Almudena Zapatero: I have the pleasure to introduce our fellow speaker, Dr. Johan Walz, zoologist from Powell Comet Center. He's going to speak about biochemical recurrence after the definitive radiotherapy of the prostate. What are the local treatment options. Whenever you want, thank you.

Jochen Walz: Thank you very much. And thank very much to [inaudible] for the kind invitation to join here, APCC 2022. And to talk about local treatment options in radio recurrent prostate cancer. These are my disclosures here. Some of them might be of relevance for this presentation. Before I talk about the treatment, I just would like to have a short look of how this clinical scenario today is looking like using modern imaging, such as PSMA, PET, and MRI. And by using those, you might encounter local recurrence after radiotherapy in 17 to 40% of the cases. So it's not that rare. And I think the most important message I would like to give to you is, think about the possibility to have local treatment in patients that do have regular recurrent prostate cancer. So happens to me, that I see patient for a second opinion for dealing with a primary prostate cancer that've seen already a radiotherapist and a urologist, and they come with the opinion that there is no treatment after radiotherapy locally. If the disease recurs, this obviously is a mistake.

If you would like to treat our patients, we need to stage the patient to have a clear idea and what situation we are with a specific patient. I would like to have a look at what is, today, feasible here. MRI obviously is very helpful to identify local recurrence inside of the prostate does have a high sensitivity reasonable specificity, but you need to be aware that the size and the lesion that we see with MRI is largely underestimating the true extent of the disease. If you compare it to home on sections, as you can see it here on the lower right, you see not all lesions and you underestimate the true extent of the disease. If you use the PSMA PET to stage the patient and to see if it's only localized in the prostate or somewhere else, 18% of the patient might have only disease inside of the prostate and 25% would have, what we could call today, local regional disease, local disease inside of the prostate and disease inside of the pelvic lymph nodes.

So one patient out of four might be a candidate for local treatment. Again, keep that in mind that this might be a treatment option for this patient. More important than these descriptions and how often you will find a positive signal on PSMA PET, this patient is probably the idea how reliable this is and how much of the disease we really can see. And there are very few data, or there's very few data out there looking really with histology as a reference, what we did see and what we missed with PSMA. And this is a study from Cologne, looking at the lymph nodes in this situation. And you see here that the sensitivity remains low, similar to what we see when staging the primary disease.

It's roughly 40%. So we still miss micro metastasis at the level of the lymph nodes with PSMA PET. And it is of note also that up to one patient out of five might be metastatic to the lymph nodes, which is of importance for those treatment modalities that we have that only treat the prostate and do not cover the pelvis. As we might do it with surgery. When it comes to the detection of their local disease inside of the prostate, we might use PSMA as well. And this is a per lobe analysis, which I think is more important than a per patient analysis inside of this study as well. And you see here that sensitivity is not at a hundred percent. You still miss also here, smaller volume lesions, and very important if you look at the specificity, the specificity is not at a 100%.

So you might have a signal inside of the prostate, which is not prostate cancer. And this brings me to the next point, which is the biopsy. I think before we go for local treatment in a patient that does have radio recurrent prostate cancer, we need to have a histological proof before we go for a treatment because the side effects might be important and we don't want to treat only a manage, we don't want to treat a false positives. And also our guidelines recommend the use of MRI and of PSMA PET to stage our patients correctly.

Another important point is the nature of the disease inside of the prostate. Is it multifocal or is it unifocal? Obviously, this is very important, once we would like to decide what kind of treatment we are going to offer. We know that prostate cancer recurs inside of the primary lesion so it's not Denovo prostate cancer developing somewhere else in the prostate. It's the first lesion that was not sufficiently treated with radiotherapy and it can be unifocal in 60% of the cases, but it can be multifocal in 40% of the cases and if basically one patient out of due is multifocal, I think it's safe to state this is a rather multifocal disease than unifocal disease and again, this might be of importance then, once you consider different treatment options.

And the big question is, is there truly an index lesion driving the biological story of the disease, or do we have here to treat all the lesion that are inside of the prostate? That is the eternal discussion that we have around focal therapy also, once we want to treat the primary with focal therapy. So these other treatment options, I'm not going to talk about hormonal therapy, that would be beyond the scope of this talk, but I would definitely talk about surveillance.

We all know that the radio recurrent prostate cancer is also a slowly progressing disease and many of these older patients that recur after radiotherapy might as well be as good of with no treatment at all, because they will not live long enough in order to have a progression of the disease and have an influence on your quality of life and their health. So we need to estimate life expectancy before we consider any local treatment in these patients. And then of course, we also need to consider the risk of the disease to progress later on, and really represent a problem for our patients. And here, according to our guidelines, if you have a patient with a high eyes of grade, they are at risk of progressing a high-t stage. They are at risk of progressing.

And if you have an early recurrence after radiotherapy, below the 18 month limit, then you might have also a high risk of progressing disease. Coming to the treatments, we have, indeed, the possibility to do very local treatment, focal treatment or ablation. And we have for the primary, a lot of different energies out there for the salvage treatment, we basically use only high for and cryo and these are the options that I would like to desk here, discuss here later on together with re-irradiation no matter whether it's brachytherapy or stereotactic body radiotherapy and of course, salvage radical prostatectomy.

This is a comparison, looking at the biochem recurrence free survivor coming from a recent meta-analysis and systematic review published in European neurology. Obviously there are no randomized prospective trials comparing here the different treatment options that we have, but at least here's the same methodology, the same analysis, which gives us some idea about the efficacy of the treatment and blue you have salvage radical prostatectomy, in red you have cryo treatment, in green you have HIFU and violet you have this salvage radiotherapy or the re-eradiation, whatever you would like to call it. And you see, there's no significant difference here in the biochem recurrence free survival at five years, but you need to be aware that we use actually different definitions for biochem recurrence, PSA being undetectable and become undetectable after surgery. And for the other treatments where the prostate remains in place, you usually use a Phoenix criteria and we all know that this generates quite a bias when looking at biochemical recurrence free survival.

But so I think we can consider them being quite equivalent with the efficacy of cancer control. So what we are more interested in is then side effects and complications, and this is coming from the same meta-analysis and systematic review, looking at GI and geo-toxicity and you see here that the best outcome is seen with re-eradiation and looking a little bit more into detail, especially when it comes to incontinence, you see here, the blue column, the highest rate of in continence is encountered after salvage radical prostatectomy, which might happen in one patient out of two.

Of course, you need to be aware that the definitions are very different. It might be no PET at all, might be one to two PETs, whatever, but you see here trend not favoring surgery in this situation, and the best outcome is observed with re-eradiation. And when it comes to ED, you see here that cryo and HIFU actually is associated with the highest rate of erectile dysfunction but obviously these often older patients do have already preexisting erectile dysfunction before any local treatment. So I'm not sure that this is a major issue for our patients in this situation.

Before ending my talk, I would like to have a hard look on what might predict a favorable or unfavorable outcome with the treatment options that we have. For HIFU, obviously it's the problem to identify unifocal disease. Obviously, you would not go for a whole gland treatment with HIFU, which would substantially increase the risk of complications and side effects. So you would like to go for a treatment of one lobe or the disease in isolation. And here you would need to be aware that you would probably not like to do this in those tumors that are highly perfused in dynamic contrast, enhanced MRI, because this might generate what we call the heat sink effect, where the blood flow will take about, take away the heat and avoid that you get to the lethal temperature inside of the lesion. So you might avoid this. And then of course, a low PSA value and a low prostate volume is a sign for an effective treatment later on.

For cryo, again, we have the same problem that we need to identify the right patient, the right lesion inside of the prostate. And then also here, the lower the PSA, the more effective the treatment will be. And the long interval between radiotherapy and the cryo treatment is also of interest. And then obviously, the better the PSA response to the treatment, the better the outcome on the long term, but this is only after the treatment. So not very helpful to decide upfront what treatment to do.

Re-eradiation, it's very important to achieve a certain amount of dose to the prostate, combined dose. Ideally, that should be above a 130 grace and also here PSA and PSA doubling cut time is of interest. The lower PSA, the longer the PSA doubling time, the better the outcome, as well as tumor volume, that is a no brainer. And when it comes to toxicity avoid doing re-iradiation those patients that do have already irradiated or irradiation induced toxicity before a server treatment. That's also very obvious, you have already symptoms. It can only get worse, will definitely not get better. And you should avoid a certain dose to the geo-organs and the GI organs for the combined dose in order to avoid here severe GI and geo toxicity.

For surgery, the best outcome also here is seen at low PSA levels and low clinical stages and a low number of positive cause, which is probably a proxy for the volume of the disease that we need to treat. And also Gleason score. We know that usually you should not assign a Gleason score after a treatment. So that is probably a little bit of virtual parameter we might consider.

And then toxicity, it's straightforward to surgical volume for the surgeon and the center. The better the surgeon, the more experienced the surgeon is, the better will be the outcome by the treatment of the primary. This data shown here, meta analysis here, showing complications on the right hand side and below you see here, the learning curves for complications, as well as erectile function and continence.

This applies for the treatment of the primary, and it's obvious for a disease that is more complicated to operate on such as salvage radical prostatectomy. The experience will be even more important than it is already when you treat the primary.

In conclusion, we can say a very important point when it comes to salvage treatment after radio recurrent or for a radio recurrent prostate cancer, consider the possibility of local treatment in these patients. If you would like to treat them, patient and cancer selection is key in order to be successful and I think it's very important also to counsel the patient with a realistic outcome from the perspective of cancer control, as well as the functional outcome. And if you go for a salvage treatment, do it in a high volume center, this applies for surgery, but I think this will also apply for those who might undergo cryo or HIFU or even radiotherapy.

With this, I thank you very much for your attention.