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mRCC: Cytoreductive Nephrectomy in the Modern Era

Panelists: Daniel George, MD, Duke Cancer Institute ; Robert J. Amato, MD, Memorial Hermann Cancer Center; Toni Choueiri, MD, Dana-Farber Cancer Institute; Richard W. Joseph, MD, Mayo Clinic; Walter Stadler, MD, University of Chicago
Published: Wednesday, Jul 25, 2018



Transcript: 

Daniel George, MD: At ASCO this year, we had a plenary session devoted to kidney cancer and in particular on a study out of France that looked at the role for cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma. The results of a phase III noninferiority study, called the CARMENA study. Walt, do you want to summarize this study for us, and then maybe we can have a little bit of a discussion about the clinical implications of these results.

Walter Stadler, MD: This was a critically important study that followed up on observations from almost 3 decades ago, in which a nephrectomy with interferon had a survival advantage over interferon by itself. That study has led to now 3 decades’ worth of discussions of the role of nephrectomy in the context of metastatic disease. It’s very gratifying to finally see another randomized study that is rigorously addressing this particular issue in the context of modern therapies. In this study, patients with good performance status of 0 and 1, but intermediate- or poor-risk disease, were randomized to either an up-front nephrectomy followed by sunitinib or sunitinib by itself. It was designed as a noninferiority study in the sense that it would be considered noninferior if the hazard ratio was no greater than 1.2. In this small study, the noninferiority margin was not met. In other words, it did look like, surprisingly, the patients who received the sunitinib without nephrectomy did better.

Daniel George, MD: Interesting. Toni, what’s your take on this study?

Toni Choueiri, MD: I think there is a lot to be done. I want to congratulate my French colleagues for finishing the study. We couldn’t do it in the United States. Many felt there’s no equipoise, and here we go with the CARMENA studies. I do think patient selection—Bob was saying that it’s key, and it remains key for CARMENA. Patients with intermediate risk, great performance status, who are young, who can go quickly through surgery and have a limited disease burden outside the kidney, should be considered strongly for an up-front cytoreductive nephrectomy. We shouldn’t take that option away. The other question I would add, Dan, is that currently we’re seeing combinations—nivolumab plus ipilimumab. Walt also mentioned cabozantinib; Rich mentioned that too. These are beating sunitinib frontline options, and we are seeing combinations with checkpoint blockers and TKIs against sunitinib. The field where you consider sunitinib as control is evolving. Will other, modern frontline therapies be applicable to a CARMENA-like study? I would say yes, probably yes.

Daniel George, MD: Rich, how will you apply this in your practice?

Richard W. Joseph, MD: That’s a great question. First of all, I’m very happy that this study was able to be done, as Toni mentioned. It’s very hard to do these studies, especially when surgery is involved and randomizing patients. The issue with this study for me is that it’s not exactly how I practice today. For instance, I rarely will, if a patient presents with metastatic, go to up-front nephrectomy. I almost always have a trial of some systemic therapy, wait a period of time, whether it be 3 to 6 months, and then pick the patients who are doing well who you think can withstand a nephrectomy. In this study, there were a lot of poor-risk patients that I probably wouldn’t have sent straight to surgery. We probably would have tried to get them with a better performance status. I know they were all 0 to 1s, but maybe we would have probably tried to debulk them to some degree. There were 40 patients on the arm that went to surgery that never made it to Sutent (sunitinib), so that leads me to believe, were these sicker patients than we’re typically dealing with that we might not have sent to surgery? The question for me still remains, what is the role of nephrectomy in the modern era? We need to address this question. If I were to design the study, I would probably think more about giving the up-front systemic therapy, and then randomizing from there, and trying to pick patients who are still good candidates at that time.

Daniel George, MD: Interesting.

Walter Stadler, MD: The burden of proof now falls upon the physician who wants to do nephrectomy first. We have a randomized phase III, apparently well-done trial where patients who got nephrectomy up front didn’t do as well. So, if you’re going to offer that to your patients, and you’re going to have to defend that as an appropriate option, and why this trial does not apply to that patient, I do think that we have to recognize that.

Daniel George, MD: I want to clarify something, Walt, because you said they don’t do as well, but this was a noninferiority study, and it was a 1-sided noninferiority study to really look to see whether sunitinib alone was noninferior to nephrectomy followed by sunitinib. Can we really say that sunitinib is superior to nephrectomy followed by sunitinib?

Walter Stadler, MD: You’re correct that it’s not superior, but now, in essence, you would be offering another intervention that has toxicities and side effects that you have not proved are better, and you haven’t even proved it’s the same. The burden on any physician providing any therapy, drug, radiation, or surgery—when you can’t even prove that it’s the same as not doing it, you have a burden.

Daniel George, MD: Is the standard of care now, for patients who present with metastatic renal cell carcinoma, to do a biopsy to evaluate the tumor, assuming that we’re going to start with systemic therapy, or are those patients still going to go first to the surgeon and get a nephrectomy and then come to a medical oncologist afterward? Does this change our referral pattern, our whole practice pattern, for up-front metastatic kidney cancer?

Toni Choueiri, MD: If you need to, you may think of a systemic therapy first; you have to do a biopsy. That has been historically a challenge because many times we ask for a biopsy, and it’s a fine needle aspiration that puts us at a problem where a patient could have renal cell. There is no information, of course, about the grade, sarcomatoid differentiation, even histologic subtype; so, at the very least, we have to go to a biopsy. It has to be a large needle core biopsy, and we have to talk to the interventional radiologist and the pathologist after that to get as much information as possible. It would be hard for some centers and some pathologists to give us more information about histologic subtype, for example, which could have implications.

Walter Stadler, MD: That’s critical because everything that we’ve spoken about up until now really applies to conventional or clear cell carcinoma of its various grades and differentiation. We really do not have level 1 data for any of the half dozen or more non‒clear cell carcinomas.

Toni Choueiri, MD: I would add that, since systemic therapies with non‒clear cell RCC, irrespective, do a bit worse data from the VEGF TKI than clear cell counterpart, you may want to—especially for the patient with limited disease burden outside the kidney—go with surgery first, see what you’re dealing with, and use systemic therapy after.

Richard W. Joseph, MD: What these data also point out, that makes it even more important than ever—and I’m sure our institutions are doing this—is multidisciplinary care. It’s very important now, if the patient presents with metastatic disease, to really have a well-informed decision from the urologist, the medical oncologist, whoever else is involved.

Robert J. Amato, MD: You would biopsy the metastatic site, not the kidney itself because the kidney itself is going to be very misleading due to sampling error.

Daniel George, MD: Ideally. There may be ones that are risky to biopsy, or they may be very small to sample, but I think your point is well taken. Whenever we can, it’s really the metastatic disease that we want to be able to profile and characterize. These are great points. I think if we can just summarize: Do we all see CARMENA as a practice-changing study, in terms of how we work up metastatic disease, in terms of how we manage this as now a multidisciplinary effort, and maybe in terms of how we now sequence, maybe not “one size fits all” for this population?

Walter Stadler, MD: I think so. I’ve argued personally for many years that patients with metastatic disease absolutely need to see the medical oncologist before they go to the operating room. I think that this is now level 1 data, and my prior personal opinion is now justified.

Richard W. Joseph, MD: I agree. For me, it doesn’t change my practice because my practice is already different with treating up front. It does really change the way I think about a patient after they’ve responded. Now I’m questioning what the role of cytoreductive nephrectomy is, which the CARMENA question did not answer, but now I’m still questioning what that is. We had a patient last week who had up-front ipilimumab plus nivolumab. We decided to take him to cytoreductive, had a great response, took it out, and everything was dead. Now I’m kind of questioning what that did for that patient. Did I take away a kidney? I don’t know; I think this raises a lot more hypotheses. It answers some questions, but it leaves a lot to be asked.

Daniel George, MD: Toni, is there equipoise now in the low-volume metastatic patients to consider a trial, to look at that question of whether or not preoperative or neoadjuvant systemic therapy versus upfront nephrectomy, in that otherwise kind of low-, intermediate-risk population?

Toni Choueiri, MD: I think there is equipoise. Whenever you can put the patient in NED (no evidence of disease) or in deep responses using a combination of cytoreductive nephrectomy and systemic therapy, you should. This trial should be done, and if we can’t do it in the United States, we may go to Europe.

Transcript Edited for Clarity 

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Transcript: 

Daniel George, MD: At ASCO this year, we had a plenary session devoted to kidney cancer and in particular on a study out of France that looked at the role for cytoreductive nephrectomy followed by sunitinib versus sunitinib alone in metastatic renal cell carcinoma. The results of a phase III noninferiority study, called the CARMENA study. Walt, do you want to summarize this study for us, and then maybe we can have a little bit of a discussion about the clinical implications of these results.

Walter Stadler, MD: This was a critically important study that followed up on observations from almost 3 decades ago, in which a nephrectomy with interferon had a survival advantage over interferon by itself. That study has led to now 3 decades’ worth of discussions of the role of nephrectomy in the context of metastatic disease. It’s very gratifying to finally see another randomized study that is rigorously addressing this particular issue in the context of modern therapies. In this study, patients with good performance status of 0 and 1, but intermediate- or poor-risk disease, were randomized to either an up-front nephrectomy followed by sunitinib or sunitinib by itself. It was designed as a noninferiority study in the sense that it would be considered noninferior if the hazard ratio was no greater than 1.2. In this small study, the noninferiority margin was not met. In other words, it did look like, surprisingly, the patients who received the sunitinib without nephrectomy did better.

Daniel George, MD: Interesting. Toni, what’s your take on this study?

Toni Choueiri, MD: I think there is a lot to be done. I want to congratulate my French colleagues for finishing the study. We couldn’t do it in the United States. Many felt there’s no equipoise, and here we go with the CARMENA studies. I do think patient selection—Bob was saying that it’s key, and it remains key for CARMENA. Patients with intermediate risk, great performance status, who are young, who can go quickly through surgery and have a limited disease burden outside the kidney, should be considered strongly for an up-front cytoreductive nephrectomy. We shouldn’t take that option away. The other question I would add, Dan, is that currently we’re seeing combinations—nivolumab plus ipilimumab. Walt also mentioned cabozantinib; Rich mentioned that too. These are beating sunitinib frontline options, and we are seeing combinations with checkpoint blockers and TKIs against sunitinib. The field where you consider sunitinib as control is evolving. Will other, modern frontline therapies be applicable to a CARMENA-like study? I would say yes, probably yes.

Daniel George, MD: Rich, how will you apply this in your practice?

Richard W. Joseph, MD: That’s a great question. First of all, I’m very happy that this study was able to be done, as Toni mentioned. It’s very hard to do these studies, especially when surgery is involved and randomizing patients. The issue with this study for me is that it’s not exactly how I practice today. For instance, I rarely will, if a patient presents with metastatic, go to up-front nephrectomy. I almost always have a trial of some systemic therapy, wait a period of time, whether it be 3 to 6 months, and then pick the patients who are doing well who you think can withstand a nephrectomy. In this study, there were a lot of poor-risk patients that I probably wouldn’t have sent straight to surgery. We probably would have tried to get them with a better performance status. I know they were all 0 to 1s, but maybe we would have probably tried to debulk them to some degree. There were 40 patients on the arm that went to surgery that never made it to Sutent (sunitinib), so that leads me to believe, were these sicker patients than we’re typically dealing with that we might not have sent to surgery? The question for me still remains, what is the role of nephrectomy in the modern era? We need to address this question. If I were to design the study, I would probably think more about giving the up-front systemic therapy, and then randomizing from there, and trying to pick patients who are still good candidates at that time.

Daniel George, MD: Interesting.

Walter Stadler, MD: The burden of proof now falls upon the physician who wants to do nephrectomy first. We have a randomized phase III, apparently well-done trial where patients who got nephrectomy up front didn’t do as well. So, if you’re going to offer that to your patients, and you’re going to have to defend that as an appropriate option, and why this trial does not apply to that patient, I do think that we have to recognize that.

Daniel George, MD: I want to clarify something, Walt, because you said they don’t do as well, but this was a noninferiority study, and it was a 1-sided noninferiority study to really look to see whether sunitinib alone was noninferior to nephrectomy followed by sunitinib. Can we really say that sunitinib is superior to nephrectomy followed by sunitinib?

Walter Stadler, MD: You’re correct that it’s not superior, but now, in essence, you would be offering another intervention that has toxicities and side effects that you have not proved are better, and you haven’t even proved it’s the same. The burden on any physician providing any therapy, drug, radiation, or surgery—when you can’t even prove that it’s the same as not doing it, you have a burden.

Daniel George, MD: Is the standard of care now, for patients who present with metastatic renal cell carcinoma, to do a biopsy to evaluate the tumor, assuming that we’re going to start with systemic therapy, or are those patients still going to go first to the surgeon and get a nephrectomy and then come to a medical oncologist afterward? Does this change our referral pattern, our whole practice pattern, for up-front metastatic kidney cancer?

Toni Choueiri, MD: If you need to, you may think of a systemic therapy first; you have to do a biopsy. That has been historically a challenge because many times we ask for a biopsy, and it’s a fine needle aspiration that puts us at a problem where a patient could have renal cell. There is no information, of course, about the grade, sarcomatoid differentiation, even histologic subtype; so, at the very least, we have to go to a biopsy. It has to be a large needle core biopsy, and we have to talk to the interventional radiologist and the pathologist after that to get as much information as possible. It would be hard for some centers and some pathologists to give us more information about histologic subtype, for example, which could have implications.

Walter Stadler, MD: That’s critical because everything that we’ve spoken about up until now really applies to conventional or clear cell carcinoma of its various grades and differentiation. We really do not have level 1 data for any of the half dozen or more non‒clear cell carcinomas.

Toni Choueiri, MD: I would add that, since systemic therapies with non‒clear cell RCC, irrespective, do a bit worse data from the VEGF TKI than clear cell counterpart, you may want to—especially for the patient with limited disease burden outside the kidney—go with surgery first, see what you’re dealing with, and use systemic therapy after.

Richard W. Joseph, MD: What these data also point out, that makes it even more important than ever—and I’m sure our institutions are doing this—is multidisciplinary care. It’s very important now, if the patient presents with metastatic disease, to really have a well-informed decision from the urologist, the medical oncologist, whoever else is involved.

Robert J. Amato, MD: You would biopsy the metastatic site, not the kidney itself because the kidney itself is going to be very misleading due to sampling error.

Daniel George, MD: Ideally. There may be ones that are risky to biopsy, or they may be very small to sample, but I think your point is well taken. Whenever we can, it’s really the metastatic disease that we want to be able to profile and characterize. These are great points. I think if we can just summarize: Do we all see CARMENA as a practice-changing study, in terms of how we work up metastatic disease, in terms of how we manage this as now a multidisciplinary effort, and maybe in terms of how we now sequence, maybe not “one size fits all” for this population?

Walter Stadler, MD: I think so. I’ve argued personally for many years that patients with metastatic disease absolutely need to see the medical oncologist before they go to the operating room. I think that this is now level 1 data, and my prior personal opinion is now justified.

Richard W. Joseph, MD: I agree. For me, it doesn’t change my practice because my practice is already different with treating up front. It does really change the way I think about a patient after they’ve responded. Now I’m questioning what the role of cytoreductive nephrectomy is, which the CARMENA question did not answer, but now I’m still questioning what that is. We had a patient last week who had up-front ipilimumab plus nivolumab. We decided to take him to cytoreductive, had a great response, took it out, and everything was dead. Now I’m kind of questioning what that did for that patient. Did I take away a kidney? I don’t know; I think this raises a lot more hypotheses. It answers some questions, but it leaves a lot to be asked.

Daniel George, MD: Toni, is there equipoise now in the low-volume metastatic patients to consider a trial, to look at that question of whether or not preoperative or neoadjuvant systemic therapy versus upfront nephrectomy, in that otherwise kind of low-, intermediate-risk population?

Toni Choueiri, MD: I think there is equipoise. Whenever you can put the patient in NED (no evidence of disease) or in deep responses using a combination of cytoreductive nephrectomy and systemic therapy, you should. This trial should be done, and if we can’t do it in the United States, we may go to Europe.

Transcript Edited for Clarity 
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