Monty Pal: Well, welcome to UroToday. My name is Monty Pal, a medical oncologist from the City of Hope Comprehensive Cancer Center.

Jaime Landman: And this is Jaime Landman from the University of California Irvine.

Monty Pal: Well those of you who can't see Jaime, I've got to describe the environment he's sitting in right now. He's got a beautiful office on the top floor of the tallest building in Orange County, and just as he presides over Orange County, he really is an authority in the field of urology as well presiding over that domain.

So Jaime, I want to probe you today on a topic that we talk about in metastatic disease occasionally and that is active surveillance. If I have patients with metastatic disease with low tumor burden, I might consider following them on occasion. I generally reserve that for patients with more comorbidities, but you know, I guess this is also a phenomenon for localized disease as well. Can you tell us about the data for active surveillance?

Jaime Landman: Well, I'll start off by saying I agree with you. There's a few patients with metastatic disease that I think we either manage together or we manage... It's a very unusual setting, but that's a great strategy. But today let's focus on those very tiny tumors, meaning the T1a's that we often find nowadays. Largely I think we'll be talking about not only the less than four centimeter tumors, but those that are incidentally found, not those that have symptoms, because that's kind of a different population. And active surveillance is an incredible strategy. I remember when this first kind of became formalized as a strategy probably 10, 15 years ago. I remember Rob Uzzo presenting at the AUA, a Kaplan-Meier curve that in fact was not a curve. He had a small series, I think it was Fox Chase, and it was a Kaplan-Meier line with 100% survival of all his patients. And it became clear at that point that for the right patient, active surveillance is an absolutely fantastic strategy. And since then we've learned a lot about it.

Monty Pal: Well that's interesting. So how do you pick the right patient for active surveillance? So can you give us a picture of that person that you might pick active surveillance for versus more aggressive management?

Jaime Landman: So that's kind of a loaded question today, because of things that have changed recently. But let's take a step back and talk about how did we previously choose patients for active surveillance. And again, there's no criteria and if you look at the European or the AUA guidelines on management of the small renal mass, which in itself is a travesty, because we don't manage masses in any other field. But if you look at the guidelines, they're not terribly helpful. Essentially it's up to the individual physician who's treating and it's usually a discussion with the patient. Unfortunately, I think that discussion is often loaded with a tremendous bias, but as a whole, it was really small tumors that were present in older and sicker people. Now that is really vague. The term small is vague, the term old is vague, and the term sick is vague, but it's never been better quantitative or qualified than that, Monty, and I actually think that's pretty sad. But those are the old criteria.

I think one of the things that we need to get into in an era where it's becoming increasingly clear to a lot of people, that small renal masses, like every other tumor in every other organ treated by every other surgeon need to be biopsied prior to making decisions. So we'll talk about the data on active surveillance and there's a fairly robust data out there, but in every series that's been published to date, they're not biopsy-driven. So usually only about 10% of these tumors are biopsied. So I like to refer to the existing body of literature, and kind of in a vulgar way, as stupid active surveillance because we've not been smart about who we're selecting.

And I think the future would be an active surveillance that's biopsy-driven and that would be kind of a proactive surveillance or a smart active surveillance for kidney tumors, where the decisions are actually guided by a histology and thus a better understanding of the biologic potential of each individual tumor.

So if we go back and look at just traditional active surveillance, which is basically the entire body of literature, a couple of thousand patients out there, less than 1% typically progress to metastatic disease and end up dying of their disease. Again, no strict criteria and it's a vague hodgepodge of different tumors.

Monty Pal: Well that's interesting. And you mentioned that there's some data that you've been affiliated with more recently, something that's sort of in the works now. Can you expand for our audience a bit more on that?

Jaime Landman: Well the data that we've been working on is really just the biopsy driven data on what happens to outcomes with tumors that are biopsied versus those tumors that are not biopsied, and it turns out, and I think this is a different discussion that you and I should have again on Kidney Cancer Today. But there's huge differences in the number of patients who have unnecessary surgery, and perhaps we can get Tony Finelli on because he recently published in the Journal of Urology, it was a multicenter trial where they compared centers that tended to biopsy versus those that didn't and their active surveillance rate went up dramatically.

Recently, we similarly published, or are about to publish, so this is not peer-reviewed data yet, but working with Mo Allaf and Mike Gorin at Hopkins and Lou Kavoussi and his team at LIJ, we've done office biopsies and as you know that's something we've been working on for a long time.

But one of the things we noticed is that our active surveillance rate when we compared these biopsy driven patients to our historical cohort, or group I should say, of patients who were just treated without biopsy, we had three times as many patients in the active surveillance group and that's a different discussion. But when you think about it, not only are we sending more patients to active surveillance, but for the first time ever we're thoughtfully putting them in active surveillance. So this is proactive surveillance. I know with pretty reasonable accuracy, as accurate as a biopsy can be of course, that none of those patients are going to have a high-grade ugly disease. Unless the patient is completely a nonoperative candidate, those patients with aggressive disease are going to be called out and get some kind of intervention, usually a partial nephrectomy or perhaps an ablation.

And I think that's going to take results of active surveillance as they exist today, which are really darn good with a very tiny percentage of patients ending up having to have metastasis, death, or any kind of systemic treatment to almost nothing with proactive surveillance with a biopsy-driven standard.

Monty Pal: Very interesting. Very interesting. Now I'm going to ask you to push the envelope a little bit here, Jaime. We've talked about T1a disease, tumors under four centimeters. What if we try to cross that threshold, are there still candidates for active surveillance in that scenario?

Jaime Landman: You mean in T1b disease?

Monty Pal: T1b, yeah, exactly.

Jaime Landman: So that's a great question. So when the original AUA guidelines, and again for the small renal mass came out, it was interesting that they said that I think it was index patient four which is a T1b patient who's older and sicker, and again, very vague criteria. They put active surveillance on as a really good strategy. It was way up there on their list of things to do, and I thought that was ironic because there had never been a published paper on active surveillance at the time.

So I was back at Columbia and we actually just used that as an opportunity. We went back and looked at our patients, and I think there were about 40 or so with T1b disease in our database on active surveillance and they had a mean growth rate that was a bit faster. Normal active surveillance patients have about 3 mm a year, and these patients I think were closer to 6. But as a group, they did very well, and I wouldn't kind of encourage active surveillance as a first-line therapy for T1b disease in general, because as you know, the results of those cancers, when they are cancers, are significantly different from the T1a population.

But for highly selected patients, meaning an older, sicker patient that is at very high risk for surgery, boy, I think it's a great strategy. And again, I don't think it's crazy to biopsy T1b's because the only tumors that we're plucking out here at UCI that are benign nowadays, because we have a biopsy-driven standard. So we have a 0% T1a benign partial nephrectomy rate. We do occasionally get the eight centimeter oncocytoma that we're plucking out, so it's actually become strange that our T1b unnecessary surgery rate, meaning surgery for benign disease, has increased and not increased, but it now exceeds our T1a rate.

Monty Pal: That's interesting. You know, for that T1b candidate, you mentioned the strategy of surveillance. Would you consider perhaps monitoring them more frequently than you would a T1a in that scenario? How does your surveillance approach change for that larger tumor?

Jaime Landman: It's funny. As you already know, there exists no set protocol for surveillance. Being that this is a fairly commonly used strategy that seems unusual, but it's left up to the individual practitioner, even for T1a. So for T1a's, I personally just talk to my patients. I see how anxious they are. For those patients that are super anxious, sometimes it's just to keep them on active surveillance when I think it's a good strategy. I'll just do an ultrasound in the office every three months. As you know, imaging more than every six months in this setting is kind of unreasonable. It's a lot of expense. If you're using CT, it's a lot of radiation, so every six months to every year is typical once we've figured out that a tumor is fairly indolent.

For T1b's, again, there is no set strategy but I do tend to go a little more often and for those, I would tend to go every six months instead of every year for a while. The interesting thing is there's been a couple of papers on what happens to patients after they've been five years out, and I think in 2014 we published a paper on what happens to those tumors that have successfully been on active surveillance for five years or more and those had a very slow growth rate, and again you've called out those that failed either for fast growth. You've called out those for any other reason, and these are now very indolent tumors. So after five years, I think T1a's, and T1b's, you can follow them very loosely because I think there's very low risk, but T1b's I think need a little bit more follow up.

Monty Pal: I'm going to push you a little further on that Jaime, because that after five year question is something that I think is a sticking point for me as a medical oncologist. I never know what to do beyond five years following resection and of course, the surveillance approach is different there. What has been your clinical practice post-five years in the surveillance setting?

Jaime Landman: We have a lot of those patients and what I really want to do is minimize their anxiety and minimize the cost to the healthcare system in a population that I know is going to do very well. So I tend to see them every year or every other year and do an ultrasound at that point, and I can do that ultrasound in the office so the patient doesn't have to make two trips. As you know, ultrasound's relatively inexpensive for the healthcare system and no radiation, which is fantastic. So we try to loosen the reins after five years and probably a lot of those patients could be let go altogether, but I think that there's a level of anxiety that makes it difficult to cut those patients loose.

Monty Pal: Got it. Yeah, totally. And I guess on a related topic, tell us a little bit about the longterm data that we've got for active surveillance. I can imagine patients in this position wanting to know five years out, 10 years out, Dr. Landman, can you tell me is this a feasible and reasonable approach?

Jaime Landman: Well, we published on that originally. There's a couple of papers that came out recently. McIntosh, this is Rob Uzzo and his group out at Fox Chase, they identified 457 patients. So a real big population of patients that had over five year followup as I recall, and it was a pretty typical population. The mean tumor size was small, around two centimeters. The growth rate, and I guess they've gotten better at selecting these patients, was only two millimeters per year. But with over five years, they only had one patient that progressed to metastasis and none that went on to die. I think that's as good evidence as you need that you're really going to have pretty good outcomes with well-selected patients. And of course, they did call out all those that grew quickly and there were some, I'm sure, that just had anxiety and ended up moving on to some kind of an active intervention.

But thoughtful active surveillance. And again, Monty, we're talking about dumb active surveillance, right? Not biopsy-driven, because I don't remember what percent in that manuscript was biopsied, but it's probably tiny. So without good histologic information, we're still having great results for these small tumors on active surveillance, and I bet you if you now had a proactive surveillance, meaning a biopsy-driven active surveillance protocol, you would absolutely have great results because you'd call out those few small aggressive tumors.

Monty Pal: That's really good insight, Jaime. And again, the landscape of therapy and systemic disease is changing minute by minute, but in the setting of localized disease, I really look to folks like you as having the most expertise around the world in techniques like cryoablation for instance. So when I think of this decision of active surveillance, I think the classic perspective is watching a tumor versus operating and resecting a tumor. But with that option of cryo sitting right in between, how does that change your perspective on the approach?

Jaime Landman: Well, again, there's no hard criteria, and you've actually nailed it. That's the tougher thinking process because, and again, cryoablation has become percutaneous standards with very rare exception in most practices. So you're talking about a procedure that's curative in about 93, at least in our hands and experienced hands, I think it's about 93% of people get one procedure, they're done. They're home that day. Low complication profile. About 7% of people need a second treatment, meaning they had an inadequate ablation. There's very clear data that the overall survival data at five years for T1a is identical between cryoablation and partial nephrectomy and it's actually pretty close for radiofrequency ablation.

So how do you choose between active surveillance and an ablation strategy? And I hate to say it, but that to me often comes down to the patient's personality, and I don't even know why I hate to say it because quite frankly, this is the patient's decision. It's their life. So most people are very comfortable with active surveillance. They can live with the fact that, especially in our hands, they'll know what they got. If they have a benign tumor, they certainly don't want an ablation. But if they have, let's say, an indolent kidney cancer, a small T1a incidentally found papillary type one or maybe a chromophobe, you're used to seeing those patients occasionally pass.

But you know, after 20 years, Monty, I've never seen somebody with a T1a incidentally found chromophobe or papillary type one end up growing and having metastasis and death. It just doesn't happen. So I think those patients have to choose between ablation and active surveillance. If they're cool customers, really can handle the fact that they have a cancer and that the data is very supportive that it will probably never bother them, they go for active surveillance. And some people are just really anxious and want it treated, and I think for an older, sicker person, that's where the ablation is a really great option.

Monty Pal: That's about as clear an answer as I think we can get on this topic. It's a tough issue and I think you've done really well to dissect that. Well Jaime, as always, the discussions with you are incredibly enlightening. I really appreciate your perspective on active surveillance for RCC.

Jaime Landman: Thanks Monty. It's always a pleasure talking with you and working with you particularly on Kidney Cancer Today, and hopefully we can get some more interesting conversations going in the real near future.

Monty Pal: Fantastic.