 I'm Perry Chinoski and welcome to this month's edition of kidney cancer news. My job is to talk about the integration of surgery and systemic therapy in the treatment of metastatic kidney cancer. I know that it's no secret to this audience the problem that is kidney cancer in the United States, the annual incidence is more than 50,000 cases. Because of the increased use of cross-sectional imaging, CAT scan MRI, we're seeing a large incidence of localized disease but also seeing a significant percentage of patients who present with metastatic disease and more than 30% of patients who present with locally advanced disease that we've just heard will progress to metastatic disease. We've come a long way in the treatment of kidney cancer back in 2000, back when I first joined the faculty back in 1998. The treatment was relatively straightforward, the vast majority of patients were treated with a radical nephrectomy removal of the entire kidney and a select few were treated with partial nephrectomy although at that time we really didn't understand or realize the importance of nephron sparing as Dr. Matine had pointed out. But nowadays we have a whole armamentarium of surgical options for patients who present with renal cell carcinoma where radical nephrectomy is actually becoming even more rare in terms of a treatment approach for patients. And the robot is changing the playing field. I would refer to myself as a reluctant laparoscopic surgeon but clearly the robot is making laparoscopic surgery more available and more facile for even dinosaurs like me. For those of you that asked me on rounds, don't you ever leave this place? This is a snapshot that explains why. These are the number of kidney cases that are done at MD Anderson over time. This year we're on a clip to do about 450, the vast majority of which I do but also Dr. Matine does as well. I joined the faculty in 1998 as you see here and I think Serenity joined in what 2000? 2002. 2002. And you can see that we're on an exponential growth rate. If I could just clone myself, this line would continue to go up. We're not doing just radical nephrectomies. We're doing a significant percentage of partial nephrectomies as well and you can see here again this line going up exponentially as the importance in nephron sparing has been realized and embraced here at MD Anderson. So again, my goal is to talk to you about the role of surgery and the integration of surgery with systemic therapy in the new targeted therapy era. If we were having this conference in 2006, this would be my last slide. Basically prior to 2006, there was not a lot to offer patients with metastatic kidney cancer. Basically those who had localized or locally advanced disease were treated with nephrectomy and those that had metastatic disease were treated with nephrectomy followed by systemic therapy which largely consisted of cytokine therapy or interleukin 2. And the response rates were dismal, usually less than 20% of patients responded to cytokines and those patients that had a durable response were even less, about 5%. But the truth is that those patients who did respond are the only patients in the treatment of kidney cancer that have actually been cured of their disease. So there still is a role for cytokines or interleukin 2 as we'll hear later on today. But at that time, the responses were very low. One of the benefits of what we've learned from the cytokine era from patients who were treated with interleukin 2 is that it has allowed us to group patients according to risk factors. So this is data from Sloan Kettering where they looked at patients who were treated with cytokines and they identified that those patients who had a prior nephrectomy had a good performance status, absence of anemia, a normal serum calcium and a normal LDH did better than those patients that did not. And if you had one or two of those risk factors that put you in an intermediate category and if you had more than two risk factors that put you in a poor risk category and it allowed us, even though we didn't really have therapies to apply, at least allowed us to give you an idea of what your prognosis was. But now we have more than, well, six therapies plus for the treatment of kidney cancer as you'll hear later on today, and we use those risk stratification to allow us to identify what would be the appropriate agent to treat a given patient. So what is the proper integration of surgery and systemic therapy in the setting of metastatic disease? Well, in the era of immunotherapy, there were two clinical trials, two randomized phase three clinical trials, one done by SWAG, which is a Southwest Oncology Group done here at the United States, and one was done in Europe, the EORTC, where patients were randomized to upfront surgery to remove their kidney followed by interferon versus interferon alone. And this is data from the EORTC study and this is data from the SWAG study, both of which demonstrated that patients who had their kidney removed prior to getting systemic therapy had a better survival than patients who were treated with their kidney in place. Now you'll see based on these data that the response rates, again, this is in the era of cytokines, were poor. And many surgeons referred to these studies as surgery plus ineffective therapy is better than ineffective therapy alone. And so these two studies solidified the role of cytoreductive surgery prior to systemic therapy in patients with metastatic disease. How does it work? I mean, isn't it sort of like closing the barn door after the horses have already left? Well, first of all, let me just tell you, as a native of Rhode Island, I can't tell you how much it bothers me that that just came out of my mouth. I've been in Texas too long, but there clearly is a role for the treatment of patients with metastatic disease with upfront surgery. Maybe it reduces tumor burden. Maybe that's how it works. Maybe it's an immunologic phenomenon where the surgery induces the exposure of some new tumor antigen. It allows the patient's immune system to attack what's left. Maybe it alters the metabolic milieu where the renal insufficiency associated with removing a kidney induces a metabolic acidosis, which somehow is anti-tumoral. Maybe there's some endocrine or paracrine factor that's being removed by the removal of the primary tumor. But the truth is, we honestly have no idea how it works, but we know it does, at least in the setting of immunotherapy. The group from Tufts University was the first group to describe the criteria that we use to select patients. Not everyone should have their kidney removed in the setting of metastatic disease. And they identified that those patients who could have at least 75% of their tumor burden removed, the absence of brain, liver, or bone metastases, good performance status, and clear cell histology did quite well with cytoreductive nephrectomy. And these are retrospective data from a variety of different institutions that ask the question, is it safe? And by safety, what I mean by that is, was the perioperative mortality low? And could most patients go on to get their systemic therapy? Because if we do surgery on you and you don't go on to get the systemic therapy, we probably haven't benefited you. And you can see from these retrospective series that with one outlier, the vast majority of patients, or the vast majority of series had acceptable perioperative mortality. And the vast majority of patients did go on to get their systemic therapy after surgery. We recently published our experience with cytoreductive nephrectomy here at MD Anderson, trying to ask the question, is there a better way that we can select patients? Because as many of you in the audience I've counseled in the clinic, there still are some patients who undergo cytoreductive surgery and for reasons we don't understand, their disease explodes after surgery. I can remember one patient that I operated on, literally on daily rounds I saw this nodal mass increasing in size in her neck over time. And she ultimately never went on to get systemic therapy and died very shortly after surgery. Clearly she did not benefit from cytoreductive surgery. So is there a way we can better select patients? So this is a retrospective study where we took patients who were treated with their primary tumor in place and asked the question, in our surgical series, how many of the patients that we treated with surgery survived as long or less than the patients who were treated with their primary tumor in place? We're in a very aggressive surgical institution. The vast majority of our patients with metastatic kidney cancer, we try to get them to cytoreductive surgery. So if you were treated with your primary tumor in place, you got to believe that those patients were, quite frankly, the worst of the worst. Otherwise they would have gone on to surgery. And then we said, in our surgical series, if you did not survive as long as the worst of the worst, then you probably didn't benefit from surgery. So the median survival of those patients who were treated with their primary tumor in place was 8.5 months. And we identified that those patients who had a low serum albumin, which is sort of a surrogate marker of nutrition, those patients who had an elevated LDH, another blood marker, the presence of liver mets, the presence of symptoms related to metastases, the presence of nodal involvement, and a locally advanced T-stage, all of those factors were associated with the worst prognosis. So if you had three or less of those factors, your survival was better than that medical group. And probably you did benefit from cytoreductive surgery. But if you had more than three of those factors, your survival was the same or worse than that medical therapy alone group, and you probably didn't benefit from cytoreductive surgery. And so now we're using these criteria to prospectively select patients for cytoreductive surgery. So if you come to the clinic with metastatic disease, we use these factors to try and better select patients who are likely to do well with cytoreductive surgery. Well, why not do cytoreductive surgery? What are the arguments against it? Well, the surgical morbidity and even mortality can be significant. These are big operations on big tumors. It's only been proven to be beneficial with interferon, and we all know that now interferon is an inferior therapy. It's quite possible that the patient may spend the rest of their life recovering from a surgery that you did to them. And it's also possible they may have significant disease progression post-operatively and never even get systemic therapy. It clearly delays the initiation of systemic therapy to treat the metastatic disease that the patient has. And we now have these new therapies that may treat the primary tumor. So maybe cytoreductive surgery isn't necessary. Maybe the delay in the morbidity associated with surgery is not worth it. We are seeing responses in the primary tumor with these new targeted therapies. So maybe we should avoid surgery. Maybe we shouldn't do cytoreductive nephrectomy anymore. Maybe we should treat all patients with just systemic therapy. There's a trial going on currently in France, leave it to the French, to ask this very question. So patients are randomized to upfront nephrectomy, followed by synitinib versus synitinib alone. The problem is this trial will not give a readout until about 2018. What are we supposed to do in the meantime? It's 2011, we've got seven years. Is there any data to guide us until this trial reads out? And the answer is yes. These are retrospective data from the expanded access trial with synitinib. And what they noted was that those patients who had a prior nephrectomy had a better response rate to synitinib than those patients who were treated with their primary tumor in place. They had a better progression-free survival and a better overall survival when they had their prior nephrectomy, prior to the treatment with synitinib. And Tony Schwere, who's gonna be talking to you later on today, published this data in the Journal of Urology very recently where he looked at patients who presented with metastatic disease and their primary tumor in place. 200 had cytoreductive nephrectomy, about 100 did not. And he noted that patients who had cytoreductive nephrectomy before receiving targeted therapy had a significantly better outcome in terms of survival than patients who were treated with their primary tumor in place, and that performance status was a significant predictor of outcome. Well, what about the concept of presurgical therapy? What this means is basically treating patients with their primary tumor in place. Maybe we could use it to better select patients for surgery and maybe we could even avoid surgery in those patients who have a great response. The benefits of this approach are that the targeted therapy may shrink the primary tumor and make the surgery easier, decrease morbidity. Maybe we could do more partial nephrectomies. Maybe we could make the unresectable resectable. Maybe it improves prognosis. Perhaps I think the greatest realization of this approach is that it can be used as a litmus test to better select patients. You're only gonna operate on those patients who have a response. What are the risks? Well, the risks are that targeted therapy doesn't just target tumor biology, it targets wound healing biology. So we may see an increase in surgical morbidity. And also, those patients who don't respond to targeted therapy, their disease may progress while on this therapy. This was the first presurgical trial that we did here in MD Anderson where patients were treated with bevacizumab, which is a vasten. And those patients that responded, we took to cyto reductive surgery after two cycles. And those patients that did not or progressed, we did not do surgery on them, but instead they went on to a different therapy. And this is a trial that we currently have ongoing. Some of you in the audience are actually on this trial where patients are treated with two cycles of pseudonitinib undergo nephrectomy and then continue with pseudonitinib after surgery. And this is a trial that we're just embarking on here at Anderson. And this is in patients with locally advanced disease. They're treated with a drug called exitinib, which is sort of a new and improved pseudonitinib has more activity. It's made by Pfizer and currently is undergoing clinical testing and probably will be approved in the coming months for the treatment of kidney cancer. So just like the advances that Dr. Matine talked about in his talk, where initially the gold standard was radical nephrectomy and then anything that came along had to measure up to radical nephrectomy with regards to cancer control, nephron sparing and being minimally invasive. I would argue that neo-adjuvant or presurgical therapy also has some several hurdles to jump before it can become part of our armamentarium in the treatment of patients. First, it has to be safe. Second, it has to improve patient outcome. And I would argue probably the least important factor, but still important is that it has to cause primary tumor shrinkage and decreased surgical morbidity. So let's cover those points. Is neo-adjuvant or presurgical therapy safe? The pitfalls associated with this approach, as I just said, are the targeted therapy, not only targets tumor biology, it targets wound healing biology. So there is the risk of having a higher incidence of wound complications. Also, those patients that don't respond and their tumor progresses, it may result in increased complexity of surgery. And when I say more ectomies equals worse outcome means the more things we have to take out of you to get your tumor out, the less likely it is you're going to do better. And timing is everything. If you are having a response to targeted therapy, why would we want to stop that to take you to surgery? And if you're not responding to targeted therapy, why would I want to take you to surgery? These are two patients that were treated with targeted therapy. These are CAT scans. And this gentleman was treated with sunitinib presurgically and was in a low speed motor vehicle accident three months after surgery and had complete dehiscence of his abdominal wall. That's his greater momentum sitting right there, which is the piece of fat that hangs off your stomach. And this is a woman who was a bit obese, but it was treated with presurgical avastin. And again, about three and a half months after surgery, coughed, felt something give, and these are her intestines that are sitting in the subcutaneous fat of her abdominal wall. And you could actually see the intestines peristalsing on her abdominal wall. So the potential complications associated with this approach are real. We recently looked at our experience with giving patients presurgical therapy. We had 58 patients who were treated with presurgical therapy and compared them to 100 patients who had an upfront surgery. These are the different agents that the patients got. The vast majority that Bevacizum have is a consequence of that clinical trial I spoke about. And we looked at complications and in the univariate analysis, indeed superficial wound healing was increased in the group that received presurgical therapy compared to the group that did not. And this was also true in multivariate analysis. But I would argue that a few superficial wound complications, no big deal if this approach holds promise in the treatment of patients. Let me skip that slide. So what about primary tumor downstaging and downsizing? Does targeted therapy shrink the primary tumor? Well, classically we're taught in the era of immunotherapy that when treated with the primary tumor in place, nobody responded in their primary tumor with immunotherapy. And in part, that served as the impetus to do site reductive surgery because the primary tumor never responded. Well, there are numerous anecdotes in the literature regarding targeted therapy. This was a patient who was treated at Cleveland Clinic. This is a CAT scan. You can see a very large tumor in the right kidney and another tumor almost completely replacing the left kidney. He was treated with Sunidinib, had dramatic response in both kidneys and actually was able to undergo bilateral stage partial nephrectomy and avoid dialysis. This is a patient treated here at MD Anderson with a locally advanced primary tumor in bulky lymph nodes who wonder what treatment with Sunidinib. And you can see the dramatic response in the primary tumor, but lymph nodes all went away and this patient actually was able to undergo a laparoscopic nephrectomy. So are these anecdotes or can we rely on these agents to reliably do it? Because if we can, I would argue let's give everybody targeted therapy because then maybe we can save a bunch of kidneys, do a bunch of partial nephrectomies and really help patients. Well, what's the data? This is the data. This was the first study that was published looking at response in the primary tumor. This was on 17 patients who were treated with Sunidinib and only a quarter of the patients actually had a response in their primary tumor and those that did respond, the volume of reduction was only 31%. Not bad, but not great. These are data from Cleveland Clinic where they again treated patients with Sunidinib with their primary tumor in place. And you can see that almost half of the patients in their study, the disease actually progressed on therapy and the vast majority of patients had either no response or disease progression in response to Sunidinib. These are data from our Bevacizumab trial where patients were treated with their primary tumor in place. And again, the same message, the vast majority of patients did not respond and in fact progressed on therapy in their primary tumor. These are data with Seraphinib from UNC and while all patients did respond, the median response was only 8%. And these are data again from UNC on a different study that they did with Seraphinib and you can see that they're, and this is called a waterfall plot and what it does is basically just show you the response in the primary tumor of all the patients in the study and you can see that some patients progressed on therapy. There were a few dramatic responses on therapy but the vast majority of patients had little if any response. And this is data from Roswell Park looking at Sunidinib. Again, some responders, some progressors, the vast majority of patients are sort of somewhere in the middle. And Jason Abel actually just recently published while he was here as a fellow at MD Anderson our experience with patients treated with their primary tumor in place, she reported on 168 patients. The reason why the patients were treated with their primary tumor in place are listed here. The vast majority either had widespread metastatic disease and were not candidates for surgery or they were enrolled in a clinical trial. And these are the therapies that they received. Sunidinib, Bevacizumab were the majority of the, were what the majority of the patients did receive. And here's that waterfall plot again demonstrating that there were some patients who had dramatic progression on therapy meaning their disease grew despite the therapy. Some patients had a dramatic response to therapy but the overwhelming majority of patients had little if any response in their primary tumor. The median tumor shrinkage was only 7%, which is really not, I would argue, clinically significant. And here that's shown graphically here. So then we ask the question, well, if we're not gonna really see responses, is there any reason to continue therapy with these patients? What this graph shows you is that the vast majority of patients who did respond to targeted therapy responded within the first 60 days of that therapy. So patients who had a greater than 10% response in their primary tumor within 60 days went on to have an almost 25% reduction in their tumor volume. Whereas those patients who had a less than 10% response had a maximum response of only 6%. So the message is, if you wanna try this approach to shrink the primary tumor, you're gonna see a response early. There's no point in continuing therapy beyond the first month or two if the patient doesn't demonstrate a response in their primary tumor of greater than 10%. Well, what about the issue of tumor thrombus? Tumor thrombus can be one of the most difficult surgeries to do, so maybe we could treat patients that get their tumor thrombus to shrink and make surgery easier. In this particular series, there were 44 patients who had a tumor thrombus and you can see only 7% of patients actually demonstrated a response. And one patient who had a level two thrombus, a level two means below the liver, progressed to a level four, which means the tumor grew up into the right atrium of the heart. So I would argue that the initial body of evidence would suggest that at least the current generation of targeted agents are not gonna result in significant primary tumor downstaging. So here's the report card. Is it safe? You know, increased incidence of superficial wound healing, we can deal with that. So I would argue yet safe. Does it downsize or downstage tumors? I think the data that I just showed you would argue that no, it does not. So is this still in advance in the treatment of patients? And I would argue, yes it is for the following reasons. In our Bevacizumab trial, we enrolled 50 patients in that trial, but only 42 patients underwent surgery. Six patients had disease progression and went on to receive a salvage therapy rather than nephrectomy. Now those of you in the audience might say, well gee, if you hadn't used that approach, you could have done surgery on those patients. I would argue that if they don't respond to the best therapy that we have for a systemic disease, all the surgery in the world is not gonna help that patient. So I would argue we saved those patients a surgery they were unlikely to benefit from. And more recently, Jason again, looked at 75 patients who were treated with their primary tumor in place with sunitinib with a median followup of 15 months. And what he noted was 24 patients or 32% of that population had a greater than 10% response in their primary tumor. And when he looked at outcomes for these patients and looked at survival, he noted that response in the primary tumor when patients were treated with sunitinib in a multivariate analysis was an independent predictor of outcome. Meaning that we can use it as a prognostic factor so that we treat you with sunitinib with your primary tumor in place and you have a greater than 10% response, your survival was 30 months as compared to those patients who did not have a response where their median survival was a year. So I would argue that cydoiductinifractomy is not really a question of if, it's more a question of when to do it. And to be honest with you, we still are not sure. There's currently a trial going on in Europe through the EURTC that's asking this question where patients are randomized to upfront surgery followed by sunitinib versus two cycles of sunitinib, cydoiductinifractomy, and then continued sunitinib. But again, the problem is, this trial is gonna take seven to eight years to generate a response and it's not clear what we should do in the meantime. So let me summarize by saying that targeted therapy has dramatically improved the outcome for patients with metastatic kidney cancer. Its efficacy in the adjuvant, neoadjuvant and pre-surgical setting is still under investigation. It's not clear when best to incorporate surgery with systemic therapy. But clearly the absence of complete responses to these agents means that surgery's going to remain as an integral part of the multidisciplinary approach, both for control of the tumor, the primary tumor, as well as metastasectomy, something we haven't had time to talk about today. Show me an agent that demonstrates a reliable, complete response and I'd be the first to argue that we should re-examine the paradigm and maybe remove surgery from the table. And the pre-surgical approach that I have to outline for you today I believe has merit but clearly needs further study and validation because it's really not clear when it is most appropriate to integrate surgery with systemic therapy. Thank you very much for your attention, I appreciate it. Join us again next month for another edition of kidney cancer news. I'm Keri Konoski, wishing you good health.