Alberto Bossi: Thank you, Felix. So, pN1 disease before lunch, and again, French accent. I'm sorry for that. These are my disclosures. First, I want to tell you that if you look to the more recent literature, you can conclude with me that oligometastatic disease is a hot topic. You have a lot of paper out there dealing with oligometastatic disease. When you move to the pN1 setting, well, unfortunately, this is not. And again, as Karim said, and this is Valérie Fonteyne quoting, "We have not so many solid data out there on which to base our daily practice, and even in the contemporary setting of patients, I don't think that what has been produced as randomized evidence, we are going back to this, is still valid." And this is really a pity. Why? Because first, I really think that pN+ patients are an important and increasing important problem. We will go about the local treatment of that very quickly. We will see that not all pN+ patients are created equal. We will see what we are doing and what we should do, and I will give you my final picture, which is a totally biased one. We don't have randomized evidence. I can tell you whatever I want.

So if you look to the incidents and cause of death in prostate patients, you will immediately check that the one that are having lethal prostate cancer are the one with metastatic prostate cancer with high-risk localized disease and with lymph node-positive cancer. So don't tell me that this is a residual, not important, category of patients. Those are patients dying from the cancer. If you can impact on these mortality data, we will get a very important point in the management of the disease. If you look, and thank you, Alberto for sending me this slide, to the number of patients that we see with pN+ disease after radical prostatectomy, this is increasing.

This is a study presenting at the last year, you meeting last year, you see in the last 20 years, this came from 5 to 18%. And why is that? Well, obviously, first of all, because surgeons are operating more and more high-risk disease. As you can see on the left-hand side, no discussion, more high-risk disease operating, more lymph node metastasis found. But also because I'm not discussing if this is clinically important or not. I'm not a surgeon, but the extent of lymph node dissection, the lymph node which are harvest in the lymph node dissection is increasing. And you'll see here, in the last 20 years this has come up to more than 15 lymph nodes. The more you're getting, the more you can find positive. If you limit the analysis on the high-risk group, look at that. One-third of your patients, the one that you operated with high-risk prognosticators, will have pN+ disease. So this tells me that this is very important category of patients.

What about the local treatment? This is a very quick assumption here, because we don't have randomized evidence. It's only hypothesis-generating evidence, but the hypothesis generated here goes in the same direction for quite a good amount of studies. I've just pick up some of those. The three first studies are coming from different institutions and different kinds of questions that are posed. The first one, aborted radical prostatectomy versus completed radical prostatectomy. Once that lymph nodes were found in the lymphadenectomy specimen, and you see that no discussion to complete the radical prostatectomy confers a beneficial overall survival benefit at 10 years. And you can check the other one, and I'm sure you know, the fourth one is interesting because this is with radiotherapy. So it's not only surgery that may confer a clear overall survival benefit once you have found lymph nodes positively influencing the lymphadenectomy specimen, but also radiotherapies. And look at the numbers, there are more or less the same. So really, in my opinion, this, even if it's not level one evidence, goes in the direction of thinking that the local treatment, and a good one, is needed in these patients.

Then you may ask, is this true for all presentation of those patients, for a patient with PSA 200 and more than seven lymph nodes? Again the Milan group, Bandini, European Urology Focus this year. He may find out that patients having more than 50 at PSA diagnosis, PSA, and more than seven lymph node, may not benefit from a local treatment, in this case, surgery. But of course, this is hypothesis-generating. The vast majority of the patients that we are treating today are safely in the left-hand side of these two curves.

Next point. This is a very, dis-homogeneous category of patients. You have to think about pN+ disease as a continuum of risk of dying of prostate cancer. Already 10 years ago, Alberto Briganti stressed the importance of the number of lymph nodes on the cancer specific survival of those patients after surgery. You can easily see that having one positive node has probably not a very big impact on your chance of cure. Having more than two positive nodes, the threshold there has an important impact on your cancer's specific survival. And more recent data from Karim Touijer are confirming this. He made some nice curves. One, twe, three positive nodes with different biochemical relapse free survival and metastasis free survival. But the numbers of lymph node you find, the positive lymph nodes you find, is probably not the only prognosticators.

Here we have a list of other that have been found in the literature to diversify the prognosis of all these patients. Of course, pT stage, Gleason score of the primary, the margin status, the lymph node density, the extra-nodal extension, the size and site of pN+, all these have been found as prognosticators. My conclusion, my vision of it, is that we have to take this into account when we will decide what to do for those patients. pN+ category is a dis-homogeneous one.

What are we doing today? We have some data from the National Cancer Database, and that's been published two years ago by Moon and coworkers. You see here what has been done in the patterns of care from 2006 to 2011 in the States. So you have numbers here. Please concentrate on the two last columns on the right-hand side of this cartoon. More than 8 patients out of 10 got nothing after surgery or ADT alone. Don't forget those data. We are coming back to this. What the literature tells us about this, so bear in mind, this is not randomized evidence. This is one of the best study, in my opinion, on this Karim Touijer comparative study I call the three M: Mayo Clinic, Milan, and Memorial Sloan Kettering. We are lacking the Martini-Klinik, but okay. So these people were treated on ADT alone versus adjuvant radiotherapy after radical prostatectomy and ADT. And even if the group having adjuvant radiotherapy had higher Gleason score, P stage, positive surgical margins, all together, this had a much better prognosis as compared to the other one in terms of overall survival, as you can see on the right-hand side. And in a very clever way, Karim was able to define some points category taking into account the prognosticators that you can see here on the left, in order to set threshold of value, and tells us that if you have accumulating evidence in terms of points, that the prognosis is terrible for your patients. You may get a much more interesting benefit when adding external beam radiotherapy after surgery.

Gupta goes a little bit in the same direction. I'm sure you are aware of this trial, the survival probability of three group of patients taken from the National Cancer Database again. A huge amount of patients, not randomized evidence again. Again, the patient that had some form of treatment, ADT or external beam radiotherapy plus ADT, or younger with higher Gleason score, P stage, nodal burden, and positive margin. But if you look to the adjusted survival probabilities, you see that the only group of patients doing better than the other were the one treated with adjuvant immediate radiotherapy and ADT. ADT alone does not impact on the prognosis of those patients. And again, in a very clever way, the idea of this [inaudible 00:09:21] was to better define the prognosis of these patients. Five groups of them following the number of adverse pathological feature to confirm that the prognosis is really different, taking into account the prognosticators we have seen down there.

And last but not least, Firus Abdollah's study. We are all familiar with it. Again, the National Cancer Database, again, a huge amount of patients here, we don't have the observation on ADT versus adjuvant immediate radiotherapy plus ADT. He took into account these four prognosticators, number of pN+, Gleason score, T stage, and surgical margins, and you could get these five categories of patients. And in these five categories of patients, in terms of overall survival at five years, radiotherapy could impact on a group of those, which are two. The one that you can see here, which account in his statistic for 75% of the whole population of patients.

So at this point, I guess I can propose you this final picture. So follow me carefully, because this is going to be a very busy slide. So based on what I've told you, the Briganti experience, Abdollah data, Touijer, and Gupta, I think that we have to reconsider all these category of patient as a continuum, in terms of risk of specific mortality. We will have on the left-hand side, patients with a very low risk of dying of prostate cancer, even if they harbor lymph node metastasis on this pathological specimen. A gentleman with a Gleason score 6, pT3b, negative-positive margins, and only two lymph nodes for sure, has a very low risk of dying of prostate cancer, not probably higher than someone which is pN0. But moving on the right-hand side, we will have people with a slightly worse prognosis, because of Gleason score coming 7 to 10, because of three, four positive lymph nodes.

And finally, the most dramatic one, because of more than four positive lymph nodes. And I really think we have to modulate our therapy based on this. If you look on how many of those are there, most of those patients will go in this 75% group out there. And so what is my proposal? Of course, for the one on the left-hand side, I'm not shocked that we go for observation alone and early salvage treatment, radiotherapy, plus or min, ADT. For the 75% group, remember the Abdollah data, adjuvant immediate radiotherapy seems important to confer a survival benefit. So this is needed. And then these data were also supplemented by lifelong ADT. For the people on the right-hand side, probably the control of local disease is not that important anymore. Of course, I'm happy to underline that this is exactly what the EAU Guidelines are saying, probably in a more confused way, but I guess that [inaudible 00:12:28] will be very happy with me.

Of course, I have a lot of question marks down there, so please don't treat this with too enthusiastic, because I don't know when to trigger the treatment in the first group on the left. I don't know how long ADT should be used. I don't believe the messing data in 2019. I don't think we can make use of them. I don't know which fields should be used, and I don't know which drugs should be used as systemic therapy. We have some group working on that. We have some non-randomized data working on that.

For example, this is the Belgium group. Charlien Berghen has proposed the PART trial. They are working on these kinds of information. These are all data from the Milan group. If you treat the pelvis, right-hand side, the disease will progress on the lumbar-aortic space. So the proposal of this group is, when you have to treat with radiotherapy, you may want to treat the lumbar-aortic space, too. Why not? We don't have solid data out there. This may be interesting. And then, the GETUG 12 also tells us something important in terms of systemic therapy. You know the design of the study, there were very high-risk patients. Some of them were pN+, exactly what we are talking today. You see, 60 patients, they were stratifying on the two arm of the study hormones alone or docetaxel.

Those patients were treated locally, mainly with radiotherapy. These are the curves that have been presented at ESMO by Karim last year. If you look to the subgroup analysis, with pN+ patients, you see that the forest plot tells us that adding docetaxel and exemestane may have a role in this very high-risk population of patients. So, ladies and gentlemen, coming to my conclusion, I really guess that if here in the audience there are young scientists that want to have some nice work to do for the next five to 10 years, they should work on pN+ patient. There is a lot to do, a lot to explore, and we should work on that. Thank you for your attention.