about curative versus non-curative so much as are we going to let the crux of the therapy be systemic versus local? That’s where I think I’m trying to make that distinction on behalf of the patient to help them understand what it is that we’re going after and why?

Silky:
One very interesting thing you said, Neha, because I talk a lot about that because we see these patients a lot. I think you get five different answers from five different psychotherapists. Right? Yes. You said pretty clearly if you do salvage, you use ADT. There’s also people who say no, right? Then, you would use… Because there is this data with 150 milligrams of Bicalutamide from the French study, are you using that one? Are you using LHRH? How long? I think also there, I guess there is a lot of uncertainty, what is the best approach really for adding this ADT, if you want to add it at all?

Neha Vapiwala:
That’s right. Yeah. No. I think part of that came from… If you look at RTOG 96.1, which did use two years of Bicalutamide 150 milligrams, even some of the study authors have said that in practice, they actually used six years of LHRH analog. [crosstalk 00:12:15]. I’m so sorry. I meant, sorry, six months of LHRH rather than the two years of Bicalutamide. I think we all know why. Some of the extra side effects of the Bicalutamide as well as the reality that two years of an oral drug for patients isn’t always as easy as it sounds. Also, if you look at that study, and I think part of the hesitation, Silky, and why not everyone agrees about giving ADT, and I do think in some lower PSA value patients, it is reasonable to omit it is because in their subset and in their retrospective subset analysis, placebo was favored for patients with PSAs below 0.7, which seems pretty dramatic that you have to wait until a PSA of 0.7 to benefit from two years of Bicalutamide.

Neha Vapiwala:
I think because of that portion, people were feeling justified in omitting any ADT unless the PSA was above a certain value based on the 96.01, but I think the wisdom is moving towards using it even in lower post-op PSA settings. I think between the SPPORT trial and the French trial, I think we have enough data that I think will support that. Maybe you don’t use it as 0.2, but certainly, I think taking all the factors into account, I think it’s going to be used more, not less with postop RT.

Chris:
Let me see if I can double down on a couple of these statements that you’ve made with a couple of case examples for the audience. A patient presents with a PSA 0.18 post-prostatectomy and they had margin positive and extra extension 18 months prior. Would you get a PSMA PET? Yes or no?

Neha Vapiwala:
What did you say the PSA was?

Chris:
0.18.

Silky:
[inaudible 00:14:08].

Neha Vapiwala:
I know. It’s what I thought I heard.

Silky:
19.2

Chris:
Okay, .0. No, these are the questions that are coming up. Some people have moved to treating with PSA of 0.1 radiating with… The reason why I say that is, it’s a question we’re having in our clinics at Dana-Farber right now, actually.

Neha Vapiwala:
Yeah. No. Absolutely. No, I don’t mind that you… I know you threw the curve ball, the 0.18 because the positive margin makes it a little bit easier for me to say in a healthy patient who’s continent, potent, motivated, I think it is absolutely reasonable to treat based on a positive margin. While I may consider a short order repeat PSA, let’s say in four weeks if the patient’s not particularly ready to start treatment, I might say, “Let’s get one in 48 weeks.” If it nudges closer to 0.2, go ahead and get that PET, but always with the caveat, and I tell every patient, it is likely I’m going to get this scan, and it’s not going to change a bit of our conversation today, that it won’t change what we’re saying today, because it’s not necessarily going to show anything.

Neha Vapiwala:
It doesn’t mean that this PSA is not real. That’s where I try to prep them before we even get the scan. The short answer to your question is I would likely consider offering treatment based on the positive margin, but not necessarily get a PET at such a low PSA.

Chris:
You did get a specific…

Neha Vapiwala:
If I did get it, at least prep them for the likelihood that it will be negative.

Chris:
If it does come back negative and the PSA is now 0.19, how would you treat them? The rate and the [inaudible 00:15:52] treatment?

Neha Vapiwala:
As of right now, and did you say they had sufficient node samples at the time of prostatectomy and I said [inaudible 00:15:59].

Chris:
Yeah, I didn’t. He had three zero node sampled and they were all negative.

Neha Vapiwala:
Okay. I would say… You said zero node samples? Sorry.

Chris:
Three nodes sampled zero involved.

Neha Vapiwala:
Zero involved. Right. Minimal. I think generally in patients who have Gleason score six or seven on final path who didn’t have SVI, who you think at least had some good pre-op staging that suggested absence of nodal involvement, the three nodes doesn’t impress me much, but at least you have some other things to go on. I would generally, for positive margin at a low PSA, consider bed only. At this point, until the SPPORT trial and others establish it, I would absolutely talk about ADT, but not be dogmatic about it, that this is a patient in whom it is very reasonable that this is coming entirely locally, and we might be able to spare him.

Neha Vapiwala:
I generally offer it, but if they wins at it or not motivated for the ADT, I have a very low threshold for letting them get out of it. But if you said to me, he’s Gleason nine, this happened within six months of surgery, I think you said 18 months here, so he’s on the border. But let’s say it was sooner than that or persistent PSA or rapidly rising to 0.18/0.19, then I feel more strongly about the ADT and I don’t let them off the hook as easily.

Chris:
They could possibly go on the [inaudible 00:17:34] study, but that’s another story too.

Neha Vapiwala:
That’s right.

Chris:
That’d be for those very, very high risk patients. The next question then, just to follow through on that, what radiation fields would you give for the patient who’s Gleason 7, four plus three, with the PSA plus 0.19? [inaudible 00:17:51]?

Neha Vapiwala:
Right. How far out from surgery?

Chris:
18 months.

Neha Vapiwala:
Same, 18 months. Again, I think for that patient, assuming positive margin, I think bed only at this time is still justifiable. I think once the SPPORT trial, as I say is out, I think there will be increasing use of pelvic nodal radiation together with a bed as a standard, but it’s not going to be 100%. I don’t see a day where we 100% treat the pelvic nodes in every single patient, regardless of PSA. I think there will be those where we just feel confident enough that it’s likely to be bed only even without PET.

Chris:
Now, I’m going to give you the scenario with the same patient, PSA 0.19, PSMA and Gleason seven, extra [inaudible 00:18:43] extension, margin positive 03 of the node samples had cancer, and he now has an internal lymph node that’s mildly positive SUV. Let’s say six PSMA PET.

Neha Vapiwala:
Any CT correlate?

Chris:
Of course not. It’s 0.5 centimeters.

Neha Vapiwala:
Oh, sorry. I didn’t hear that.

Chris:
No. No. I’m just saying the scenario that we all play here.

Neha Vapiwala:
I know exactly… We always… No. Don’t be silly. Right. That’s a patient where I… Again, this is where I wholly admit I’m conveniently fitting the data that I want to fit the clinical scenario that I think I see. Right? With that complete disclaimer of what I’m doing, being convenient, I think this is a patient where I would say, “You know what? There are data to support treating the nodes.” You’re somebody, if you don’t have major abdominal surgery, don’t have major risks where I’d be concerned about the additional volume of treatment, even though we don’t know that this is absolutely for real, it’s too small to biopsy, we should go ahead and treat the nodes anyway. If I did have any CT correlate or anything that I thought I could see more grossly, I would even consider what’s called an infield boost, where we actually deposit some extra dose. Within the microscopic nodal volume, we give extra dose to the parts that are radiographically concerning or biopsy proven.

Neha Vapiwala:
In this particular case, you could argue, “Well, you don’t even have to boost anything, just go ahead and include the nodes. Be safe.” I would just add if there was a patient who said absolutely no to the radiation piece, for some reason was adamant that they only wanted the bed radiated, on occasion, I would convince them then to do the ADT and perhaps re-image, and see if that lesion’s gone away, and delay the RT piece. Sometimes we’ve used that as a surrogate to see if there’s ADT response, not necessarily in this case, I don’t think, but in other cases where it’s really indeterminate and would be helpful to establish.

Silky:
Neha, would you give the radiotherapy only to postpone ADT if someone would like to have them?

Neha Vapiwala:
They’d have to make a compelling case, not in this guy with the concern of the node and the higher Gleason, or actually I forget if Chris gave him a higher Gleason, but in my mind, I did. Yeah. If he’s presenting within two years of surgery and then there’s any suspicion on the PET, I would try to first understand why they’re trying to avoid the ADT. A lot of times, they are reasons that aren’t really rational and you can make a compelling reason why they need it. Yeah. There will be those handful that no matter what, they’re not getting it. Then, you, at least can make the argument to try to maximize the RT as much as possible.

Chris:
The reason why… One of the arguments, I think we should have or one of the conversations we should have, saying, “If we double down on our therapies now and maximize the chance your PSA goes down, it never comes back. You’ll never need the hormone again.” A six-month investment of hormones now may save you a lifelong later [crosstalk 00:22:07].

Neha Vapiwala:
I always do say that. It’s interesting, Chris, I’m sure you get the question all the time. Well, why can’t I just do the RT now, and I’ll just save the ADT for if I need it? I always make that distinction that. While it’s the same therapy, it would be with different intent and different duration and purpose. That’s how I often am able to help them understand.

Chris:
Can we go back to the EMPIRE-1 study and the conversation we’ve just had and how that study informs what we’ve just talked about?

Neha Vapiwala:
Yeah. The EMPIRE-1 study was recently published by our colleagues, Dr. Johnny and others at Emory. It actually stands for the Emory Molecular Prostate Imaging for Radiotherapy Enhancement trial, and specifically used Fluciclovine in patients who were presenting with biochemical recurrence in the post-prostatectomy setting. They essentially were looking at whether the failure rate at three years after salvage radiotherapy was better in patients who had PET versus not. It’s a relatively small study. There were about 80 patients, 81 patients without PET, 76 with PET. They essentially were able to show with the primary endpoint of three-year failure free survival, statistically significant difference using the Z test where they basically showed that the patients who were treated with the use of PET guiding their therapy did better. You always wonder, “Well, what was the actual decision that was made as a result of the PET?” Right?

Neha Vapiwala:
If you look at how many of the patients had a change in management as a result of the PET within that arm, there were some that essentially had pelvic nodes treated in addition to the bed, whereas previously they would’ve only had the bed. There were actually 10 patients for whom the volume of radiation was increased as a result of the PET. Then, there were 14 patients for whom initially the intention was to do bed only. Then, they moved to doing both that and the nodes. I’m sorry, it’s confusing to say without a visual.

Chris:
Yeah. [crosstalk 00:24:30].

Silky:
I think Chris, we could probably talk for another 30 minutes, but we are already overrunning. I feel at least because I don’t have my watch in my vacation. I guess if you don’t have a burning question, do you have a last burning question?

Chris:
I do. One question. What I would just say is how are we going to address this at the APCC meeting, Dr. [Gilison 00:24:56]?

Silky:
In October, we don’t have that topic because we had to do it virtually and very small, but we will have a lot of these questions for 2022 for April. We hopefully can meet again in [inaudible 00:25:11]face to face. It will be really nice, and we will hopefully get some consensus after we have new data. Thank you very much.

Neha Vapiwala:
Absolutely. Thank you for having me.

Speaker 3:
Neha, thank you very much. Silky, I’m very impressed. It sounds like you’re in a major incident with police cars going by. I’m very impressed. I hope [Rudy’s 00:25:31] not been arrested or…

Silky:
I hope my husband is not arrested [crosstalk 00:25:39].

Speaker 3:
I hope so. Neha, listen, thanks so much. It was really interesting.

Neha Vapiwala:
Absolutely.

Speaker 3:
I hope we can see each other soon.

Neha Vapiwala:
Same here. Thank you so much everyone.

Silky:
Bye-bye. Thanks everyone.

Speaker 3:
Cheers everybody. Bye-bye.

Silky:
Thank you. Bye-bye. Bye-bye.

Neha Vapiwala:
Bye-bye. Bye-bye.

Silky:
Thanks, Tom, for…

Chris:
Ciao. (silence)

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