The Uromigos Episode 127: APCCC—Adjuvant Radiotherapy Postprostatectomy

Dr. Alberto Bossi discusses the role of adjuvant therapy.

Episode Transcript

Tom:
Welcome, everybody, to our second super exciting APCCC podcast series. I’m here joined with my great friends, [Silke Gillessen 00:00:32] and Chris Sweeney and Alberto Bossi. And we’re going to ask Alberto to introduce himself first. He is our guest speaker today. Welcome Alberto.

Alberto Bossi:
Well, thank you very much for inviting me today. I am a radiation oncologist based in Paris, France, even if my origin is an Italian one, as you can guess from my name, I am working in the genitourinary field in the last 25 years of my professional practice. And I’m really excited to discuss with you some items concerning adjuvant and salvage radiotherapy.

Silke Gillessen:
Great. So welcome Alberto. And I also to tell Tom that he’s Alberto, maybe that for the next time. So, we have …

Tom:
That’s helpful, Silke. Thank you for that.

Silke Gillessen:
I’m very sorry. So yes, we have some interesting questions, I think. And so, we are coming a bit from the APCCC where we find consensus and some questions that go for advanced prostate cancer and non-consensus in others.

And I guess one of the big questions that still stays is which are these patients who really still need adjuvant treatment, radiotherapy after prostatectomy, because there are all these new trials showing that probably early salvage is so much better and obviously has less toxicity, but then are they still some patients who really could profit from adjuvant radiotherapy after prostatectomy, Alberto?

Alberto Bossi:
Well, Silke, this is a real $1 million question, because as you said correctly, the result of three major randomized trials seems to have recently put in hand on this debate, adjuvant versus salvage radiotherapy. I’m referring to the radicals, the GETUG 17 and the RAVES trial. We all know that they showed, as you said, that there is no difference in these two strategies.

So why do we may irradiate patients early after radical prostatectomy if this translates into higher toxicity. But still, if you look into numbers of those trials, you may argue that few patients were randomized in the high-risk group. I’m referring here to a very wise editorial of [Danz Pratt 00:03:04] that recently said, even in the postop setting, we should start to consider that there are heterogeneous patients with very different characteristics.

And if you look to these three major trials, it really seems that the number of patients in the high-risk grouping was not so important.

And indeed, if there is a role for adjuvant immediate radiotherapy, this should be limited to patients having bad prognosticators, certainly not to Gleason 6, negative margins, and disease, which is not outside the capsule or as infiltration of seminal vesicle.

For patients having these prognosticators, there is perhaps still a role for adjuvant radiotherapy, and of course, if you only look to evidence-based medicine, and I think we should today, the results of those trials have pushed the radiotherapy community to shift certainly to early salvage radiotherapy.

Chris:
Alberto, can I just pick up on one question? Why do we not want to give radiation to everyone? What’s the downside for doing it?

Alberto Bossi:
Well, the argument not to irradiate everybody in the adjuvant setting immediately after radical prostatectomy is certainly linked to side effects. We know, and this is not only clear from the last three trial that I mentioned, but also from the experience of radiation oncologist and series published all over the world, that immediate radiotherapy after radical prostatectomy may translate into a higher toxicity. And this is probably the real argument that should be considered in this respect.

There is a second one, which is, in my opinion, oncologically a little bit more sound that tells you that if you wait for rising PSA, you will really identify patients needing radiotherapy. Not all patients will need radiotherapy after radical prostatectomy, even in the high-risk group. So, PSA may tell you after radical prostatectomy, which subgroup may need radiotherapy.

Chris:
And that makes perfect sense to me, Alberto. I’ll pick up on one point. So, the side effect profile, there’s the notion that you start the radiation therapy when they maximize their urinary incontinence post prostatectomy, and that can take a few months, but I’ll actually be interested to hear Silke and Tom’s thought on this.

There’s the acute side effect profile, but without the prostate in place, there’s a greater risk of proctitis and cystitis. And I’ve just, forever, noticing many patients when they’re in their CRPC state, so these are young men that matriculated through multiple therapies, and 10, 15 years later, radiation seems to be that keeps on giving with cystitis and oftentimes they’ll present with hematuria and sometimes it clots or significant proctitis and the like.

So that’s one of the main reasons why I really, really have some reticence about giving radiation [crosstalk 00:06:36] to patients in the prostatectomy. How do you respond to that?

Alberto Bossi:
Well, that’s indeed true. If you look to the data of Parker published on Lancet last year, referring to the radicals number, it’s indeed mostly the genitourinary toxicity, which is enhanced dramatically by adjuvant immediate radiotherapy. If you look to numbers, you will see that you have twice the risk of developing cystitis after adjuvant radiotherapy is compared to early salvage and 10 times the risk of developing late hematuria.

As you said, these are very bothersome effect for the quality of life of our patients, but of course, once the patient has bad prognosticators on his pathology, soon after radical prostatectomy, I think these should be put in balance. So, side effects and the risk of side effects should be discussed with him, knowing that probably the only therapeutic intervention that may change his future is radiotherapy.

You know that more than 40 to 50% of those patients will develop a rising PSA, which some series have also correlated to much more important endpoint. So, I really think that at least for the high-risk group, they should be discussed with patients.

Silke Gillessen:
Alberto, maybe another question considering this, because obviously we are talking a lot about early salvage now, but what does that mean for you? So how often, how frequent are you doing the PSA controls, or do you recommend to do PSA controls after prostatectomy? Because I guess it’s the same in France. Like it is also in other countries, like in Switzerland where we really see a lot of patients coming with high PSA after prostatectomy for the question of salvage radiotherapy.

So, what is your recommendation to avoid that?

Alberto Bossi:
Well, Silke, this is a real danger. This is the urological community, I may guess, are a bit reluctant to speak about radiotherapy in the salvage setting to their patients, because they may have recovered so well from radical prostatectomy that you say, okay, if they have to go through radiotherapy, they may have some bad quality of life soon after.

And as you said, if you look to statistic only one third of patient with a rising PSA, will receive some form of salvage radiotherapy, and this is really something which urological community, our colleague, the surgeon should be aware of, because if we go for salvage, it should be early salvage.

And indeed, PSA should be checked very frequently, especially in the high-risk group of patients. You are certainly aware that the European guidelines, both from the urologists and from the radiotherapist have mentioned for years, a threshold at 0.2 nanogram milliliter, but in the more recent version of these guidelines, this threshold has been totally abandoned, which is to me a real advancement, because come on, you cannot just think that a stupid threshold will translate over different biology of the patients you have in front of you.

So, I was always a little bit reluctant to use threshold to indicate the need of early salvage radiotherapy.

Chris:
Alberto, how …

Alberto Bossi:
So, in my daily practice, sorry.

Chris:
Alberto, how do you increase the numbers of people getting early salvage therapy? Is it because about education in the community? Is it because of the confusion between adjuvant versus non-adjuvant therapy?

And is it actually more important to educate about giving early salvage therapy than having this debate about whether we should be giving adjuvant therapy at all?

Alberto Bossi:
Yeah, this is totally, totally correct. I think that, as you said, we have to educate urologists and probably patients also, and general protectionist too, because lot of follow-up on those patients, at least here in France is done by general protectionist, the surgeons when they have done radical prostatectomy, they don’t seem to be so interested in following carefully their patients, I have to say.

And this is left to general protectionist, and general protectionist may just look on the results of the exam and telling patient, okay, your PSA is just growing, it’s 0.6, 0.9, 1. But you know, the threshold is 4 nanogram milliliters, it’s dramatic.

And so, we can wait. And this, as Silke has said, may translate into a very late salvage, which is totally nonsense. So, in my opinion, the urology community should be targeted. And probably also the general protectionist ones and the patient itself.

Believe me, I see still in my practice, quite a number of patients just coming from their own or with the wife telling me, “You know what I’ve been operated six years ago, nobody ever checked my PSA, but I’ve done it on my own. And these are the results. What do you think?” So, there is three groups of major actors that should be, in my opinion, targeted.

Silke Gillessen:
And, Alberto, maybe we can say, also tell Tom, a new risk is now, Tom, that people are doing PSMA PET CTs when the PSA is rising. And then if this is negative, they say, oh, it’s fantastic. Your image is clean. So, we don’t have to do anything.

So, I don’t know, maybe, Alberto. You want to comment on that because there are people now who really wait until they see something on the PSMA PET CT and then want to irradiate what they see. And obviously this is also a bit contrary to the concept of early salvage, or I don’t know, Alberto, you are the expert.

Alberto Bossi:
This is another very, very tricky question. In a couple of years, all this landscape of the postop treatment has really exploded. So, you are right, Silke. What to do with new imaging technique like PSMA. And indeed, I also so see patients followed by the surgeon where PSMA are regularly checked every three, every six months …

Silke Gillessen:
Yes.

Alberto Bossi:
… Before sending the patients for radiotherapy. So, there are two things in my opinion. First, we will not stop this PSMA mania. We will see more and more patients asking for PSMA because they look on internet. They see that PSMA is the future of imaging in prostate cancer. I want to have it, so we will not stop it.

What I would like to see is a much more, how can I say, evidence-based use of the result of PSMA, as you said, if the PSMA is negative, when the PSA is rising after radical prostatectomy, you will probably identify the patients will best respond to early salvage radiotherapy.

These are the patients to irradiate. These are the ones that are going probably better than the others. When you see something else outside the pelvis, for example, we know that these are the results of at least 40 to 45% of patients having PSMA for a rising PSA.

When you see something else outside of the field of radiotherapy, well, this is a difficult decision. Should I enlarge my field? Should I go for metastasis-directed therapies, stereotactic body radiotherapy or whatever? Should I jump to androgen-deprivation therapy? And who cares about the local control?

All these should be, in my opinion, should be topics for randomized clinical trials. For the time being, I would not modify this rule if the PSMA is negative, please irradiate your patient.

Chris:
Alberto, can I pick up on two lines of thought that you and Silke and Tom have had? One is what is the benefit of radiating a patient with the rising PSA? Is there a survival benefit that we can reference? Is there a quality of life where there’s a short-term treatment burden, and the PSA goes down and they never have their PSA go up and they never need hormonal therapy. What are the benefits you explain to your patients when you counsel them on the benefits of salvage radiation?

Alberto Bossi:
Yeah. Yeah. This is a very good question. So, we have some data out there showing, and I’m referring to old series published by [inaudible 00:16:43] that there may be a relationship between, at least in the high-risk group of patients, between a rising PSA and more dramatic at point like distant metastasis.

[inaudible 00:16:58] showed this for the high-risk group of patients. So, irradiating a patient in the early salvage setting, for sure, may translate in stopping the rise of PSA, which altogether, I wouldn’t consider such a trivial result, even from the psychological point of view of those patients, but certainly at least for a group of those, these may translate in a survival benefit.

So does this also translate in postponing some other systemic therapy. I’m not that convinced because if you look to the results of our GETUG16 trial, and if you look to the [RTOG 00:17:48] trial of Shipley, it seems that at least for the very high-risk group of patients, we are discussing tonight, hormone therapy should be added. So, I don’t believe that much in this idea that radiotherapy may postpone ADT at least for this high-risk group of patients.

Chris:
I’ll pick up on that line of thoughts. So, and I’ll have you comment on the approach that I’ve adopted and see if you can dissuade me of this approach. So, the patient with a very high risk that you’re describing, I cannot find a sweet spot of intense, when the PSA gets above 0.1, and it’s confirmed to be above 0.1, because there’s a lot of movement below 0.1 that I find that it never gets above, never relapses or progresses. So, if they have high respect to this, I will give six months of hormonal therapy akin to the GETUG-16 approach with radiation therapy and double down in that situation.

Is that trying to find not too early in the adjuvant for everyone, not too late, but giving the hormonal therapy, hoping that you never see the PSA go up again. What do you think about that approach?

Alberto Bossi:
Yeah, honestly, I would like to know what Silke thinks about that as being an oncologist dealing so much with genitourinary cancer.

Tom:
I love the way you dodged that question, Alberto … [crosstalk 00:19:21].

Silke Gillessen:
Alberto, this is not the idea of the … [crosstalk 00:19:23].

Alberto Bossi:
Okay so …

Tom:
It’s going to be cool. The Alberto Pass.

Silke Gillessen:
Right. Yeah, yeah, yeah. It’s like a [inaudible 00:19:34], right? No, idea. [Inaudible 00:19:36]. I don’t know. So yeah, I have to say Alberto, this is a question I think I already discussed some patients with you as well, right?

Alberto Bossi:
Yes.

Silke Gillessen:
So, I have to say it’s always very difficult to really decide what is the best thing to do, and you have to discuss with the patient. So, there are some hints in the data. I agree totally with Chris, here that maybe in some specific patients who have really a high risk.

There is this EAU low risk and high risk of biochemical relapse with a very fast PSA doubling time and so on. And maybe these patients could profit from an ADT that is together with the salvage radiotherapy. We don’t have the data. So, it’s really, I think a discussion with the patient, if he wants to take the side effects and wants to go for the maximum or not.

So, I would agree with, Chris that we mostly discuss it, but I just saw a patient yesterday who’s a bit elderly. And he said, no, he doesn’t want to do the ADT as well, even if he, maybe, doesn’t maximize the effect. So, I think that …

Alberto Bossi:
Yeah, if I may add something …

Silke Gillessen:
Now it’s back to you.

Alberto Bossi:
If I may add something, if you look carefully to the RTOG and the GETUG-16 data, you will see that the driver of the benefit of hormonal therapy in the salvage setting together with radiotherapy is probably the PSA [inaudible 00:21:12], as we said. So, if you see a patient presenting with a rising PSA, which is really 0.7, 0.8, or 0.9 nanogram milliliter, I think you have an argument to add some form of androgen-deprivation therapy.

The discussion may be which sort of ADT you rely to those patients. You know that the RTOG trial we’re using two years of bicalutamide, we here in France, have been using six years of an analog.

Silke Gillessen:
Six months.

Alberto Bossi:
Sorry, six months of an analog, indeed. I would probably go for the second option.

Tom:
Alberto, we’re running out time, although I’m told time is infinite. It’s not the case on our podcasts. We’ve got probably time for one more question, Chris, Silke, what do you want to go with?

Chris:
Silke, why don’t you present a case to Alberto that sums all this up that and gets Alberto on the record, not passing it off to you.

Silke Gillessen:
So, I think I have actually another question if it’s okay, Chris.

Chris:
Yeah, sure.

Silke Gillessen:
And that would be, are there patients, Alberto, where you think after the prostatectomy, you should not control the PSA at all?

Alberto Bossi:
That’s a very good question. I would say patients, they would’ve been manageable with active surveillance. I still see some of those patients, which had a very low PSA Gleason score on biopsy, two biopsies Gleason 6, 3+3, and that wanted absolutely radical prostatectomy or that were convinced by their surgeon to have radical prostatectomy.

So, for those patients, probably there is very little sense in checking the PSA repeatedly after surgery.

Chris:
Can I give, Alberto, the case?

Silke Gillessen:
Okay.

Chris:
Yes, Alberto. A 56-year-old man who’s in great health. No comorbidities, has a Gleason 4+5 with some seminal vesicle invasion, margin positive. His preoperative PSA was 5.2. And his postop PSA is 0.02 at month three, and he’s completely recovered his contents. How would you treat him? Adjuvant or wait his PSA to rise? And would you add hormonal therapy in at this stage in either setting?

Alberto Bossi:
So, I would discuss with him the data we have from these three trials. I would tell him that we know that immediate adjuvant radiotherapy would probably enhance the risk of urinary side effects, but I would also explain him that due to this bad prognosticators, Gleason score, infiltration of seminal vesicle, extra prostatic disease is probably the profile of patients who would benefit from adjuvant radiotherapy.

So altogether, I think that this is clearly the patient. Of course, there is something, which I have not mentioned up to now, which is very common in the states, much less in Europe, which is-

Tom:
[inaudible 00:24:54] It’s a late time to bring it in, but far away.

Alberto Bossi:
I’m sorry.

Chris:
No, I’m joking, joking, joking.

Tom:
Okay. Okay.

Alberto Bossi:
No, I was mentioning genetic profiling.

Tom:
Yeah.

Silke Gillessen:
Yeah.

Alberto Bossi:
Which may play a role in those patients, that’s all.

Chris:
And what’s that profiling look like?

Tom:
You’re referring to the decipher high risk profile for risk of a [inaudible 00:25:17].

Silke Gillessen:
We’re talking about it at another time, Tom, this is a really large field.

Tom:
Okay. So, we’re not going to go into that. What I would say, Chris. So, Alberto, you haven’t said, whether you’re going to give him hormone therapy, you’re giving him … Is it going to be just radiation therapy or is it the combination for this patient?

Alberto Bossi:
I would give six months of ADT.

Tom:
That sounds really good.

Chris:
With the PSA of 0.02, you wouldn’t wait for it to get to 0.1?

Alberto Bossi:
No, no.

Chris:
Yeah. And the one thing I would just say is that when we look at a nomogram, you can see that, that person has almost an 80, maybe, I won’t quote an actual number, go to a nomogram, but the chance that he won’t be getting radiation at some stage of relapsing, at some stage, he is very, very low.

So, the chance of over treatment is very, very low when you look at a nomogram for a patient like that. I agree with you, Alberto.

Tom:
And Sweeny, how often do you look at those sorts of nomograms? Is that something that’s in your mind thinking, it sounds to me like if the radiotherapy is inevitable at some point, why not do it now? Is that sort of what you’re saying?

Chris:
Yeah, I do. I pull up the nomogram. The more Memorial Sloan Kettering online nomogram is very good for this. And I will look at it, and it has the 10- and 15-year rates of prostate cancer death and relapse. And it really helps patients put it in.

So, if it’s like only a 10% chance the PSA is going to go up. They [inaudible 00:26:36] well, do we really have to? And I go, no. If it’s 80%, [inaudible 00:26:40], well maybe yes. And so, I use the nomogram to help patients make decisions with together.

Tom:
Alberto, this is an incredibly exciting podcast. It’s also an exciting time for both Italy and Paris, Italy with your fantastic Olympic games. I saw those sprinters coming in the hundred meters, which I thought was terrific and Paris-

Silke Gillessen:
40 medals. They made 40 medals this time.

Tom:
But Paris with the Olympics and with Lionel Messi coming. I don’t know how good he is anymore, but he’s coming anyway. And, of course, with ESMO coming up in Paris, and I don’t know if you’re going to be at ESMO, but I’m certainly going to be there and Silke is too well, I’ll do my best.

Even if I’m not invited, I’m going to go. So, I’m looking forward to seeing you very soon. This has been terrific and in great work in this really important disease.

Silke Gillessen:
Thanks, Tom. See you in Paris.

Tom:
Thanks, everybody.

Alberto Bossi:
Thank you very much.