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Thomas Steuber: Dear scientific committee, thank you for bringing me into the panel and giving me the opportunity to talk about the role of surgery in metastatic prostate cancer. It's a wonderful meeting so far. These are my disclosers. So, I'm potentially biased by the fact that I'm a prostate cancer surgeon. So, what's the rationale? We've talked about what arguments can be found to do the local treatment on metastatic prostate cancer, which was obsolete for the case. It's considered the standard of care from others, in other malignancies, so we can learn from other tumor entities. It may prevent local complications like obstruction, hematuria, rectal stenosis, and it may prevent further seeding from an uncontrolled primary. And it may destroy cells with potential genetic instability, so the latter arguments may lead to improved overall survival in patients with centralized metastatic disease.

This cartoon displays the emerging treatment landscape on hormone-sensitive metastatic prostate cancer with novo-androgen receptor-targeted drugs that are pushed into the primary treatment setting with improving overall survival in hormone-sensitive metastatic prostate cancer. The question is if should we intensify treatment by focusing on the prostate by surgery or radiation to further improve survival. This has been sufficiently and positively addressed by radiation oncologists, and they, as has been stated before, found positive results for the effect of radiation on the prostate on low-volume disease. This data has been adapted by the EAU guidelines and also by the NCI guidelines. Recommending or giving a weak recommendation that patients with M1 disease, low volume according to the CHAARTED definition, should be offered ADT in combination with radiation of the prostate.

So this leads to further discussion, and Chris Parker, the author of this MP data, also part of the panel, has discussed and cited that it's possible that other forms of local treatment such as radical prostatectomy might also be effective, however radiotherapy might be effective via other mechanisms such as immune modulation, so the role needs to be clarified in prospect of randomized trials such as g-RAMPP and TromBone. So, the future of surgery and centralized metastatic tumors lies in the hands of these two guys, PS, difficult name nice guy and Markus Graefen Hamburg this are the two PI's of the prospective trials from Europe.

So Let's go back, is cytoreductive Prostatectomy feasible? Or do we, or does it have substantial side effects, do we harm our patients more than they benefit. And this question has been addressed by a multi censored trial by PS and they collected data from five high volume European centers. They did cytoreductive prostatectomy in synchronous metastatic disease. And they found moderate complication rates and reported also quite positive functional data on early continence, 80% mild or no incontinence after three months with the prospect of further rehabilitation beyond one year. And they concluded cytoreductive prostatectomy is feasible. 

The side effects are comparable to high risk localized prostate cancer. This report may be criticized because they did not report Clavien complication so the standardized protocol and they did not report a quality of life. The TromBone trial is efficiently randomized 51 patients and they could report in a randomized fashion on complications found, major complications 8% which compares favorably to the complication rates locally high-risk prostate cancers in the British urological community. And surprisingly they've found an improved quality of life in favor of patients undergoing surgery probably reflecting disappointment of men that were not selected for surgery so this of course raises hope in the patients. 

So does is prevent local complications, we have not yet heard a lot about local complications. This is a significant bother and harm for patients with an uncontrolled primary. It grows into the bladder, it leads to hydronephrosis, kidney insufficiency and so forth. So the patients spent the rest of their life in the ambulance or hospitalized setting. So, therefore, it might be useful to, ahead of this, eradicate or remove the prostate. This has been addressed by a multicenter Australian trial so they looked at 263 patients from five hospitals they eventually developed metastatic castration-resistant disease. And they looked, or they came out with the result that if prior local treatment has been administered in particular in surgery, that there was a significant advantage in terms of local complications so 20% for the prostatectomy treated patient versus 55% in patients that did not undergo prior local treatment. And this has also been reported by case control studies by Axel Heidenreich. 20% versus 29% in favor of radical cytoreductive prostatectomy versus ADT alone. And in a case-controlled study from our institute 7% versus 35% local control, local complication rate.

So the one million dollar question of causes does cytoreductive prostatectomy prolong survival. First, we look at large registry date and they come out that selected patients have it better prognosis, have a longer overall survival when prior cytoreductive prostatectomy has been performed. Of course, if we look at the number only five, three to five percent of large, pool of metastatic patients underwent cytoreductive prostatectomies so there is an adherent selection bias potentially. They tried to correct for confounder like age, Gleason rate, year of surgery. But of course, in such registries other significant prognosticators, like the number of meta static's paying performance stages were not available so there may be an adherent selection bias and what we see here may be just the effect of the selected, low volume population in comparing to the rest are not the effect of local treatment.

What they further preformed our sensitivity analysis and it comes out that if you predict three, three-year prostate cancers specific mortality and if it becomes, is it, is it lower than forty percent there is a significant benefit in favor of local treatment. But if it become beyond a point, so a worse prognosis there is no more benefit for the local treatment. And the same has been explorative by Piers Acatuf so patients in the M1B setting with only [inaudible 00:06:55] in Piers level below a sixty benefited from local treatment beyond they did not benefit. So this pretty much reflects the concept that beyond a certain level of disease it extends so name it low volume disease, whatever, a local treatment doesn't work that good anymore. 

We performed a case-control study. So we did a prospective phase, two trial and we selected patients with a PSA below 150 M1b low volume and matched our cohort to register data from Copenhagen patients that did not undergo local treatment and so far we did not find a difference in time to castration resistance and overall survival, however it's not prospective data its case-control study. And overall Doctor Tiliki, she did a meta-analysis and found our that in all the retrospective register and case control the trials there is a significant hint here in direction cytoreductive prostatectomy may also improve survival. So, of course, retrospective, so what we need is a randomized trial, randomized trials are underway. We have seen the list of randomized trials from the US and the Anderson phase two trial and the SWOG trial and, of course, the European trials trombose, tromBone not trombose which has successfully completed recruitment and the G-RAMPP trial and I want to go into detail a little bit further for the G-RAMPP trial. 

So we initiated this trial in 2015. Maximum 5 bone metastasis limited PSA, local [inaudible] tumor have the patients and we were running far beyond our expectations in terms of recruitment. I would say we re-, we took the same time than some people who did more than two thousand patients that it took us for one hundred and thirty-one patients. And with the event of the stampede era we though with poor recruitment and the fact that there is a treatment option for low burden metastatic disease it would be unethical to randomize in a control arm with ADD or systemic treatment alone. So we stopped the prospect of ra-, G-RAMPP trial, unfortunately.

So what are my conclusions, cytoreductive prostatectomy is feasible, feasible, similar side effects compare to localized, high-risk disease. It is a demanding procedure, it should be restricted to high volume surgeons, and of course, selected patients, healthy patients, without no complication for surgery. Its prevents local control, may, therefore, lead to an improved quality of life. There is an overall survival benefit visible in a retrospective in other case-control trials. Mainly large public health registries. It should be offers to men not suitable for external beam radiation therapy for significant lower urinary tract symptom or irritative voiding symptoms etc. or patients who simply deny radiation. We have to look at the data from gRAMPP and TromBone we are going to pull the data because they, are based on identical protocols so then we come out with at least one hundred eighty-two randomized patients. And we are eagerly waiting for the results from SWOG, MD Anderson. 

Open questions of course some is, are, for example, is surgery better that EBRT or visa versa. I don't think that's its really very relevant question. And of course does the local treatment also work in the context of combined systemic treatment because data from Horat or Stampede stem from the time where ADT alone was administered in only small proportions up to seventy percent. Simultaneously got Doce so does it also work in the context of the combination of drugs and this is sufficiently addressed I think in the PEACE1 trial. 

So I leave hear with some impressions, so first a statement of ASCO the multimodal approach in oligometastatic disease is the way to go, with the standard of care radiation treatment but also room for cytoreductive surgery. And now I'll leave you with an impressions from Hamburg from the new concert hall the Elbphilharmonie. Id like the thank you for your interest