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Discussion summary and concluding remarks
Dr Montorsi concludes the symposium by highlighting the importance of personalized treatment strategies, a holistic approach to patient care by a multidisciplinary team, and patient education. He calls for raised awareness of the increased cardiovascular risk and new onset diabetes associated with use of GnRH agonists, noting that GnRH antagonists are under evaluation as an option with less cardiovascular toxicity.
Summary and Conclusions - Francesco Montorsi
I would just like to ask if there are cards or if there are microphones? Please use them; don’t be shy. Take the opportunity to ask questions to the patients but clearly, being a urologist I have to ask Mike, what are your indications for surgery in high-risk prostate cancer patients?
Michiel Sedelaar: We are changing a little bit because let’s say it used to be when you have pT3a or b or lymph nodes you would have a case for radiation oncology, but if you would have a young patient with an operable T3 which is, of course, a discussion point, maybe even with one or two metastases in the lymph nodes, I think we are now growing towards a place where we do more surgery.
Francesco Montorsi: Mike raised a point which is extremely important and for those who are surgeons, the issue of resectability. The old digital rectal examination remains an important step when counselling a patient.
Professor Abrahamsson, it is a pleasure to have you here with us.
Per-Anders Abrahamsson: Francesco, I have to defend my old friend, Heather Payne. Together you don’t know a drug is a certain excellent one and also in a ?commission from Manchester, we critically scrutinised the literature – there is no real, true evidence that radiation therapy plus ADT should be inferior to extensive surgery. If you look at randomised prospective trials with long term follow-up we don’t have enough tangible evidence unfortunately.
On the other hand, as you said and raised among us being urologists, we are more aggressive, even when we find one or two spots on bone scans, but we don’t have any evidence in the long term.
Francesco Montorsi: I think you are right. Let me start from what you said to tell the audience that we had, earlier today, the meeting of the Editorial Board at large of European Urology and probably I know that all of you read our journal and that recently, three or four months ago, there was this publication about a meta-analysis of those studies who compared radiation therapy and surgery. That is telling us that also well-done meta-analysis can give you results which are really not true, because if the studies are not well-done to start with, the final results of that analysis will not be good.
Typically, you already know that the results suggest that surgery is better than radiation therapy. I don’t think this was the case. There was a very nice editorial that the Editor-in-Chief requested that was saying “This was as an exercise probably useless, because you cannot compare apples and oranges” but guess what? The press picked up not the editorial, but the articles, so everybody is now saying that surgery is better than radiation therapy in these patients. I agree with Per-Anders, we don’t have information to support this, so I think we should just talk to our patients, explaining to them the various indications and then the patients themselves must have the final word.
The question that is coming from the audience is what is the role of chemotherapy in the early treatment for metastatic prostate cancer? Perhaps both Mike and Heather can say what they do at home? The role of early chemotherapy for metastatic prostate cancer?
Heather Payne: I can almost go one better than that because we have just completed a survey of all the oncologists in the UK asking if they would be using docetaxel within the first three months of ADT for hormone sensitive disease? 98% said that they felt they would offer this to patients who were fit enough to have chemotherapy with high-volume disease, more than four bone metastases, one outside of the spine or pelvis and 50% said that they would offer up-front docetaxel to those men with low volume disease, although the STAMPEDE study doesn’t distinguish between the volume of the metastatic disease. I think the data that we have from both CHAARTED and from STAMPEDE means that we now have to discuss this with our patients, especially the young ones and the fit ones who present with widespread metastases.
Francesco Montorsi: Michiel, do you want to add something on that?
Michiel Sedelaar: No, it is the same, what we do in the Nijmegen, we follow the CHAARTED study, although the evidence of the STAMPEDE could mean that in the coming years we would even treat patients with low volume disease, but now we still stick to the CHAARTED, high volume disease category.
Francesco Montorsi: Alex you have a question that was directed to you.
Alexander Lyon: There is. In many ways someone has got to the million dollar question which is how to explain the possible different effects of GnRH antagonists and agonists on cardiovascular related risks?
When I think about this it is the fact that the agonists are clearly activating a receptor pathway and you think of that in the pituitary gland leading to a surge or a flare followed by the desensitisation, but of course there are GnRH receptors in other tissues in the body. Probably critical ones include the liver and skeletal muscle and in fact the liver and skeletal muscle are where diabetes develops. There is a growing evidence that it is the skeletal muscle first and then liver second and that abdominal adiposity that drives diabetes. This thought of exercise treating the skeletal muscle and if you have activation of the pathway that starts to have adverse effects, I wonder if the combination of the low testosterone and the activation is a double-hit that leads to this metabolic remodelling, because we see signals in orchidectomy but it is not as overt. Of course if you have an antagonist that is going to be always blocking activation of those off-target pathways.
The final thing is what I mentioned earlier which is this T-cell activation of inflammation and again, if you are activating anything that causes inflammation in the body, it destabilises coronary disease. We know from cardiovascular epidemiology if you have poor dentition and chronic gingivitis from inflammation to your gums you have a higher risk of cardiac death because your immune system has this chronic low-grade activation and maybe that is one of the other reasons why these agonists are causing further activation of pathways in inflammatory plaque of the vasculature.
There is some preclinical data where mice that were essentially made to develop atherosclerosis treated with GnRH agonists have more inflammation in their blood vessels compared to those that had surgical orchidectomy or degarelix as an antagonist, but this is mechanistic and we are treating men not mice.
Francesco Montorsi: Thank you very much. That was very clear.
I will conclude with this question about the role of metformin in castration resistant prostate cancer. To the best of my knowledge there is an ongoing placebo controlled trial with metformin, but not on castration resistant prostate cancer, but certainly time will tell if there is an interest for this drug.
I think this was an interesting session. I would like to thank Ferring for organising this, you all being here at seven o’clock in the evening, the speakers, because I think that they gave wonderful talks and clearly our patients and families for their contribution. Thank you very much and enjoy the rest of the evening.