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Umberto Capitanio: Good morning, everybody. Actually, I'm very excited to be here this morning. I'm going to show you in a few minutes what we have learned in the last 10 years in terms of kidney cancer research. I would like also to thank Professor Necchi because I think that he put together something very, very special. The program is amazing, and again, I'm very honored to be part of this fantastic program.

Actually, I also want to highlight, I think, a very pretty cool thing. When I was preparing these slides, I just realized that the logo of the hospital, so the San Raffaele logo, is actually a graphical representation of a kidney with the renal archery, the renal vein, the renal pelvis. So, probably this means that kidney cancer research is and will be very key in the future of the San Raffaele hospital.

Anyway, so what we have learned in the last 10 years. 10 years ago, 2012, at the time, the world was ending. You remember the Mayan prophecy? So, probably according to the eschatological beliefs that some events would occur on December 2012, the world was actually ending. What I'm saying, that if you take a look to 2012, we had some recommendations that are completely now different in kidney cancer from a clinical point of view, surgical and also in terms of medical oncology.

Have a look to all the stages of patients with kidney cancer. First of all, according to the international guidelines 2012, surgical therapy was the only curative therapeutic option for the different treatment of RCC. And take a look, radical nephrectomy. Partial was accepted in selected cases, and only open and laparoscopic surgery were in the field. No robotic.

However, now 10 years later, we have so many options in T1 and T2 kidney cancers that are accepted in all international guidelines. First of all, active surveillance. We have so many prospective studies that now have been published. One of the most important one come from the US. The registry is one of the PI of study. And now, we have also the long-term follow-up of patients observed in active surveillance programs. We know that if the patient is well-selected, we can expect a very low grow rate over the year. We know that less than 20% of patients will have a very fast grow rate, and we also know that after the first or two years of observation, the grow kinetics rate stabilize thereafter. So, those are patients that can be safely followed, and the cancer-specific mortality with very stringent selection criteria is virtually zero.

Another therapeutic options in case of stage one and stage two kidney cancer patients are all the focal therapies that we can use. We have several energies. And again, we don't have randomized clinical trials, but all the retrospective studies confirm that at least when the tumor size is smaller than three centimeters, we can safely use all these options.

Then, unfortunately for urologists, also new treatments are coming. For example, the stereotactic ablative body radiotherapy. This is the last publication in Lancet Oncology just a few days ago. Now, we can treat with this kind of external radiotherapy, also organ-confined disease. What I think is very exciting is that, I mean, the authors took a look to many outcomes. These are almost 200 patients. But if we take a look to the cancer specific survival and the follow-up was longer than five years, we got, especially in patients receiving a single radiation therapy, a very similar cancer-specific survival relative to patients treated with, for example, surgery. Also, related to the fact that this kind of external radiotherapy has a virtually no grade three or four toxic effects and also no effect in terms of chronic kidney disease or detrimental renal function. So, again, is not the good news for the urological department, but probably this is something that will be very important in next future.

Take a look now to the stage three, so locally advanced disease. Again, we can come back 10 years ago and in the guidelines, there is no indication for adjuvant therapy following surgery. Actually, also in the years later, we thought that probably there was no field for adjuvant therapy because all the randomized clinical trials that were published using in comparison to placebo, all the TKIs were completely negative.

So, probably we were thinking, okay, probably it's true, adjuvant therapy is not useful in kidney cancer patients. However, last year, two years ago actually, was published the KEYNOTE-564, that was this very important randomized clinical trial using pembrolizumab. So, not a TKI, but immunotherapy in the advanced setting. For the first time, we could see a significant benefit, at least in terms of progression-free survival, because the other survival is not mature. But probably we'll see in the next future, but we see a significant benefit for progression-free survival for patients receiving pembrolizumab after nephrectomy.

Obviously, not in all the patients, but those patients with the characteristics for higher recurrence rate in the month later, after the surgery. This is the last update that was published in Lancet Oncology. Now, the follow-up is longer than three years, and again, the hazard ratio of 0.63 was confirmed. So, probably we hope at least that we will see also an overall survival effect in the next years and will become the standard for our patients with a locally-advanced disease or also patients with the metastatic disease that are without metastasis after metastasectomy. That was another criteria of inclusion of this trial.

The last part is a stage four, so we are talking about metastatic disease. Again, let's have a look to the recommendation in 2012. At the time, cytoreductive nephrectomy was recommended even in metastatic RCC because there were two randomized clinical trials confirming that nephrectomy was important even in presence of metastasis. The trials were both from [inaudible 00:07:27] and Flannigan, both demonstrating a statistical significant benefit for patients receiving also a nephrectomy. The medical therapy was based mainly on sunitinib, bevacizumab, and pazopanib.

Now, everything again after one decade has changed because a nephrectomy is not any more standard. Was published an important paper that was the CARINA trial comparing patients receiving sunitinib alone or sunitinib plus a cytoreductive nephrectomy. Again, unfortunately for urologists, but the child was negative. This means that sunitinib alone was not inferior in comparison with sunitinib plus nephrectomy. However, as you know, this was based on sunitinib, so a TKI inhibitor that is not anymore the standard. Now, we use immunotherapy and also we have very frequently in clinics, symptomatic patients. My point is that probably also in the field of immunotherapy, cytoreductive nephrectomy has still a role, but not in all the patients it was 10 years ago.

Finally, also the drugs completely changed. Sunitinib is not anymore the standard. Now, we have combination therapy. These are the four combinations that are approved at least in the European EAU Guidelines. So, the combination are immunotherapy plus immunotherapy or immunotherapy plus TKI inhibitors.

The second part of my presentation is related to what changed in terms of research and clinical and surgical point of view in the last 10 years. First of all, functional outcomes. 10 years ago, all the urological research was focused on many surgical aspects. So, ischemia, time, bleeding, complications, so on. What we understand now is that probably patients' outcomes are even more influenced by other things, especially from comorbidities, frailty, cardiovascular events, renal function. So many other things that should be considered in the urological research as well as in the medical oncology research, because probably are going to affect even more significantly all the outcomes.

For example, chronic kidney disease. So, a functional outcomes is probably difficult to see the correlation, but a patient that is going to develop CKD is also an effect in terms of cancer-specific mortality. Because CKD can lead to a loop in which the immune system is both activated and suppressed. And finally leading to uremia-related immunodeficiency with a loss of function of lymphatic cells, attrition of telomeres, a lot of things that leads to a premature immunological aging. Also, the CKD may decrease the physical mental health status of the patient. So, you can see that the preservation of the renal function may also have an effect at the end of the day to the cancer control in that specific patient.

The second point is frailty. Especially in the medical oncology literature, but now also in the surgical research, we understood that besides age and comorbidities, the so-called frailty that is related to age comorbidities but is not the same concept, is a very, very important predictor of all our outcomes. To be able to understand which patient is frail, means also to target this frailty and maybe to improve all the outcomes. Talking about also complications, transfusions, length of stay, and also the economical burden to cure our kidney cancer patients. This topic that 10 years ago was completely neglected, nowadays is one of the most important things, also in all the trials that are ongoing.

The third thing is related to the fact that centralization of the cure is a key to improve patient's outcomes. This was one of the most important publication in European Urology in 2018, showing that the quality of what we do in terms of surgery, for example, is going to affect not only functional outcomes, quality of life and so on. But also in an independent way, also the overall mortality of the patients. This means that how we centralize the care, how we interact with the medical oncologist and all the doctors that are involved in the care, this is going to change the long-term history of our patients.

Final, genomics. Now, we have so many papers showing that if we can understand within the tumor but also in the germline of the patient, which is the chromosomal complexity, the diversity, and so on, we can at least predict and hopefully in the next future also to choose the best treatment according to the fact the patient will have a low risk of progression or a very slow progression or a very rapid progression. We are starting to analyze this. Probably is not still a standard of care, but will be the next future.

Indeed, what I show you in these few slides is that in the last decade, everything changed for patients with kidney cancer. But probably in the next decade, will be even more changes. Because still, we don't have any biomarker in screening, detection, prognosis, prediction and follow-up. There are several papers, there are several ongoing trials, but no biomarker is nowadays the standard, in clinical decision at least. Radiomics. Because still, we are using standard imaging to characterize our patients. Professor Briganti show you regarding PSA, PSMA, PET. A lot of things that unfortunately in kidney cancer are not still the standard.

We will have a more tailored clinical decision. Drugs are coming, new drugs. Finally, as I told you, probably SBRT, especially in combination with monotherapy, will become the standard in the oligomet population and probably also in patients with organ-confined disease, and also disseminated metastatic kidney cancer.

So, I open these very few minutes to giving you a summary of what happened in the last decade was a very exciting decade. Hopefully, in the next years, we will see even more changing, very important for our patients, for all we do for the research. Thank you. Thank you very much for this honor.