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Monty Pal: Welcome to Kidney Cancer Today. My name is Monty Pal and I am a Medical Oncologist at the City of Hope Comprehensive Cancer Center.

Jaime Landman: My name is Jaime Landman. I am the Chair of the Department of Urology over at UC Irvine.

Monty Pal: Usually on Kidney Cancer Today, we have a special guest who has published a bit of important work that we like to discuss.  Here I am really delighted to review an article that Dr. Landman has just published in Urologic Oncology. A really great and important piece of work in my mind related to renal mass biopsy and this really centers on the concept of an office-based renal mass biopsy. Jaime, can you tell us a little bit about how that works? What are the mechanics of that?

Jaime Landman: So Monty, it's always a privilege to be your partner, and today it's your privilege to be your unspecial guest. But I do think this was a very important manuscript, which is more than a decade in the making. As you know, about 10 years ago, our team started working in the laboratory on trying to develop techniques for urologists to be able to do what we do for the prostate in the office. So it was strange to me that I could do a prostate biopsy in the office, but could not do a kidney biopsy. So we worked in the lab and we had found a good partner in Hitachi and ultimately came up with the technique. We wrote a few early manuscripts on the feasibility, and ultimately it became a standard here at UC Irvine where pretty much every small renal mass that is being considered for some type of intervention gets a biopsy. And many of those are done in the office and our interventional radiology colleagues and friends do the ones that are a little more complex and challenging, or if the patient is a little bit sicker.

Anyway, doing it here is great, but we really want to know if it can be done nationally and internationally? So I partnered with a couple of good friends over at Hopkins. We had Mo Allaf and Michael Gorin who was originally our partners there. And then, of course, Lou Kavoussi is wonderful. He's in the Northwell system at LIJ. And we decided we try and do this as a multicenter trial. And in fact, a couple of years back, we all did this prospectively under the protocol, of course, approved by the IRB. And ultimately we were able to capture 72 patients who had the biopsy and this was between the three centers. And then we had a control group, which was 73 patients who were treated without biopsy prior to the initiation of the biopsy. And we wanted to see A, could we make this biopsy thing a multicenter, perhaps transferable skill, and B, would this impact the way we treat kidney cancer?

Monty Pal: So, so let me ask you about the mechanics of this biopsy because this just fascinates me. So, you see a patient in the clinic, you identify that they have, by definition in your study, a clinical T1 mass. Are you able to consent them and biopsy them there right on the spot? Is this an additional clinic visit? And I'm thinking about this because I oftentimes refer a patient to get a renal mass biopsy, because A, there's a bit of attrition, B, you've got the patient waiting sometimes weeks to get that result. This concept of doing things in the office really seems to have some distinct advantages.

Jaime Landman: So, I think what you felt is what everyone feels. No, we can't do it the same day because obviously, you need to schedule it, it's a little bit of a procedure. But you see a lot of attrition when you tell a patient or suggest to a patient that they need a biopsy. You have to schedule with interventional radiology, it's a different group. They have to go there and know where it is, et cetera. There are a lot of barriers to that happening. I can't do it on the same day because it just doesn't work in the schedule. I've seen you, we've talked about the fact that you may need a biopsy, we go through the risks and benefits, but I schedule you in the very near future, usually the next week. So that very day, I do a quick ultrasound in the office, make sure that the patient and their anatomy are suitable for an office biopsy.

I mark their back and give them a prescription for EMLA cream. The EMLA cream is magical. That is the technic mixture of lidocaine anesthetics. It makes this so most patients have almost no pain and that is one of the things we quantitated in this study is that most patients had zero to one pain on a 10 point scale at worst and only 7% of patients in the entire study required even a pain pill. Most people just went home afterward and were just fine. So yeah, it operationally is not so efficient. You can not do it the same day, at least not in our hands. But you do it a week later in the same office and it's super easy with much less attrition or barriers to the patient getting their biopsy.

Monty Pal: Yeah that makes a lot of sense to me. And the other thing, the other practical consideration that comes up, and I'm kind of getting out of my lane here a little bit, but when I see these patients with a renal mass, sometimes there are lesions that are septated, et cetera. I send them to the interventional radiologist and they are there to do the biopsy. They do the biopsy and the patient comes out of it with a benign result, but maybe they sampled the wrong lesion. Do you find that doing this office biopsy gives you a little more control over the regions that you are sampling within a suspected tumor?

Jaime Landman: So your point is well taken in that a small percent of biopsies are unsuccessful because we do not capture the right tissue. Just so you know, that is very technician-dependent. In our study, in this current study that we are talking about today, there was a 75% successful biopsy rate in terms of getting the diagnosis. That means that 25% of the time somebody needed a second biopsy. Now, the funny part about this is even though that we engendered this technique at UC Irvine, my results were worse than those of Lou Kavoussi or Mo Allaf and Mike Gorin in that they are just technically better than I am at this. So they got better results than I have. And that's absolutely fine. I like to be as good a technician as I can be, but those guys have a slightly higher diagnostic rate than I do. This also tells you that if people choose to adopt this technique, they will probably have a better rate than I will, or many of them will.

So, no we didn't get better, but we were pretty close to what our colleagues in interventional radiology get. They are somewhere around 85% successful and about 15% of people need a second biopsy. And if you do that second biopsy and there is some nice work that comes out of there, the majority of those patients do get a diagnosis. So a very small percentage of people have two biopsies and do not have a really accurate diagnosis.

Now just to follow up on that, if you do get your diagnostic biopsy, meaning you hit the proper tissue, 97% of the time, at least in our study, it correlated with the final diagnosis. So if you do get a tissue, it's very accurate. So some urologists are concerned that their biopsy is inaccurate. Renal biopsies are extremely accurate. When you get the tissue, it is 97% concordance between the biopsy histopathology and the final histopathology. Grade, not so great. So grade is only about 50/50 for high versus low grade. And again, that was very variable. It turns out that Ted Farzaneh here at UCI is great, and he was higher than some of the other pathologists. But then again, that depends on your urologic pathologist.

Monty Pal: Very interesting. Very interesting. So, Jaime, I think the other question that comes up as you look at a paper like this and really dive into the weeds is constituting a control group. There are obviously some really, really impressive findings here. You mentioned in the paper the rate of active surveillance in the biopsy cohort was three times higher than in the control group. How did you guys come up with that control group?

Jaime Landman: Yeah, the control group was just a bunch of patients that had been treated with what is currently the standard of care in the United States, which is you have a small renal mass, you get an intervention, there's no biopsy. Now, mind you, and you know this Monty, that outside of urology, and in fact outside of urology and the kidney, every single solid tumor treated by every surgeon in every organ in the human body is biopsied prior to intervention. In fact, urology and renal urology is the only place where there are actually guidelines for a mass. There are guidelines for the masses to decide between active surveillance and biopsy, but nobody decides treatment without biopsy. So this is a very weird cultural phenomenon that is not based on any biology. The fact that urologists are treating renal masses without biopsy and that's part of my mission is just to show the world that.

And in fact, when you can go and reduce your surgery rate for benign disease, by the way, the most recent data out of JAMA Surgery was that urologists, 30% of our partial nephrectomies, are for benign disease. That was somewhere around 20% or 25% and that has gone up. And with these three centers with biopsy, we were able to reduce our 23%, which by the way, by national standards is terrific, down to 3%. So only 3% of people had a partial nephrectomy for benign disease. And by the way, the UCI rate is lower. The funny part is our T2 disease rate, we are talking about T1a's here, our T1b and T2 disease rate for benign tumors is actually higher with partials because we do not biopsy those.

So you're right, active surveillance went from 14% to 35%. And by the way, traditional active surveillance, which if you read the literature, has great results in these older sicker patients that we watch. Very few of them end up having bad cancer outcomes. This is a biased population, which I call biopsy informed active surveillance. You know they are going to have an even better outcome because we've called out all the bad cancers, so more active surveillance that's going to be better. I don't have data to support that, but intuitively it's got to be better when you take out the bad cancers and less unnecessary surgery, which of course has terrible cost at every level, the cost to the patient, pain, suffering, cost to the health care system, et cetera.

Monty Pal: This just seems like such a slam dunk, Jaime. Why would anybody not do this? Maybe I'm asking the wrong person, but why would anybody not proceed with an office-based renal mass biopsy based on the data that you're presenting here.

Jaime Landman: Monty, I'm not going to argue that most people need an office-based biopsy because quite frankly, less than 50% of my biopsies are in the office. Patients who have comorbidities, who are likely to bleed or maybe could have a cardiovascular event, I want that done in a setting where it's a little safer, but for a healthier patient that has an easier tumor, in the office..... the argument you are making is why not biopsy people, and the truth is it's highly debated and considered controversial. But in my mind, it's quite silly because like I said, there is not another solid tumor that is not biopsied without damn good reason and there is no biological good reason.

My dad would treat kidney tumors because they largely presented symptomatically. And before he passed, I'd spoken to him about this. And he found a couple of IVPs where they found a little kind of contour abnormality on the nephrogram and they found a small tumor after exploring, not on a CT, they didn't have it, but that cultural bias of kind of just, find a tumor treat it, was appropriate when all the tumors you found were big ugly ones. Now we are largely finding these incidental lesions that are asymptomatic. A lot of T1a's, meaning less than four-centimeter lesions, and our treatment strategies are poor and in fact, nonsensical.

I was just reading on Monday, this coming week, I'm going to be doing the grand rounds here at UCI reviewing the updated AUA guidelines. And there are several references to understanding the biology of the disease before making the decision on how to treat a patient. And yet there is no mandate for biopsy and in fact, a biopsy is quite minimized. That is nonsensical. It's illogical. It makes no sense. And this scenario is a bit frustrating to me because it does make no sense, but I think this manuscript here is one step closer. So the question is, can preoperative renal biopsy change clinical practice? The answer, according to this manuscript, is yes. And that's actually not the question. The real question is, can pretreatment biopsy, be it in the office or not, improve treatment? And guess what, the answer is yes. You are going to have more and better active surveillance for patients who do not need surgery and less unnecessary surgery.

Monty Pal: So I'm going to ask you a very controversial question. I didn't prep you for this before we chatted today.

Jaime Landman: I'm going to brace for this question, Monty.

Monty Pal: I'm going to try to do the protocol justice but Brian Shuch, he's a urologist at UCLA and I know you know him very well, is putting through a protocol right now through the NCI, which is going to randomize patients to renal mass biopsy or observation to essentially prove that the renal mass biopsy can influence decision-making and so forth. My understanding is that outcomes are going to be sort of a secondary measure. I know in medical oncology we always talk about systemic therapies needing that sort of randomization to prove their worth. Would you have the equipoise in randomizing a patient in that fashion to prove this point? Do you think it's a study that needs to be done or do you think the benefit of biopsies is well enough illustrated at this point, just to make it standard?

Jaime Landman: As a friend of Brian's, I will tell you that I would support almost anything he does, but I don't understand the study. You're randomizing people to biopsy or not, in what setting?

Monty Pal: So this is in the case of a small renal mass. You either observe the patient or do a biopsy in that context. And the certain patient has to [crosstalk 00:14:28].

Jaime Landman: Is this in the setting of active surveillance you are going to biopsy versus not biopsy for active surveillance?

Monty Pal: Correct correct.

Jaime Landman: I love that effort. And in fact, the term BIAS, which is biopsy informed active surveillance, I coined last week for our team. Only in the process of thinking of this manuscript that literally is just being published did we decide that we are going to go back and look at our own active surveillance experience here at UCI and look at BIAS versus what I call stupid active surveillance or SAS, although I don't think that is going to make it into the manuscript.  When we are stupid and we do not know which person we're putting on active surveillance, it really should be uninformed or nonbiopsy guided active surveillance. There are going to be a very small percentage of those that are more aggressive cancers.

So I'm going to do that in a retrospective way and I would fully support Brian's effort of doing that in a prospective way. The problem is with Brian's study if you'll look, and I remember back in the day I was at the AUA and this is probably 10 or 15 years ago, and where was it at? There was a manuscript where they literally had a Kaplan-Meier curve with 100% going across the top. And it was a survival curve for active surveillance in kidney cancer. The truth is, you need an enormous number of patients in active surveillance to show a difference because dumb active surveillance or nonbiopsy informed active surveillance, those patients do so unbelievably well that to show a statistical difference is going to be very difficult.

So I don't know how Brian is going to power his study, but it's going to require a lot of patients because all active surveillance patients generally do really well. And in fact, about 150 years ago, really 15 years ago, I think, I published the first T2 active surveillance series for some patients and those patients actually do pretty well. So I'm not saying kidney cancer is not a bad disease and nobody more than you knows that. But what I'm saying is that we really have to start being more precise about characterizing the smaller masses because we are over-treating for sure.

Monty Pal: And I have to probe you on that T2 population because that's fascinating to me, but I assume that's a biased population as you've put it, for biopsy informed, or are these patients that-

Jaime Landman: No, this is back in the day, this is before I was doing a biopsy, I was at Columbia University, an Associate Professor just thinking this out, and I had a bunch of people coming to me. They were in their mid-eighties, some, had a heart attack last week and some, a stroke the week before and they have a five or six-centimeter tumor or even an eight-centimeter tumor, and they'd say, "Hey, what do I do?" And you understand intuitively that person has a very short life expectancy and you want that to be optimized. And you know that the probability of their eight-centimeter kidney tumor that is incidentally found, incidentally found not symptomatic, will not affect their lifespan because quite frankly, they have a short life span.

And that's how I collected, I think it was 30 or 40 of those patients, it was not a large population. But the manuscript was actually engendered after the first AUA guidelines came out where they had put people into four categories. And one of them was that they had suggested active surveillance for very sick people with larger tumors. And I was like, "Oh, I don't know what the population does. Nobody does." So that's why we looked at them.

Monty Pal: Brilliant, brilliant. Well, Jaime, I got to tell you, I learned so much today from this conversation. We have to do this more often. We usually try to bring in a third party, but I have to tell you, I learned so much just from this conversation with you. Thank you for that and I guess that wraps it up for Kidney Cancer Today.

Jaime Landman: It was a joy talking to you, Monty, and I look forward to torturing you on your next publication. We'll make it a habit. Thank you all for joining us on Kidney Cancer Today. We will hope to see you in the next episode. Bye-bye.