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Sunitinib Before Cytoreductive Nephrectomy in mRCC

Insights From: Dan J. George, MD, Duke Cancer Institute
Published: Wednesday, Oct 04, 2017




Daniel James George, MD: EORTC 30073, or SURTIME, was a randomized study comparing, in patients presenting with metastatic kidney cancer at diagnosis, an immediate cytoreductive nephrectomy versus a lead-in of sunitinib for 3 months followed by cytoreductive nephrectomy. And that was the intention-to-treat population, about 100 patients accrued at about 20 centers over a few years. These are patients who are considered surgical candidates upfront, patients primarily with the bulk of their disease in their primary tumor—so, relatively small burden of metastatic disease.

And generally speaking, these are going to be good performance status patients. But this is an intermediate- to poor-risk patient population, make no mistake, and the reason we still do and offer debulking nephrectomies is because these patients can get very symptomatic by that extra tumor burden in their primary tumor. And historically, our drugs, like sunitinib, are less effective at shrinking those large primary tumors than they are controlling that metastatic disease burden. So, it has made sense, even in the era of targeted therapy to do this debulking.

What has been really a question is whether or not it’s better to do a debulking first or whether it’s better to treat these patients for a period of time and then do that surgical debulking. And there’s a rationale for both. For patients who might have a little difficulty tolerating the Sutent, or sunitinib, or complications from that, it could jeopardize the ability to get surgery, it could put them in worse functional status going into surgery and get more complications, and it could risk wound healing and other complications after the surgery. On the other hand, for the patients who don’t use the sunitinib up front, the rest of their disease could progress while we’re waiting for them to recover from their surgery. There could be complications from not controlling that metastatic disease burden first. So, it’s a very reasonable question to consider, and a randomized study made sense. We’re really glad this was done.

The results are interesting because on one hand, they look very similar. Most of the patients were able to get surgery whether we did it immediately or deferred. The complications associated with sunitinib first were really not that much greater than the complications of patients who got surgery first, so that was reassuring. The average time of progression was about 42 weeks for both arms, so it really looked pretty similar in terms of whether or not they got sunitinib before and after or just after. So, all of those things looked pretty similar. What wasn’t similar, which is really interesting, is the overall survival. For the patients who got deferred, got immediate surgery, and then sunitinib, median survival was about 15 months, which is a little bit on the low normal side for what we expect in this TKA era of intermediate- and poor-risk patients. That’s OK, but it’s kind of what we expect.

On the other arm, the overall survival was on the high end, 32 months, more than doubling of the overall survival for this population starting with sunitinib, doing that surgery, and then going back to sunitinib. Now, again, we didn’t see that immediate effect, but perhaps there’s something else going on associated with that immediate on-and-off sunitinib that allows either the immune system to engage in this disease before taking out that bulk or some other biology that’s really changing the natural history beyond that initial progression.

I find that a little bit hard to believe. I suspect some of or most of this is due to some of the imbalances between these arms that just maybe wasn’t controlled for. It is a randomized study, but when we do really small randomized studies—50 patients or less—that’s when we come into unanticipated imbalances. And so, to me, what this really justifies is a larger study. In the meantime, I think there is a good rationale for asking, “Hey, why not start with some sunitinib in that
prenephrectomy setting?” It certainly doesn’t seem to be doing any worse, and for reasons we may not understand, they could be doing better.

Transcript Edited for Clarity 
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Daniel James George, MD: EORTC 30073, or SURTIME, was a randomized study comparing, in patients presenting with metastatic kidney cancer at diagnosis, an immediate cytoreductive nephrectomy versus a lead-in of sunitinib for 3 months followed by cytoreductive nephrectomy. And that was the intention-to-treat population, about 100 patients accrued at about 20 centers over a few years. These are patients who are considered surgical candidates upfront, patients primarily with the bulk of their disease in their primary tumor—so, relatively small burden of metastatic disease.

And generally speaking, these are going to be good performance status patients. But this is an intermediate- to poor-risk patient population, make no mistake, and the reason we still do and offer debulking nephrectomies is because these patients can get very symptomatic by that extra tumor burden in their primary tumor. And historically, our drugs, like sunitinib, are less effective at shrinking those large primary tumors than they are controlling that metastatic disease burden. So, it has made sense, even in the era of targeted therapy to do this debulking.

What has been really a question is whether or not it’s better to do a debulking first or whether it’s better to treat these patients for a period of time and then do that surgical debulking. And there’s a rationale for both. For patients who might have a little difficulty tolerating the Sutent, or sunitinib, or complications from that, it could jeopardize the ability to get surgery, it could put them in worse functional status going into surgery and get more complications, and it could risk wound healing and other complications after the surgery. On the other hand, for the patients who don’t use the sunitinib up front, the rest of their disease could progress while we’re waiting for them to recover from their surgery. There could be complications from not controlling that metastatic disease burden first. So, it’s a very reasonable question to consider, and a randomized study made sense. We’re really glad this was done.

The results are interesting because on one hand, they look very similar. Most of the patients were able to get surgery whether we did it immediately or deferred. The complications associated with sunitinib first were really not that much greater than the complications of patients who got surgery first, so that was reassuring. The average time of progression was about 42 weeks for both arms, so it really looked pretty similar in terms of whether or not they got sunitinib before and after or just after. So, all of those things looked pretty similar. What wasn’t similar, which is really interesting, is the overall survival. For the patients who got deferred, got immediate surgery, and then sunitinib, median survival was about 15 months, which is a little bit on the low normal side for what we expect in this TKA era of intermediate- and poor-risk patients. That’s OK, but it’s kind of what we expect.

On the other arm, the overall survival was on the high end, 32 months, more than doubling of the overall survival for this population starting with sunitinib, doing that surgery, and then going back to sunitinib. Now, again, we didn’t see that immediate effect, but perhaps there’s something else going on associated with that immediate on-and-off sunitinib that allows either the immune system to engage in this disease before taking out that bulk or some other biology that’s really changing the natural history beyond that initial progression.

I find that a little bit hard to believe. I suspect some of or most of this is due to some of the imbalances between these arms that just maybe wasn’t controlled for. It is a randomized study, but when we do really small randomized studies—50 patients or less—that’s when we come into unanticipated imbalances. And so, to me, what this really justifies is a larger study. In the meantime, I think there is a good rationale for asking, “Hey, why not start with some sunitinib in that
prenephrectomy setting?” It certainly doesn’t seem to be doing any worse, and for reasons we may not understand, they could be doing better.

Transcript Edited for Clarity 
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