 I'm going to talk today about the promise of adjuvant and neo-adjuvant therapy in kidney cancer. So I think this point has been made already, but kidney cancer is a real problem in the United States, greater than 50,000 annual cases. About half of these are localized disease, but about half either present with or will develop metastatic disease in the course of their illness. Prior to 2006, we really didn't have a lot to offer patients. Those who had localized or locally advanced disease were offered nephrectomy, and those that had metastatic disease were typically offered nephrectomy, followed by some form of systemic therapy, which largely was immunotherapy. We'll hear more about that later. But the median survival for patients was less than a year. But it's a whole new world in the treatment of kidney cancer, and you'll learn more about this as the morning goes on. But we now have many arrows in the quiver to offer patients who present with metastatic disease, and it's really just a new horizon with regards to outcome for patients, improved survival, improved progression-free survival due to the employment of these agents. But while these are base hits, they are not home runs. And what we've learned is that these agents are not curative. They control the disease for a period of time, but the cancer ultimately learns to outwit these agents and grow back with a vengeance. And although we do have multiple choices to offer patients, ultimately patients who present with metastatic kidney cancer are destined, unfortunately, to die of their disease. So, you know, probably the most common question that I get asked by patients who are either getting ready to undergo surgery or have just undergone surgery is, am I going to need radiation? Am I going to need chemotherapy? So, what they're asking is, am I going to need adjuvant therapy or neo-adjuvant therapy? Adjuvant therapy means to give some form of therapy after surgical resection of all visible disease in the hopes of decreasing the risk of recurrence. Neo-adjuvant therapy means to give some form of therapy prior to surgery to potentially downsize or downstage the primary tumor and make the surgery easier. And also it may eliminate micrometastatic disease that has already gone on to spread. And then there's presurgical therapy, which means to give therapy in the metastatic setting prior to surgery as a prior removal of the primary tumor. In many ways this can be used as a litmus test where you only operate on the patients who are doing well with their systemic therapy and showing a response. So, here's a summary slide of where we stand with regards to adjuvant therapy. So, when you ask, am I going to need chemotherapy after my surgery to decrease the risk of recurrence, unfortunately the trash heap is replete with numerous agents that have been tested in the adjuvant setting, radiation, tumor embolization, energy ablative therapies, hormonal therapies, a variety of different immunotherapies, a whole host of different vaccines. We even did a trial with the drug thalidomide. And unfortunately not one of these agents has proven to be beneficial in the adjuvant setting. And as I showed you, we're now in the era of targeted therapy so where do things stand with regards to the efficacy of targeted agents in the adjuvant setting? Well, there have been numerous trials that have been performed. This is one such trial. This was with a drug called rencorrex. And basically it's an antibody against a protein that is not specific to kidney cancer but highly expressed in kidney cancer called carbonic anhydrase 9. And basically this was a randomized trial where half the patients got saline and half the patients got this antibody and then they looked and said, does this decrease the risk of recurrence? And the answer, unfortunately, again, is no. Patients that received the antibody did not have a decreased risk of recurrence relative to those who got placebo. One other use of this agent, however, that does appear to be promising if the company will continue its development is the so-called kidney cancer-specific PET scan where this antibody can be used to both identify the histology of a primary tumor in situ but also potentially identify metastatic disease that may not be clinically evident on conventional radiographic imaging. And this is the Assure trial. MD Anderson was the largest accruer to this trial. It was a randomized trial looking at patients who had locally advanced disease that underwent surgical resection and they were randomized to either one year of synitinib, one year of serrapinib, or placebo with the primary endpoint, again, being disease-free survival. This trial has completed accrual, meaning that all the patients we need to answer this question have in theory been enrolled in the trial and taken the drugs and now we're just basically sitting on our hands waiting for the result. What we have learned from this trial, however, we don't know whether these agents are effective in decreasing the risk of recurrence but they are toxic. And toxicity in the adjuvant setting is not really well tolerated as it is in the metastatic setting. And in fact, in this trial, almost half of the patients dropped out not because their disease recurred but because of toxicity. And my concern about this trial, this was a huge national effort, but my concerns about this trial are at the end of the day, if the trial is negative, is it negative because the drugs don't work or is it negative because not enough patients took the right amount of drug for the right amount of time or dropped out because of toxicity. The hope is that this trial is going to read out in the next couple of years. This is the S-Track trial. This was a trial sponsored by Pfizer. And I think of all the different trials that I'm going to show you this morning, this trial has the best hope of telling us whether or not synitinib in the adjuvant setting is effective. Again, patients were randomized to one year of synitinib versus placebo but the compliance rate for this trial, meaning the number of patients that actually completed the therapy is significantly higher than it was in the assured trial. Again, we're waiting for the answers on this trial as well. This is the source trial. This is ongoing over in the United Kingdom, I think also in Canada. This was a randomized trial looking at one year of syraphanib versus three years of syraphanib versus placebo. This was an extremely difficult trial to enroll to. I think even patients with metastatic disease have a hard time tolerating three years of syraphanib, never mind those in the locally advanced setting. You can see that it said primary result was due August 2012. It's currently what? April 2014. This trial hasn't even completed a cruel yet. This is the so-called protect trial. This was sponsored by GlaxoSmithKline. And this was an adjuvant study looking at the role of syraphanib in the adjuvant setting. Patients were randomized after surgery to one year of syraphanib versus one year of placebo. Again, this trial has completed a cruel. We're waiting to see what the results will be probably in the next three to four, maybe five years. That's really the challenge with these adjuvant studies, is that they take a long time to accrue patients, but then even longer to wait for patients' disease to recur to give us an answer as to whether or not these drugs are effective in the setting. There currently are two trials that are open and accruing patients. This is the so-called Everest trial. This is a SWAG or Southwest Oncology group study where patients are randomized to one year of everolimus, which is an mTOR inhibitor versus placebo. And this is, again, currently accruing patients. And then this is the so-called Atlas trial. Again, Pfizer, we're related to Pfizer, where patients are randomized in one-to-one fashion to three years of accident, which is one of the new targeted agents you'll hear more about today, versus placebo. So you can see that there's a tremendous amount of interest and a tremendous amount of research ongoing in the adjuvant setting to determine whether or not there is a drug that decreases the risk of recurrence. But in May 2014, or sorry, April 2014, the standard of care following surgery for locally advanced disease is observation. Radiation therapy, chemotherapy don't work. So now let's talk a little bit about neo-adjuvant therapy. And this is not a new concept, although it is very new in the treatment of kidney cancer. And, you know, 10 years ago, the idea of neo-adjuvant therapy for kidney cancer was a pipe dream. We had no effective agents that reliably were anti-tumeral. But it is the standard of care for a variety of different locally advanced solid tumor malignancies. We hear about it in patients who have breast cancer, bladder cancer, esophageal cancer, pancreatic cancer, rectal, gastric, and so forth. There have been numerous phase II trials in other malignancies, such as prostate and sarcoma. So why not kidney cancer? Well, at least traditionally, it's been a relatively chemo-resistant tumor. The chemotherapies that we give for things like lung cancer and breast cancer don't work in kidney cancer. And we really had no effective systemic therapies that reliably impacted tumor biology. But as I've alluded to, it's a new world in the treatment of kidney cancer. And over a period of approximately five years, seven new treatments were approved for the treatment of kidney cancer so that now we have many arrows in the quiver that we can aim at this cancer. So here's a typical case that I would see in my clinic. A 55-year-old white male presents with blood knee urine. He has a few comorbidities, hypertension, hyperlipidemia. He has a staging evaluation, which includes a bone scan and a CT chest, both of which are negative. And again, you can see a locally advanced tumor involving the left kidney. So just... There's a locally advanced tumor involving the left kidney. Here it is in sagittal section. And we all know that stage determines outcome. I mean, it is the most important predictor of outcome for patients. So this gentleman would be classified as a Stage 3. And you can see here that his five-year survival is about 60%. But if you're a glass half empty kind of person, that means that he's got a 40% chance that his cancer is going to come back and he's going to die of kidney cancer. So what are his options? Well, radical nephrectomy, followed by risk-based surveillance, that would be considered the standard of care. His risk of recurrence, again, is somewhere between 40% and 60%. And if he does recur, he's not likely to be curable. He could do radical nephrectomy, followed by adjuvant therapy, but this can only be done really in the context of a clinical trial, because as I just got done telling you, there are no effective adjuvant agents. He could enroll in the ATLAS or the Everest trial, which are currently ongoing, but he's got a 50% chance of getting a sugar pill. He's got a greater than 50% chance of either reducing his dose or stopping therapy early due to toxicity. And to be honest, except for the tincture of time, there's really no way to assess efficacy. If he remains NED, is it because he had a fantastic surgeon or is it due to the drug? We may never know. So why neoadjuvant therapy? Well, preoperative systemic therapy may eliminate micrometastatic disease and improve prognosis. It may downsize or downstage the tumor, allowing us to perform nephron sparing, which we heard from Dr. Matine as critical, or allow us to do a minimally invasive approach to a large tumor. And we can also look at evidence of response to therapy to potentially influence therapy in the future if the patient does demonstrate evidence of metastatic progression. So why not neoadjuvant therapy? Well, maybe your tumor didn't read the book and didn't know that it was supposed to respond to the therapy and may progress locally or regionally or even systemically. And we may lose that window of opportunity for cure, but I would argue with you that if your tumor is so bad that it doesn't respond to the current agents that we have to treat kidney cancer, you're probably not curable anyway. And it's also possible that the toxicity of therapy may increase the morbidity of surgery. You have a patient with a large tumor that's already a man-eater and you beat them up with systemic therapy, they don't make great surgical cases. So for a neoadjuvant therapy to take hold, I would argue that it has several hurdles to jump, just like partial nephrectomy did 20 years ago. Patients who presented, even with a one centimeter tumor, increased nephrectomies until partial nephrectomy was demonstrated to hold oncologic equipoise or equivalent cancer control to radical nephrectomy. And then it had the added benefit of being nephron sparing and now we have minimally invasive approaches, as you've heard. Well, neoadjuvant therapy has several hurdles. It has to be safe. We have to demonstrate that patients don't have disease progression or increased surgical morbidity associated with surgery. It has to improve patient outcomes. And, you know, as you just heard from Dr. Karam, it is the rare patient that has an unresectable tumor. But if you can get the tumor to be smaller, perhaps you can increase utilization of nephron sparing and minimally invasive approaches. So is neoadjuvant therapy safe? Well, these are two patients of mine that receive presurgical therapy. So they have metastatic disease, but one gets, bevacizumab and one gets synitinib in the presurgical setting. And you can see on these radiographs that this patient had complete abdominal wall dehiscence. This is actually his greater omentum, which is a piece of fat hanging off the stomach sitting on his anterior abdominal wall. And this is a woman who received bevacizumab in three months out from surgery. She coughed and heard something give and all this white stuff here was her small intestine sitting in the subcube. You could literally see it peristalsing on her abdominal wall. So there could be real problems with complications associated with this approach. Well, Brian Chapin, who's a member of our faculty and speaking later today, when he was a fellow did a retrospective review of our experience with presurgical therapy and asked the question, is it safe? Looking at complications within the first year of surgery. So he compared a group of patients, 70 in fact, who had presurgical therapy to a group of patients who had upfront surgery and asked, was there a difference in the rate of complications? And the short answer is no. There was a difference in complication rate between those that had upfront surgery and those that received presurgical therapy. However, there was a significant difference with regards to the type of complications. Those patients who received presurgical therapy were much more likely to have a wound complication relative to the patients that had upfront surgery and they were also more likely to have delayed complications. But in fact, presurgical therapy was the most important predictor of having a wound complication in this series with an odds ratio of almost four above four. But in terms of predicting overall complication rate, receiving presurgical therapy was not a predictor of complications in this setting. So again, you're more likely to have wound complications with presurgical therapy but in terms of the overall rate of complications that are equivalent between the two groups. So then we asked the question, okay, if patients are more likely to have a wound complication, is there anything that we can look at that might predict it? So that maybe at the time of surgery we can do something to the wound, put in retention sutures, leave the staples in longer, put in more unobservable sutures to decrease the risk of them having a complication. And we found that those patients who had a decline in their serum albumin, which is a blood test that we can get, those patients were more likely to have a wound complication and therefore we could do something at the time of surgery to reinforce their wound. One of the other things we noted from this study from the perspective was that those patients who had presurgical therapy did not have a different survival from the group that had up front surgery. So what that tells us is that with this approach we're not hurting people, we may not be helping them, but we're not hurting them by using this approach and studying it in this setting. And that's shown graphically here. So what about primary tumor downsizing or down staging? Are we seeing that with presurgical therapy? Well, classically in the era of immunotherapy, and these are patients that were treated nobody had a primary tumor response. And in large part, that's why we're doing cytoreductive nephrectomy, something you're going to hear about in subsequent talks today for patients with metastatic disease. But there are numerous reports in the literature showing things like this in patients who receive targeted therapy. So you can see here this patient has a locally advanced tumor involving his right kidney, as well as one involving his left kidney, and he receives synitinib and went on to have bilateral partial nephrectomy, saving his kidney improving his overall renal function. And this is a patient of Dr. Matines. Again, locally advanced tumor involving the left kidney here with bulky lymph node involvement and went on to receive synitinib and you can see a dramatic shrinkage in the tumor and loss of the lymph nodes, and this patient actually went on to have a laparoscopic nephrectomy. And this is a patient that we treated with exitinib, something I'm going to talk about in a few minutes. Again, locally advanced tumor involving the left kidney that shrank dramatically with exitinib therapy. And here's the surgical specimen. You can see a huge reaction around the kidney tumor. And this is one more example. So the question is, are these anecdotes or can we reliably rely on these agents to downstage tumors? Because I was arguing let's give it to everybody and then maybe we can increase the utilization of nephron sparing. Well, this was a study that was published some time ago looking at patients who were treated with their primary tumor in place with synitinib. The response rate in the primary tumor was about almost 25% with a mean volume reduction of 31%. Well, we published a study a few years ago looking at 168 patients who were treated with their primary tumor in place. These are the different agents that the patients received, the vast majority receiving synitinib which was the standard of care and remains. And you can see that the overall response rate unfortunately is a very disappointing 7.1%. Okay? So that means that you have a 10 centimeter tumor if you give pre-surgical targeted therapy it's going to shrink to 9 centimeters. Kind of a let down. And while there were some patients who had dramatic progression and some patients who had dramatic regression the overwhelming majority had little of any change at all. So what about patients who have a venous tumor thrombus? We heard from Dr. Karam how difficult those surgeries can be can we maybe shrink the tumor thrombus and make the surgery easier? There were many patients in this study that had evidence of tumor thrombus and again unfortunately the overwhelming majority had no response. 75% had stable disease 15% of patients actually progressed on therapy and only 10% of patients actually regressed. The good news is however treating patients didn't hurt them there were no cases of pulmonary embolism. So I would argue that the initial body of evidence would suggest that this significant primary tumor down staging is not going to be realized by the targeted agents although the jury is out with regards to newer agents so I'm going to show you some data that's kind of exciting in that regard. So we recently completed a trial and this was just published in European Urology looking at the role of neoasbin excitinib in the locally advanced setting. So we took patients that did not have metastatic disease had locally advanced tumors treated them for three months with excitinib and then took them to surgery. So I want to give you an idea I was the principal investigator of this trial so we have the guy sitting in front of us he has a locally advanced tumor probably presented with blood in his urine and it's curable with surgery and I say to this guy we want to give you this drug it's going to make you feel like crap may work, may not work we don't really know we're going to give it to you for three months your tumor may in fact progress while you're on therapy and then we'll take you to surgery otherwise we could take you to surgery now in Curia what do you say? So I actually mired the bravery of the first guy that went on this trial because once we could demonstrate that we were seeing responses it was much easier sell to patients and then we were able to rapidly accrue to this trial so patients started at a dose of 5 mg twice a day for 12 weeks and they titrated up to 10 mg a day and we continued the drug until about three about a day and a half before surgery 24 patients and there's the clinical criteria right there all of them were stage 3 at the time of presentation 22 patients stayed on drugs for the whole three months one patient stopped at 11 weeks all 23 patients underwent surgery as planned without delay one patient had to stop at 7 weeks due to toxicity and was taken to surgery early and in this trial we had a 46% unheard of 46% partial response partial response means that the tumor shrank at least 30% and 13 patients had stable disease and importantly nobody progressed while they received the drug so these are the tumor plots and you can see from this that the overwhelming majority of the response is within the first 6 to 7 weeks and that the following 6 to 7 weeks there really wasn't much of an additional response and that's important to us as clinicians because what it tells us if we don't see a response early we're not going to see a response and it's time to move on and this is a waterfall plot again demonstrating the response that we saw so a partial response was within 30% and here you can see that almost half the patients had that significant response which from a surgical perspective I would argue is clinically significant so 19 patients were treated with radical 5 with partial 19 open, 5 laparoscopic and you can see the pathologic stages there now this drug was not without its toxicity significant number of patients had hypertension some had hoarseness the vast majority had fatigue some patients had hypothyroidism some of the toxicities were reversible and I would argue that 3 months of toxicity before surgery versus 1 year of toxicity after surgery is probably better tolerated and this is another example of a response I think I showed that so we concluded that exidinib is well tolerated in the neoadjuvant setting that it showed downsizing activity when given for 12 weeks prior to surgery and that adverse events were common but easily manageable so here's where we stand effective adjuvant and neoadjuvant therapy do not exist for kidney cancer in the year 2014 toxicity of targeted therapy in the adjuvant setting is poorly tolerated and may impact efficacy effective neoadjuvant therapy may increase the utilization of minimally invasive and nephron sparing surgery which we learned is important neoadjuvant and pre-surgical approaches may also be used as a litmus test to better select patients for surgery but you should leave here knowing that adjuvant and neoadjuvant approaches are not the standard of care and clearly they need further testing in the context of clinical trials thank you very much for your attention