 Good morning. I would like to thank the organizing committee for the opportunity to be here today to discuss the role of metastasectomy in patients with kidney cancer. This is my disclosure. And this is the outline of the talk for the next nine minutes and 46 seconds. I'm going to start simply with the epidemiology and as we know from the statistical papers that come every year, there's about 65,000 patients who will be diagnosed with kidney tumors. About 90% of those will have kidney cancer. And almost one third of the patients will have synchronous metastases at diagnosis. And about 30 to 40% who are initially non-metastatic will develop what's considered to be metachronous metastases. So there's a large number of patients who ultimately will have metastasis and need to be treated either by drugs or by surgery. There are several challenges in patients with metastatic kidney cancer. The minority will respond to cytokine therapy. There are rare complete responses with targeted therapies. And the disease is typically not responsive to chemo or radiation. So I'm going to review very briefly a few retrospective studies that show some survival benefits for patients who undergo metastasectomy. This is the Kevolya study, one of the first and most cited papers on this topic from Memorial Sloan Kettering that showed that in patients who had complete metastasectomy, the five-year overall survival is about 44%. This is another paper from Memorial Sloan Kettering. Again, five-year survival, if you've had any metastasectomy, is about 49%. And this benefit was seen across the Memorial Sloan Kettering risk groups. This is a large multi-center European retrospective study, again, showed that if you've had any metastasectomy done, your five-year overall survival is 44%. And this is one of the more recent and more thorough and well-analyzed papers from the MEIA group that showed if you do a complete metastasectomy, the five-year cancer-specific survival can be 45%. Let me go through a few metastatic sites, and I'll start from the top and work my way down. The brain, we can do different treatments, including surgical resection, stereotactic radio surgery for specific lesions, or whole brain irradiation for patients with multiple brain meds. Unfortunately, these are associated with other metastases, and the overall survival is poor in this particular patient population. However, there are some good prognostic factors if you have one brain metastasis, if it's suprateontorial, and if you don't have any symptoms at the time of diagnosis. Thyroid gland is another organ that can be affected by metastases, and metastasectomy is possible with a five-year overall survival of about 51% if surgery is done. Lung, as you know, is the most common organ, and surgery can be anywhere from a simple wedge-reach section up to a pneumonectomy in selected patients. However, you certainly need good pulmonary function to have this kind of surgery, and a five-year overall survival in this group can be anywhere from 31% to 37%. A good outcome can be achieved occasionally in patients who have a complete resection, who have a disease-free interval of two years or longer, and in the absence of medias tonal metastasis in the lymph nodes, and in patients who have a small number of pulmonary metastasis. Unfortunately, liver is one of those organs who, in kidney cancer, if you have a metastasis in the liver, it's not a very good outcome. The two-year survival in one study was 56%. In another study, the median survival was 16 months. However, you could have better outcomes if that's done with a curative intent with a lung disease-free interval in smaller tumors with normal laboratory values. Pancreas is one of those organs that actually have a good prognosis if metastasis is discovered. And this is a very nice meta-analysis of over 300 patients that most of these patients, or two-thirds of them, had a solitary pancreatic metastasis. Most of these metastasis are actually metachronous. They occur about 10 years after the nephrectomy. And surgery can be anywhere from a simple nucleation of the lesion to a distal pancreatectomy to all the way to a Whipple procedure in very selected patients. The five-year overall survival in patients who have pancreatic metastasis who undergo successful surgical resection can be over 70%. And the predictors of good outcome in this meta-analysis are if you have no extra pancreatic disease, so a solitary pancreatic metastasis, and if you have no symptoms related to the metastasis in the pancreas. Bone surgery or metastasectomy can be done for different reasons. It could be done for patients who have no symptoms, but from the images one can tell that there is an impending pathological fracture. So this is done prophylactically. It can also be done for symptomatic patients, either because of pain or neurological compromise, but it can also be done in very selected patients for curative intent without any symptoms or impending fracture. The five-year survival is poor in the majority of patients. However, the selection that we can use can improve the survival if the patient has one bone lesion, a long disease-free interval, and surgery is done with a curative intent. The retroperitinium is another organ where local recurrences can be noted, and this could be anywhere from the adrenal gland to a FASA recurrence to lymph nodes, and this is a retrospective study on 54 patients, and this study noted five predictors of poor outcome. They were surgical margins if they're positive, if they're a sarcomatoid component, if the size was more than five centimeters, and if you have abnormal laboratory values, such as alkaline phosphatase and LDH. The survival, if you had none of these risk factors, was 111 months, and if you have one, it was 40 months, and if you have two and more, it was eight months. So the next four minutes, I'll talk about the integration of systemic therapy in metastasectomy. We talk about this more often inside of reductive nephrectomy. I don't think we discuss it as much in this setting, and I'm gonna introduce these new terms, the pseudo-neoadjuvant therapy and the pseudo-adjuvant therapy. I promise I didn't make up these terms last night. These are terms that have been used in other cancers, such as colorectal, breast, and soft tissue sarcomas. The pseudo-neoadjuvant therapy is for a patient who had a metastasis. They have targeted therapy or immunotherapy, and then they have a metastasectomy, and the pseudo-adjuvant therapy is when patients have a metastasis, they then have a metastasectomy, they are NED, and then they have systemic therapy. So let me start with the pseudo-neoadjuvant. This is a retrospective study on 38 patients who had immunotherapy. They had no progressive disease, and then they had metastasectomy. 76% had a complete resection, and 90% had additional pseudo-adjuvant therapy. The median time to progression was almost two years. The median survival was almost five years, and eight patients were NED at the last follow-up. And in this retrospective study, the predictors of good outcomes were being NED after surgery, and those 76% of patients, and if a patient had a pulmonary metastasis. This is another study that used targeted therapy this time, another small study retrospective, and the recurrence rate was half the patients had a recurrence, and nine of these patients did receive targeted therapy after the initial surgery, but the mean time off the targeted therapy was over a year. Survival for the 21 out of the 22 patients were still alive at 25 months, or over two years. But a word of caution, all this retrospective small study is shown that this is feasible, but is certainly not a standard of care when faced with these patients. The pseudo-adjuvant therapy, I went to clinicaltrials.gov and found three studies. One of these studies already was briefly mentioned today by Dr. Haas, the last one on the right. And these are the identifiers here, in case you need to look up some more information. These are all randomized, either phase two or phase three studies. The drugs are anywhere from seraphonib to synitonib to bisopenib in these studies. The metastasis site can be in any location or pulmonary only. And again, this is pseudo-adjuvant, so patients had a metastasis, had metastasectomy, or NED, and then were randomized to either placebo or one of these drugs. Most of these were clear cell only, and the primary endpoint as expected in this group was disease-free survival. Just some random thoughts when doing this talk. I think we need to better select patients as far as when we are faced with synchronous disease or metacronous disease. When do we pull the trigger and say, okay, you need a metastasectomy now? I don't think we know that very well yet, and it's very subjective. Can we use the pseudo-neoadjuvant therapy as a litmus test in this patient population to decide if we should proceed with metastasectomy or not? What about metastasectomy in non-clear cell histology? And I think we should report the number of patients who have metastasectomy in phase three targeted therapies. When I looked at the seminal phase three trials, I could never find the word metastasectomy in those trials. Maybe they're having it and they're not reported or maybe the patients aren't having metastasectomy. And an important question in our practice is how many patients are potentially eligible for metastasectomy and are not getting it? Maybe they're not being offered metastasectomy, maybe they're not eligible, but I think whenever we see a patient with a small number of metastasis, we should always keep in the back of our mind not just seraphanib, synatinib, all the IBS, besopenib, devosinib, but maybe simple metastasectomy might cure the patient. And the question that I had is how many patients have solitary metastases in recent studies? Most of these studies include patients with ECOG zero or one and they're good or intermediate risk, except the synatinib open access study because it included 7% of patients with brain mats, 13% of patients non-clear cell and 13% of patients with poor risk. But if you look at these trials, anywhere from 14% to even 31% in the most recent trial have solitary metastasis. And these are numbers I got from table one and from supplementary tables from the papers. So up to potentially a third of patients have solitary metastasis, but you can't find the word metastasectomy anywhere in that paper. So some take home messages, metastasectomy is important in selected patients, not in every patient, of course, with kidney cancer and we should consider it at least in patients who have good performance status, good surgical candidates, limited metastatic burden, a long disease-free interval, but we can also use it for palliative purposes in very selected patients and it's ideal when complete resection is feasible, but there are some papers that show that even incomplete metastasectomy is better than no metastasectomy. I believe we need better tools to select the patients who are qualified for this type of surgery and we should continue to study integration with systemic therapy. There are three pseudo-adjuvant trials I mentioned, but there are no pseudo-neo-adjuvant trials that are being done and that's potentially something that can be explored. Thank you very much.