On this episode of Cleveland Clinic’s Cancer Advances podcast, host Dale Shepard, MD, PhD, talks with Steven Campbell, MD, PhD, on selecting between partial nephrectomy and radical nephrectomy for patients with localized kidney cancer.
Campbell is a urologic surgeon, and member of the Section of Urologic Oncology in Cleveland Clinic's Glickman Urological and Kidney Institute. Shephard is a medical oncologist at Cleveland Clinic who oversees the Taussig Phase I and Sarcoma Programs.
Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest, innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic, overseeing our Taussig Phase I and Sarcoma Programs. Today I'm happy to be joined by Dr. Steven Campbell, a urologist in the section of urologic oncology at Cleveland Clinic's Glickman Urological and Kidney Institute. Particularly relevant to today's podcast topic, he is the chair of the American Urological Association Guidelines Committee for evaluation and management of localized renal masses. He's here today to talk to us about the controversy between partial and radical nephrectomy. So welcome, Steve.
Steven Campbell, MD, PhD: Thanks, Dale. It's great to be here.
Shepard: Maybe just start off, tell us a little bit about your role here at Cleveland Clinic.
Campbell: Okay. My main area of interest from a clinical and surgical standpoint relates to urologic oncology, but kidney cancer specifically. And from a research standpoint, we've done a number of studies on localized kidney cancer, and so I mentor the residents with respect to all of that.
Shepard: Excellent. So today we're going to talk about one of the biggest decisions really that that clinicians need to make for patients, and that's patients with localized kidney cancer, and whether a partial nephrectomy or a radical nephrectomy would be appropriate. So maybe we can talk a little bit at first, just to start out, when we talk about partial nephrectomy or radical nephrectomy, what exactly that means. When we say partial nephrectomy, how much of the kidney is being lost? Give us some perspective.
Campbell: So with radical nephrectomy we're removing the whole kidney, all the fat around the kidney, Gerota's fascia, if there's any lymph node enlargement, we're removing the nodes. So it's a classic, radical approach, oncologic approach to the disease process. Partial nephrectomy, we're opening up Gerota's fascia, we're resecting the tumor with a little rim of normal parenchyma. We're trying to save as much kidney as possible. On average, we save about 80% of the kidney that we're operating on.
There's a reconstructive component to partial nephrectomy, because after we removed the tumor, we've got a kidney that needs to be reconstructed. We put some sutures in, we close the capsule together. And then you've got this highly vascular, reconstructed organ that needs to heal. So that there's a slightly increased risk of complications with partial nephrectomy, because it's a little bit more complex of a procedure.
Shepard: Yeah, so we'll be touching on that a little bit later in terms of the differences from a complexity. So we think about radical nephrectomy, we think about a partial nephrectomy. Tell us a little bit about the pros and cons of each approach.
Campbell: So radical nephrectomy, it's a more simple procedure. So in this area we can almost always do the radical nephrectomy. It's minimally invasive. We just mobilize the kidney, we can throw the stapler across the blood vessel. So it's a relatively straightforward procedure with a pretty low risk of complications. There's nothing that really needs to heal there because we're removing it all.
Radical nephrectomy also has potential oncologic advantages, especially if the tumor has increased oncologic potential by not opening up the system, by not opening Gerota's fascia, it's clearly going to have a slight oncologic advantage.
Partial nephrectomy, the downside is it's a little bit more complex. We can still do ... Most of the procedure is minimally invasive, but some of them do need to be done open. And the bottom line is there's always going to be some risk of complications when you've got a reconstructed, highly vascular organ that needs to heal. But the real advantage of partial nephrectomy is we're saving more kidney function, which for some patients is really, really important. If the patient already has preexisting CKD, this can be the difference between them needing dialysis down the road, versus maintaining good kidney function.
Shepard: So across the board, what percentage of patients would have a radical nephrectomy compared to a partial nephrectomy?
Campbell: So at our center it's about two thirds or three quarters partial nephrectomy, and the remainder are radical. Certainly all the small renal masses, they should really be managed with a partial nephrectomy. Those smaller renal masses up to about four centimeters or so tend not to have a lot of oncologic potential to them. So the risk of doing a partial nephrectomy from an oncologic standpoint is relatively low.
We do partials for larger tumors too. If the patient needs it or if it's sitting in a pole and it's relatively easy. But then there's a whole other population with larger, more aggressive tumors that really does need a radical nephrectomy.
Shepard: And if we were to look in, say, community practices instead of an academic center, how did those numbers change?
Campbell: So that's a great question, and the reality is in a community setting it's different. It might be two thirds or more radical nephrectomy, and part of it is that, again, the radical nephrectomy is a little bit easier, it's cleaner. So you've got a somewhat older, slightly frail patient and you're out in the community, you're going to want to get that patient through as clean and safe as possible. And you're going to definitely lean more towards a radical nephrectomy.
We worry about that because some patients out in the community there are losing a kidney when they don't really have to. And that could put them at risk long-term from a functional standpoint.
Shepard: Are there particular patients that you think would benefit from coming to see you and your colleagues here at the Clinic, instead of going to just get their kidney removed?
Campbell: Yeah. Just in general, patients with pre-existing CKD or proteinuria, patients with a solitary kidney, patients with bilateral tumors, these patients really need a partial nephrectomy. We think that younger patients, like early fifties and forties, that sort of thing, they probably should have a partial nephrectomy if at all possible. They can then move on for the rest of their life with 1.8 kidneys instead of one kidney. Patients with familial kidney cancer, well, they almost always need a partial nephrectomy because they have multifocal disease more often than not.
So those are some of the examples. Also, patients with severe hypertension. Really significant kidney stone diathesis, morbid obesity. We really believe in pushing the envelope towards partial nephrectomy in all of those patient populations, because they'll be at risk for progressive decline in renal function as the years go by.
Shepard: So I know that you've done work with looking at renal function and the reduction of renal function and its effects on survival. Could you tell us a little bit about that?
Campbell: So this is one of the great controversies in the field, and this has been going on for well over a decade. And basically what's happened is that we know that in the general medical population, patients who have CKD usually due to hypertension and diabetes, they're at risk for progressive decline of renal function. They have a GFR of 45 because their diabetes has been impactful. Well, it's going to continue to be impactful. So those patients in the general medical populations, they really have reduced survival related to their CKD.
And so just in general, our field, we thought, "Well, if that's the case then we really ought to do a partial nephrectomy whenever it's possibly feasible. Because we'll save as much kidney function and, well, we'll end up with better overall survival. And most of the studies and the literature, and it's over a hundred studies, they're almost all retrospective. And they're almost always showing a survival advantage to the patients who get the partial nephrectomy versus the radical nephrectomy. But we think that a lot of that's selection bias. It's just the healthier, younger patient is more likely to be able to recover well from a partial nephrectomy. We're more likely to select that patient for a partial nephrectomy, and that patient's going to live longer no matter what we did to them.
So we really think a lot of that is selection bias. And in reality, there's only been one randomized trial in the literature, it's called EORTC 30904, and it randomized patients with relatively small kidney tumors to partial versus radical nephrectomy. And this was a population where partial nephrectomies should have provided a real advantage, they were patients with small renal tumors. But the reality was when the study was analyzed, it did not show an advantage to partial nephrectomies.
So this has left us with a long-term, ongoing controversy in the field and the perspectives about this can vary tremendously. Some people have said that if you could do a partial, maybe, but you did a radical, maybe that's almost malpractice. We think that's way out there. So there is sort of an ongoing controversy in the field, how far should we be pushing the envelope towards partial nephrectomy? And perhaps the pendulum has swung too far.
And I can tell you, we have seen patients at our center and patients we pick up, who really received a imprudent partial nephrectomy. They should have had a radical. They've run into oncologic problems long-term and they can die of kidney cancer. When a smarter decision upfront for a radical nephrectomy might've really made a difference. So sometimes these decisions can be very impactful for patients on a long-term basis.
Shepard: So I'm certain that anytime there's a trial like this EORTC 30904 trial, you get both sides clamoring to say that, "My side was right." Are there any glaring issues with that trial that would suggest that there may be bias in one direction or is it just impossible to tell?
Campbell: Yeah, that's a great, great point. So what happened was when the trial first came out in 2011 ... It's hard to believe. It seems like yesterday. But when it first came out, we all in the field, we didn't know what to think. And for about six months everyone just tried to sweep it under the carpet, because we wanted to believe in partial nephrectomies. Especially at academic centers, we wanted to believe in partial nephrectomy, because we get referrals for patients who need partial nephrectomy.
But anyway, the long and short of it is, it's not a perfect trial at all. It didn't reach its accrual. It was supposed to have 1,200 patients and it stopped at about 550. It was relatively early in the partial nephrectomy experience across the world, so maybe the partial nephrectomies weren't quite as optimal as what they might be today. So maybe partial nephrectomy was put at a little bit of a disadvantage.
But the more we thought about it here at the Cleveland Clinic, we thought to ourself you would take 540 patients and randomized them to partial versus radical. Then you would follow them for 10 years. And these are patients who are perfectly designed to be the patients who should benefit from the partial nephrectomy. And at the end of 10 years, actually the advantage was to radical nephrectomy. Not only did it not show an advantage to partial, but there was actually a statistical advantage to radical.
So we said to ourself, "This trial is probably trying to tell us something." And so we started doing research on this. And what we found was that a lot of times radical nephrectomy will drop the patient into having CKD. So we call that CKD surgical, because they only got the CKD from surgery. And we asked the question whether all CKD is created equal because we know CKD due to medical causes, it really does compromise your survival on a long-term basis.
But when we studied it, CKD due to surgery, these patients had a pretty much equivalent survival as if they didn't have CKD at all. And basically the idea is they only have CKD because we operated on them. We're never going to operate on them again. They can stabilize with a GFR of 48 or 43, and they can live long-term. And that's pretty much what we found in the study. And what that suggests is that, if you go into surgery with pretty good kidney function, even if we're going to drop you into CKD, you can have good long-term survival if you're a well-selected patient.
So the long and short of it is that the idea that radical nephrectomy is killing patients by causing CKD just isn't true. And this trial really supports that concept.
Shepard: Yeah, you raised a good point. You had mentioned that the medical CKD just keeps getting worse, and you have more of a plateau effect with surgery. So when we think about measuring renal function, how are you approaching that at this point? Are you doing that through radionuclide scans, or you're doing this through this parenchymal volume analysis? Or how are you guys approaching measuring the renal function?
Campbell: Yeah, I mean, it's gotten really simple through the years. We used to do iothalamate scans and a more sophisticated nephrological test. But in this era, everything's just creatinine based estimations of GFR, which comes out in our lab reports from the MDRD2 equation. When we want to get really sophisticated, we do the CKD-EPI equation. But these are real simple ways to take the creatinine, and based on the age and the gender and the race, we can estimate the GFR.
And so we'd done a number of studies related to functional recovery after surgery. And what we've found was really very, very simple that how much mass is saved by the surgery, a vascularized nephron mass is really is the key thing for the recovery of function after any kind of kidney surgery. So when we do a partial nephrectomy, if we save 80% of the mass, and we can measure this on the CAT scans, we'll get 80% of the function. That's really the key factor, not the ischemia.
So that's another thing that really shifted in our field. At one point we thought the ischemia was really accounting for changes in function, but it's really not so much that, it's all a matter of getting in and out of there and saving as much vascularized, mass as possible.
Shepard: Saving the mass, does that also help you predict loss of function? If you consider radical nephrectomy versus partial nephrectomy, that holds true as well, instead of the old scanning techniques and things like that?
Campbell: Right. So until about two years ago, if we wanted to predict what your function was going to be after a radical nephrectomy, we would do a renal scan. And based on the split rental function, we could estimate the function of the contralateral kidney, the kidney that's going to be left behind. And then we could multiply that by a compensation factor. The average kidney has compensatory hypertrophy of about 25%, and based on that, we could estimate what the final GFR is going to be. And if that GFR is going to be greater than 45, then the patient really could have a radical nephrectomy without any negative effects.
Now in this era we do what's called differential parenchymal volume analysis, which has been done in the kidney transplant world for years. They look at a potential donor, they measure the amount parenchymal mass on each side, and then they can predict. They generally leave the donor with the better kidney, they'd give the kidney to the recipient. And based on that, they could predict what the final creatinine is going to be, and can predict what the final creatinine of the donor is going to be. Well, now we're doing this for kidney cancer. We have special software to measure the amount of healthy parenchyma on each side. And based on that, we can predict the final GFR of the patient after whatever surgery they have.
Shepard: That's great. What are the current AUA guidelines on partial versus radical nephrectomy?
Campbell: So one of my jobs in the field has been as Chairman of the AUA Guidelines for the management of localized kidney cancer. And one of the biggest things we did with our latest guidelines is we came up with a very specific statement about radical versus partial nephrectomy.
And what we say is that radical nephrectomy should be considered whenever the tumor is thought to have increased oncologic potential, based upon increased tumor size, larger tumors are more aggressive. Based on renal mass biopsy, if it's a aggressive histology or a high grade tumor. And based on imaging features, that they have infiltrative features or locally advanced features. If you're seeing any or several of those factors you're going to be worried about increased oncologic potential. In that setting radical nephrectomies should be considered.
Now, if in addition to that they also have a normal contralateral kidney, which is going to provide a GFR of greater than 45, if they do not have pre-existing CKD. And especially if the tumor is right in the middle of the kidney, what we call high complexity, where the partial nephrectomy is going to carry some risk to it.
Bottom line is if the patient has all those characteristics, those are really the patients who really absolutely need a radical nephrectomy to give them the best, most efficacious and safest outcomes. If the patient doesn't fit that profile, then really partial nephrectomy should be considered. And that's still leaving a lot of patients who really should get a partial nephrectomy and will benefit from a partial nephrectomy.
And of all the guidelines in the field, our guidelines from the American Urological Association are the only ones to provide a real granular description of what these parameters are that should help urologists to make the right decision, so that the patients who need a radical nephrectomy get a radical nephrectomy. But at the same time, radical nephrectomies hopefully will not be over-utilized, which has ill effects too.
Shepard: You mentioned renal mass biopsies. So how often are those being obtained?
Campbell: Yeah, in our field we moved away from renal mass biopsy in about 2000. We became impressed with the glass half empty side of the equation with renal mass biopsy, that it's not as accurate as a biopsy for a woman with a suspicious breast lesion, which is the biopsy in that setting is almost 100% accurate. In our world the biopsies of kidney tumors, they're imperfect. And the reason why is that the oncocytoma tumor is benign, but on a biopsy it's very difficult to differentiate from clear cell renal cell carcinoma.
So the bottom line is renal mass biopsies are not perfect, but they're still pretty good. The overall accuracy is really pretty strong, it's in the high nineties. So while biopsies aren't perfect, they're still helpful. And now the field has shifted back towards doing more renal mass biopsies in any patient where we're having a difficult time deciding whether they should be treated versus active surveillance. Or if they're going to get treated, whether they should be treated aggressively with radical nephrectomy, versus partial nephrectomy.
A renal mass biopsy can be extremely useful. It provides additional oncologic risk stratification, and it can be extremely helpful for counseling and management of these patient populations.
Shepard: And so what's going to be the next big break to improve the field. What are the barriers?
Campbell: In our field we have randomized trials in some areas, but we've not been really good about obtaining Level One: Evidence. So as far as this controversy about radical versus partial nephrectomy, we really need another randomized trial of partial versus radical nephrectomy for somewhat larger tumors where it's really more of a question mark. When you're in clinic, as a surgeon, as a doctor, you really honestly don't know for certain what the best treatment is.
So we proposed a Phase Three, randomized prospective trial, partial versus radical, in that patient population. Unfortunately, we've proposed it twice and we've not succeeded yet, in 2014 and 2018. So long and short of it is, this is something we really need to give us high quality data to help move the field forward. And I think until we do that, it's just going to be a long-running controversy.
Shepard: What do you think is driving the hesitation to do the trial?
Campbell: Well, it's always hard to get surgical trials. I think that this trial would be mostly done in the academic world. I think some people in our world are a little bit hesitant to sort of ... They feel like it's opening can of worms. They feel like are our stance in academic urology should be strongly in favor of partial nephrectomy to try to encourage as many partial nephrectomies as possible. And when we open up the idea that maybe there should be equipoise about partial versus radical, we're really going to cause more trouble than good.
So just to be completely clear, we strongly believe in partial nephrectomy for patients with small renal masses. All those patients we talked about at the start of the podcast, it's just the tumors with a little bit increased oncologic potential, those patients, we may be hurting some of them by doing a partial nephrectomy and we really need a better trial. We're really hoping that as the years go by our center and other centers have contributed a lot of good evidence to argue that this is something we really need to do, that just a mindless approach to partial nephrectomies whenever feasible is not really a good place to be. So we're hoping that someday we'll come around and we'll realize we need this randomized trial.
Shepard: Well, I certainly appreciate your insight and giving us the insight on pros and cons of each, and letting us just in on what those decisions entail. And I appreciate you being here with us today.
Campbell: Okay. Thanks, Dale. I've enjoyed it.
Shepard: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify SoundCloud, or wherever you listen to podcasts. And don't forget you can access real-time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website, at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.