BackTable / Urology / Podcast / Transcript #10

Podcast Transcript: Management of Locally Advanced Kidney Cancer

with Dr. Vitaly Margulis and Dr. Aditya Bagrodia

Dr. Aditya Bagrodia interviews Dr. Vitaly Margulis, professor of urology at UT Southwestern Medical Center, about locally advanced kidney cancer. They discuss various topics including classification of locally advanced kidney cancers, various imaging modalities for staging cancer, special considerations for tumor-thrombus formation, targeted therapy vs. checkpoint inhibitors, and robotic vs. open nephrectomies. You can read the full transcript below and listen to this episode here on BackTable.com.

Table of Contents

(1) Staging Locally Advanced Kidney Cancer

(2) Management of Kidney Tumor Thrombi and Metastases

(3) Treatment of Locally Advanced Kidney Cancer

(4) Vascular Complications During Surgery and Budd-Chiari Syndrome

(5) Lymph Node Dissection: Indications and Contraindications

(6) Indications for Partial vs. Radical Nephrectomies

(7) Robotic and Laparoscopic Approaches to Tumor Resection

(8) Adjuvant Therapy for Locally Advanced Kidney Disease

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Management of Locally Advanced Kidney Cancer with Dr. Vitaly Margulis and Dr. Aditya Bagrodia on the BackTable Urology Podcast)
Ep 10 Management of Locally Advanced Kidney Cancer with Dr. Vitaly Margulis and Dr. Aditya Bagrodia
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[Dr. Aditya Bagrodia]
Hello everyone and welcome back to the BackTable Urology Podcast, your source for all things urology. You can find all previous episodes of our podcast on iTunes, Spotify and at backtable.com. This is Aditya Bagrodia as your host this week and I'm very excited to introduce our guests today, Vitaly Margulis from the UT Southwestern Department of Urology.
Thank you for joining us here today, Vitaly. How's the weekend going so far?

[Dr. Vitaly Margulis]
Great, Aditya, and great to be here with you.

[Dr. Aditya Bagrodia]
All right. Fantastic. So brief introduction. Vitaly is a professor at UT Southwestern. He did his residency here, trained at MD Anderson for fellowship, and he's been back now and really a backbone of our department. He's been a thought leader in management of localized and locally advanced kidney cancer. So we're really excited to hear your thoughts today, Vitaly. And with that, we'll just kick off. So I want to ask you, Vitaly, when you hear about locally advanced kidney cancer, what clinical states does that exactly mean for you?

[Dr. Vitaly Margulis]
So these will be non metastatic patients, first of all, with some radiographically advanced features. So things like extension of the primary into perirenal tissues, with extension into things like perinephric fat, adrenal gland, extension into the venous system, as you may know, kidney cancer unusually has propensity to invade venous outflow structures, such as renal vein, cava and so on. And those tumors really with regional nodal disease. So those, I would consider to be locally advanced.

[Dr. Aditya Bagrodia]
Okay. Okay, good. Just to make sure the audience is on the same page in terms of the clinical states that we're talking about. And 101, any particular aspects of the history and physical exam that become more relevant in these patients?

[Dr. Vitaly Margulis]
Certainly. I mean, I think in any case it's probably prudent to do a good history and physical focused things to think about, specifically pertaining to this situation are things that may have to do with, for example, the signs or symptoms of venous obstruction because it would change how you ultimately manage the case. Things to look for, again, pertaining to the signs of venous obstruction, your legs swelling coupled with Medusa, any signs of hepatic congestion, hepatic insufficiency, when you start talking about locally advanced things may be important to probe around any cognitive defects, anything that has to do with CNS and your usual things like obviously weight losses, appetite changes, things like that, that may have ensued over upcoming months.

(1) Staging Locally Advanced Kidney Cancer

[Dr. Aditya Bagrodia]
Okay. Helpful. And what about staging? What are your preferred means of staging these patients?

[Dr. Vitaly Margulis]
Generally, I would say majority of the cases, a quality cross-sectional imaging, whether it be CT or an MRI are generally sufficient. I think it's important to know that once we start looking into or understanding that we're dealing with a tumor that invades into the venous system, I think MRI is probably preferable, again, in terms of appropriate staging, but also to plan the subsequent surgical management.

[Dr. Aditya Bagrodia]
Okay. And for the chest, chest x-ray is sufficient, chest CT preferred, any strong thoughts?

[Dr. Vitaly Margulis]
Yeah. Certainly again kidney cancer is notorious for predilection for pulmonary metastasis. And I think if you're really interested in determining if the pulmonary metastases are present, the CT of the chest probably should be performed. Certainly in more advanced cases where there's extension above the diaphragm, certainly chest should be much imaged thoroughly. But my go-to now for advanced kidney cancer is certainly CT of the chest, CT or MRI of the abdomen and other testing directed based on concern for other metastatic sites.

I have shifted gears in recent years and generally when I deal with tumors that invade into the venous system, I now routinely obtain a brain MRI because there's higher prevalence of metastatic disease to the brain even if it's asymptomatic. Certainly if there are symptoms, CNS symptoms that are present and if there's bone concerns, then direct radiographic imaging is probably warranted in addition to what we've just mentioned.

[Dr. Aditya Bagrodia]
Okay. Yeah. And I think one of the things that I certainly learned from Vitaly in training is, particularly in patients with higher level thrombi that may undergo cardiopulmonary bypass with the anticoagulation, you really want to have a lay of the land with respect to brain imaging. You don't want them to be anticoagulated and then have a catastrophic CNS bleeding event. Fantastic. And what about bone scans? Routinely ordered, reflex for abnormal laboratory values?

[Dr. Vitaly Margulis]
Yeah, unexplained markers of bone turnover, certainly bone related symptoms, I think these will be triggers, but that's not something that I routinely would get because outside of those findings, the yield on something like this will be pretty low.

[Dr. Aditya Bagrodia]
Okay. Pet scans, any role?

[Dr. Vitaly Margulis]
Very limited specifically in RCC. I would say for all intents and purposes, minimal role, right now.

(2) Management of Kidney Tumor Thrombi and Metastases

[Dr. Aditya Bagrodia]
Got it. You'd mentioned a little bit of leg swelling and so forth. And sometimes with tumor thrombus cases, we see two clinical scenarios, one is bland thrombus, and one can be pulmonary emboli. Can you talk about how that impacts your perioperative management and approach to those patients?

[Dr. Vitaly Margulis]
Yeah. These now we're started getting to some of the more challenging scenarios and what you're alluding to are our patients with cava tumor thrombus and sequelae, which can be bland obstruction or bland thrombus that form below the tumor thrombus resulting in lower extremity swelling, and also obviously pulmonary emboli. These are tricky situations and what you've... one has to balance anticoagulation, but also you have to carefully balance that with the risk of pretty massive bleeding from the primary.

Generally, patients with evidence of bland thrombus and or pulmonary emboli, I would probably anticoagulate going into surgery and resume that anticoagulation shortly once the patient is deemed safe after the operation.

[Dr. Aditya Bagrodia]
Okay. And this is a clinical scenario that we encounter not frequently, but not infrequently. Can you talk a little bit about your patient with a bleeding mass transfusion-dependent hematuria that either due to patient or tumor factors, wouldn't be an ideal candidate for upfront nephrectomy? Do you have an algorithm that you could share with us?

[Dr. Vitaly Margulis]
Well, yes. The first thing you would do, a lot of these bleeds are self-limited and just simple supportive measures may resolve. Obviously, in some cases, if patient is on anticoagulation, we may have to hold the anticoagulation, maybe resume, but at a lower dose. But if that doesn't work and there's really, truly a transfusion-requiring bleed, you might have to reevaluate your strategy of not operating. Sometimes you just have to pull the trigger and operate.

But in situations where that is not possible, then I think there's a couple of tricks up our sleeve that we have. One of these would be obviously angio embolization and the second, which works well but obviously has subsequent sequelae that one has to deal with. Another option is actually delivery of radiation to the primary, and that's something I think we have pioneered... well, not pioneered, but have quite a bit of experience here at UT Southwestern. We're very fortunate to have a very robust radiation outfit here, radiation oncology outfit. And in several cases I've been involved with, delivery of SBRT to the primary has been very effective in diluting the bleeding.

[Dr. Aditya Bagrodia]
Yeah, I think that's a very rational approach and I wholeheartedly agree that I would say that the paradigm in Dallas has largely shifted to in these relatively rare tumors unresectable for whatever reason, start out with radiotherapy, if that doesn't work, reserve embolization. Okay. So I think these are some really nice pearls for management of these sometimes difficult features. And I know that we're primarily focusing our efforts on locally advanced, but in the cases where you have metastases, and let's just say, these are not extensive metastases, maybe a pulmonary nodule that's a centimeter or so, maybe a pancreatic met or a liver met. Can you talk a little bit about the role of biopsy and what to biopsy?

[Dr. Vitaly Margulis]
That's a good question. I wanted to add something to our previous discussion with something that I routinely see in the communities, is this going back to the thrombus, and it'll answer your subsequent question, I didn't mean to skip, but just for the audience, it's not uncommon for me to see a patient with thrombus and for example, maybe a pulmonary embolus who's completely stable, but comes in with a filter.

And so there's this knee jerk reaction to place a vena cava filter to suppress further, or prevent further tumor thrombus emboli from the tumor thrombus in the patient. That's actually exactly the wrong thing to do. Not only complicates further surgical intervention, I think it then makes it a lot more dangerous and really has not been really shown to prevent additional pulmonary emboli. So I think we just have to temper our immediate need to put a vena cava with tumor thrombus. It's just one of those things that don't be reminded, but I see that happen very frequently in the community.

So, back to your question of what to biopsy, I think this has to be a discussion with your interventional radiologists. I think the first thing is safety to the patient and the comfort level of the interventional radiologist. I mean, if your only goal is to get tissue diagnosis to start treatment, I think probably not super important where you biopsy, I would probably go for the easiest site to get tissue. There are nuances. Some of these renal tumors are excessively vascular, and actually a biopsy can trigger a significant hemorrhage of the primary.

Maybe sometimes it's best to go for the metastatic site, but there are other situations where you want to make sure in your scenario that you gave, with a, for example, solitary pulmonary nodule. It's not unheard of for a patient to have a second primary. So in that case, perhaps to further apply treatment, may be more prudent to biopsy that the lung nodule. There are other nuances, and something recently that I've dealt with was a relatively indolent looking primary, but massive retroperitoneal lymphadenopathy.

And so one has to think about, again, secondary malignancies, lymphomas, and maybe it's more prudent to biopsy your lymph nodes in that setting. There's no one answer to fit all scenarios. I think several things are at play here, but these are the conversations that should happen in a multidisciplinary setting.

[Dr. Aditya Bagrodia]
Absolutely. Couldn't agree more that multidisciplinary collaborative management is absolutely key and that would actually dovetail in quite nicely to the next thing, which I think is rapidly expanding in this area, which is consideration of neoadjuvant or induction therapy for locally advanced kidney cancer. Could you comment a little bit about that, Vitaly?

(3) Treatment of Locally Advanced Kidney Cancer

[Dr. Vitaly Margulis]
Yeah. If we think about management of locally advanced kidney cancer over the last how many years, there's not been much of a change to this date. If you look at gold standard of care, this remains a surgical disease and we unfortunately have not embraced, although this is about to change, but we really not embraced multimodal management as a routine for advanced kidney cancer like some of the other urologic malignancies, bladder, testicular cancer, penile cancer, et cetera, where multimodal management is probably a standard of care, not so much in advanced kidney cancer.

So, this is a rapidly changing field, I think, with newer therapies that we have access to. So, I think this is an exciting field. To your question about neoadjuvant therapies. Again, this is something that I would say that has to be considered on a case by case basis. Certainly I would say not the standard of care. And again, your locally advanced disease mainly is surgical disease at this point. Some of the things that, where I utilize neoadjuvant paradigms would be in unique situations where we need to say, to reduce the primary, to be able to deliver, for example, nephron sparing in a situation where it complete nephrectomy would result in an anephric state.

Typical example, a patient with a solitary kidney and large tumor where a partial nephrectomy may not be feasible, delivering a systemic therapy in a neoadjuvant fashion to shrink the tumor and allow me to perform a partial nephrectomy would be a very common example. Other uses, I would say there are, again, pretty rare situations where the primary may not be rephrectable safely. Again, that's a rare burden, we need to shrink the tumor to be able to do the surgery safely. That would be a second indication, probably less common in my practice.

[Dr. Aditya Bagrodia]
Okay. And can you just give us a little bit, without getting into the details, general systemic therapy that you use, the general duration of use, the general period of wash out prior to surgery and when you reimage to assess response?

[Dr. Vitaly Margulis]
There're two broad categories of systemic therapies that we know are effective for kidney cancer or your targeted therapies that target the VEGF pathway and are checkpoint inhibitors that the modulate the immune response. And you have to think, what are you trying to achieve with just systemic therapy. If it's purely for situ reduction, then your later generation targeted therapies, such as, for example, like Sunitinib that we know have been shown to be effective in situ reducing or shrinking the tumor is something that should be considered.

Again, we don't have much data in this. And so a lot of what I will say is anecdotal. I have recently, again, shifted my approach to this and now actually use a combination of third generation or a later generation targeted agent with a checkpoint inhibitor. So something along the lines of Axitinib, Pembro prior to surgery and just anecdotally have had very good success with this.

And the nice thing about this combination is we know that with purely, again, not getting too much into the weeds, but purely with targeted therapies, there's almost zero chance of a complete response, but when you add Pembrolizumab or some a checkpoint inhibitor, we now have and I've personally had several cases where there has been a complete response in a primary. So, I've shifted gears recently. And now basically my go-to combination would be... my go-to therapy would be a combination type therapy. How long? Again, something that I use in my clinical practice, I go on until maximal response. And so patients get the therapy, we get essentially almost monthly imaging. And once I see maximum response, this is probably the time to intervene.

And when we know with when you started utilizing, and this is an important caveat, when you start using some of these checkpoint inhibitors, you actually can get an initial, almost unit progression where the tumor seems to swell but then will eventually start shrinking. So, in support, not to pull the trigger, it's very uncommon for patients actually to have a disease progression on a dual therapy like this. And usually during the first round of imaging, you're going to see some swelling. It's usually this element of pseudoprogression, I usually continue that therapy. Again until maximum progression, if the image of targeted agents is used, it might usually give it about a couple of weeks to wash out and patients should be ready to go for surgery.

[Dr. Aditya Bagrodia]
Perfect. You mentioned solitary kidneys' almost absolute indications to avoid an anephric state. Just to comment, bilateral masses, one more oncologically threatening than the other, of course, you're going to have that patient see medical genetics, but general strategy in terms of... this is, that's been historically debated, go for the partial nephrectomy potentially first, and you have some nephrotic reserve from the other side, or do you typically go for the more oncologically threatening tumor?

[Dr. Vitaly Margulis]
Yeah, my thought has been to remove the most biologically threatening entity from the equation. So I usually tend to go for your bulky, non partiable side first and then deal with the other side. But again, when you start considering systemic therapies, if for example, one side is clearly partiable, the other side maybe, one may consider doing a lead-in with systemic therapy and see if we can deliver nephron sparing at both sides. And so it's a little bit nuanced, but generally to answer your question, I would go for the biologically aggressive entity first and deal with the nephron sparing on the other side.

[Dr. Aditya Bagrodia]
Fantastic. And I think it really highlights the coordinated care between medical oncologists, radiation oncologists, radiologists that are familiar with progression, pseudoprogression, careful administration of these systemic therapies to really have a smooth course. Really nice. And who all are you sending for medical genetics referral?

[Dr. Vitaly Margulis]
So certainly obviously these are young patients, these are patients with family histories, so certainly anybody under 50 with a kidney tumor now in my practice gets essentially automatic genetic testing. Certainly if there's family history, certainly if there is syndromic features in these other patients with adrenal tumors, pancreatic tumors, any concern for BHL and your concern for other RCC types of drugs. Young women, for example, pretty classically ignore scenarios, small, small renal mass, but his true uterine malignancy of some sort, you should screen each of RCC and these are more biologically aggressive tumors, you may decide to manage in a nuanced fashion.

(4) Vascular Complications During Surgery and Budd-Chiari Syndrome

[Dr. Aditya Bagrodia]
Yeah, couldn't agree. More. And I think just little things like carefully reviewing your imaging to make sure there's not any suggestion of any type of uterine pathology, little things like this can be massive in terms of tipping you off for focused questions. All right. Very good. So we've talked a little bit about staging. We've talked a little bit about biopsy, the role.

I think we could have a whole another conversation on cytoreductive nephrectomy, risk stratification, who may benefit and not, and perhaps it'd be a good topic for a future episode, but maybe now let's just jump into it. And in a way, I think about these as for locally advanced, as you described earlier, is you have your perimetric fat invasion family, then you have your sinus fat and Hyler structure is close to the kidney, then you have your regional lymph node patients and then finally, of course, your thrombus patients.

I would just request that you comment on that and also just talk about aspects of imaging that you're really dialed in on as you're planning surgery. Let's just say that you've discussed with them some clinical trials. I know Vitaly has been a leading accruer for the PROSPER trial, which is a very, very exciting, but when you're looking at the imaging, what are the things that you're dialed in on?

[Dr. Vitaly Margulis]
Yeah, so again how big is the primary? So I started thinking, okay. I mean, obviously if we start talking about tumor thrombus, that patient, obviously the level of the thrombus, degree of obstruction, degree of colorization, I almost think about my thrombus patients completely differently when I plan my surgical approach, almost every single one of these cases will be done in an open fashion.

And some of the things to understand is, as we said, what team do I need with me? And so when you, when you do these thrombus cases, I think you need to have a well oiled team. This has to be... you don't want to experiment, you want to have a well assembled partner in crime, whether it be a cardiovascular thoracic surgeon, vascular surgeon, liver transplant surgeon, I actually utilize probably all of them, depending on where the thrombus is for your retro hepatic thrombi, the thrombi did want to extend above the diaphragm. I've recently shifted to partnering with a liver transplant colleague, and these surgeons are very useful to help you mobilize the liver, get all the hepatic branches controlled, get the liver out of the way, control the cava just below the diaphragm. And so the tumor thrombi that radiographically are above the diaphragm, obviously this is where you have to have a good partnership with their cardiovascular and thoracic team which we do here, and those cases probably are best done in collaboration with them in case of bypass or circ arrest will be needed.

So, again, the level of thrombus is critical. Is there a blunt thrombus? Do we need to resect the cava? Is there enough colorization to allow for safe resection of cava up without reconstruction? Those are all the technical things that go through my mind. But these specific to the thrombus cases. Now, when you start looking at other cases-

[Dr. Aditya Bagrodia]
Maybe Vitaly, since you've jumped into thrombi, which is always a challenging multidisciplinary case, I'm going to ask you a few questions before we move on to some of the other ones. Budd-Chiari syndrome. If you get in, you've got to evidence of liver chemistry elevation, or you encounter ascites, any unique considerations in that patient population?

[Dr. Vitaly Margulis]
Well, I mean, ideally yes, of course, but ideally this is something that you... it's true Budd-Chiari syndrome should be identifiable prior to surgery. And these are not the patients that should be managed with upfront surgery. So this is one rare indication where I would consider leading in with multi-modality therapies first to allow for recanalization and proper drainage to deliver, because these are not generally survivable surgeries.

So if you have a full blown Budd-Chiari syndrome, I think rushing into the surgery is not the best thing for the patient, it's mortality rates are nearly a 100% in that case, if you have, for whatever reason, encountered some maybe early manifestations of a Budd-Chiari syndrome as maybe some degree of hepatic dysfunction without full blown hepatic toxicity, then it's a clinical decision, I think, whether one should proceed and remnants of it... in some cases very hard to make that decision, just presence of ascites alone doing surgery probably is not contraindication. Then in case we get in, but there are other signs of liver dysfunction, such as terrible appearing, completely congested liver that’s friable, this with immediate bleeding upon everything that you touch with ascites and this may be the case where I would say, "You know what? Maybe we’ll close and manage with systemic and or radiation therapy first and then come back to fight another day. But ascites alone probably wouldn't be the reason to stop. And again, I just want to stress that this is one condition where we really need to diagnose before taking the patient to surgery.

[Dr. Aditya Bagrodia]
Okay. Good point. So you'd mentioned bland thrombus, caval resection, broad strokes, when you start these operations, do you typically work on the vascular structures first? If it's a right sided tumor, early control of the artery, for instance in the intra caval space, gaining access to your contralateral renal vein, your infrahepatic IVC, super thrombus IVC. Can you just talk a little bit about how you think about that and approach that?

[Dr. Vitaly Margulis]
There'll be some differences in technique among different institutions. So what I've done over the years is have good control of the primary without unnecessarily disturbing the thrombus. And the idea here is we don't want the thrombus to embolize. So the primaries control the arterial flow to the primaries control and in some cases, this results in shrinking at the thrombus, perhaps making the thrombectomy portion easier. Once the primary and the arterial inflow is controlled then we go through our routine steps to isolate the tumor thrombus within the venous system.

So it's generally isolating the super thrombus cava, isolating that portal system if necessary, certainly infra thrombus cava. So once you have the cava isolated, then thrombectomy ensues and the rest of the primary is removed once the cava is closed. Some of the nuances you mentioned in some cases the cava has been obstructed for a long time, and it's probably even safer to resect the thrombus with the cava. And if that is your clinical judgment, then it's very important to preserve that colors, collaterals that have formed over the years, the patient has proper venous return.

[Dr. Aditya Bagrodia]
Excellent points. I think it's very obvious to me that each one of these cases is unique. You've really got to study the imaging. You've got to have a plan going into it. And I think you've also got to be ready for some various things that can happen intra-operatively. I recall as a resident doing a case with Vitaly. It was a relatively low level two thrombus, for no reason, with no manipulation of the cava, there was an embolization event, rapidly mobilized, performed thoracotomy embolectomy and the patient had a wonderful post-operative course, but you can imagine that if you don't take these cases seriously, you could have a very different outcome.

I think again, Vitaly's really stressed the need to prepare, to plan, to be ready, intra-operatively. I think you routinely use intraoperative echo in close collaboration with the cardiovascular anesthesiologists, but any other things that you'd like to mention specifically about obviously thrombus cases?

[Dr. Vitaly Margulis]
Again, if I have to mention one thing is to have a well-oiled team put together and it can be your choice, but you want to work with people that you're comfortable working. You want to have a good anesthesia, anesthesiologists that generally understands all of the nuances are there applicable to the cases where it could be high volume blood loss. You want to have an anesthesiology team with cardiac echo capabilities. And as you know, I do. Essentially every one of these cases in a situation where access to a quick pump, if we need to crash on pump during some of the situations you've just described is available.

That would be the most critical aspect you have to have... then you have to think about how am I going to reconstruct my cava. So you have to have access to things like catheters to embolize bland thrombus or de-embolize bland thrombus. If necessary, you have to have access to your Dacron grafts. You have to have access to your patches that they were given needs to be patched. It's a highly nuanced surgery, but the key here is it cannot overstress this, to have a team in place that is familiar with those cases.

(5) Lymph Node Dissection: Indications and Contraindications

[Dr. Aditya Bagrodia]
Perfect. So maybe now we shift a little bit to clinically node-positive radiographically node-positive patients. And maybe I'll ask you to just talk a little bit about the role of lymph node dissection in those patients, as well as the performance of routine lymph node dissection in other high-risk patients without radiographic evidence of nodal involvement?

[Dr. Vitaly Margulis]
Certainly your first case scenario where we have gross radiographic evidence of nodal disease with modern imaging, those most certainly will have a metastasis that's seems pretty rare to have a false positive. And if this is the only side of their disease, then I think a resection of the primary, the thorough lymph node dissection, not just note plucking, probably template dissection as something that should be performed.

It gets a little bit more murky, I would say, with a lymph node dissection in the setting of clinically node, negative disease. The data has gone back and forth over the years. I certainly can make a reasonable case to perform this in high-risk population. So these are your thrombus cases, these are the cases perhaps where there is a super bulky tumor with ipsilateral adrenal involvement, for example. I can make an argument to perform lymph node dissection, even if they’re radiographically or clinically negative, because there's high risk for regional nodal involvement.

The implication of that is a little bit less clear, but we certainly all had cases over the years where lymph node dissection was not performed. And we had to go back in to remove that lymph node. So it’s a lot easier to get it at the time of surgery. I would say that added morbidity to performing a regional lymph node dissection at the time of the nephrectomy, is I would say limited. This can be not quickly without significant morbidity to the patient. So I do this and I show you the data that it changes patient outcome routinely, it probably can't. But if you, if you look at the description of a classic nephrectomy, it's still a hint to remove the regional lymph nodes with the bulky primary.

[Dr. Aditya Bagrodia]
Okay. And again, I recall from training and my understanding of the literature that certain high risk populations where you're suspecting say HL RCC, or any of the more aggressive hereditary cancer syndromes, you'll oftentimes do a lymph node dissection, even if a partial nephrectomy is planned. Is that right?

[Dr. Vitaly Margulis]
Yeah. That's a good point. And these are, again, nuanced situations. So things like, certainly HLRCC or probably even more common in my practice will be your translocation carcinomas. So these are young folks with translocation tumors, that have a higher propensity for nodal disease. And so these are the patients I would offer a routine lymph node dissection in the setting of clinically negative notes. But this is a minority. These are very few of them. The real question is whether we should be doing lymph node dissections or just in your regular average, bulky tumor, and here's the data is a little bit murky.

[Dr. Aditya Bagrodia]
Yeah. And I think those patients that you mentioned oftentimes have a prolonged local regional phase where you can really help them and potentially get to a curative state, so fantastic point. You mentioned adrenalectomy, when are you performing adrenalectomy, tumor location, tumor features? What are some of the things that are driving that discussion?

[Dr. Vitaly Margulis]
Yeah, certainly with modern radiographic imaging leading to the surgery, and again, the data supports this, if the tumor is away from the adrenal, adrenal is not involved and it looks normal radiographically, probably can be left alone. And there are certain situations there's concern for, again, direct extension into the adrenal. And certainly in situations where there is a tumor thrombus, especially on the left side where as you know, drainage of the adrenal and drainage of the kidney are intertwined, at least I performed the adrenolectomy again and there's high propensity for adrenal involvement in those situations. So again, it's a concern for direct involvement, a concern for ipsilateral adrenal metastasis and bulky tumor thrombus cases, adrenal comes out.

[Dr. Aditya Bagrodia]
Makes sense. And I think it's supported data as well. Okay. You mentioned template dissections. Are these going to be commensurate with testis cancer dissections, or are there any considerations you'd like to share?

[Dr. Vitaly Margulis]
Yeah. So this is basically... for template dissection, what I mean by this is your ipsilateral lymph nodes plus one area next to it. So if you're on the right side this will be paracaval, internal aortic caval, I don't think one needs to take this to the same degree as what we do for teratoma debulkings in testicular cancer. But I think a thorough, especially in the setting of where we do purely staging lymph node dissection, I think it's one area removed from where you are, it's probably sufficient.

[Dr. Aditya Bagrodia]
Okay. And this is the primary driver consideration here, obviously, but when you bill for these cases, any tips and tricks?

[Dr. Vitaly Margulis]
Yeah. It can be challenging. I mean, I think you really have to work with your coders and billers because these are pretty nuanced cases. And I think, again, you want to have ongoing discussions with the billing team because there's quite a variability of how these could be billed. So, to your point, if you bill for radical nephrectomy but you also do a template lymph node dissection, there's a separate code that should be utilized because what's rolled into your lymph node dissection with the primary are just regional Kyler piler nodes. So if you go outside of that, this could be billed in these quite a few RVUs and could be left in the table if you don't.

(6) Indications for Partial vs. Radical Nephrectomies

[Dr. Aditya Bagrodia]
Okay. Perinephric sinus involvement, is that a reflex? And I'm talking about extending towards Gerotas, is that a reflex radical nephrectomy in your hands?

[Dr. Vitaly Margulis]
Nothing should be reflex, but generally yes. I mean, if we have clear-cut evidence of the tumor's central... if it extends into the sinus certainly. Some of the tumors extend outward of the kidney. Again, you have to... it's a multi-factorial decision. You have to think, "Okay, is this obviously in an elective setting? Is an imperative setting? Borderline? How technically is partial feasible?"

And it's also now the discussion that has to be held with the patient. Obviously, last thing you want to do is do something like this in an elective setting, get into the tumor, have local tumor recurrence, and we've all had these disaster cases where patients came in with peritoneal carcinomatosis from an attempted nephron sparing that shouldn't have been performed. So I think it's nuanced decision. Does it automatically mean radical nephrectomy? No, but I mean, I think one has to evaluate this from the multi-sectoral perspective.

[Dr. Aditya Bagrodia]
And what about sinus fat? One thing I recall is oftentimes for very central tumors, you will obtain a biopsy just to make sure that you're... and a patient that's a high risk of receiving a radical nephrectomy potentially that you want to make sure that this isn't something that's a benign or likely to be a very little oncologic threat. Are you still doing that?

[Dr. Vitaly Margulis]
I'm doing this. So if you have... there's a smaller tumor that doesn't look biologically aggressive, but located in this such location that perhaps you may have hard time finding it, or where you know that if you start opening the kidney up and getting to the sinus, there's pretty good chance for a radical nephrectomy. And so I would probably obtain a biopsy of this to confirm that this is in fact, a cancerous lesion before performing a surgery that could potentially result in a kidney loss. It would be a shame to do something like this for oncocytoma and something that can be safely monitored and then have a patient lose the kidney.

[Dr. Aditya Bagrodia]
And of course there's patient's back factors, there's renal function, reserve and so forth. But if you have central tumors that are relatively smaller concern for segmental, subsegmental venous branch invasion or sinus fat invasion, do you still keep partial nephrectomy as a part of your armamentarium?

[Dr. Vitaly Margulis]
It's really hard to definitively show a segmental radiographically segment involvement of the venous system by a tumor and a lot of this stuff, a lot of the times this is artifactual. So you have to make a decision whether you could, again, in your hands, and again, it's different from surgeon to surgeon. You have to factor in your experience and your comfort level into the equation, but for an elective setting, I would have a pretty good reason not to offer radical nephrectomy, honestly, if I highly suspect that there's venous involvement in an elective setting.

[Dr. Aditya Bagrodia]
What about if you encounter a tumor thrombus intraoperatively?

[Dr. Vitaly Margulis]
Well, again, I mean, if the partial goes well, and there's a nodule of the tumor that goes through the vein, that I'm confident that I've removed appropriately and all the tumor's out, then I would probably complete a partial nephrectomy, reconstruct the venous system and move on. Certainly at that point, you've already committed, most of the tumor's been dissected properly, and you're getting a negative margin. There's pretty good data to suggest that partial nephrectomy provides equivalent oncologic outcome compared to radical nephrectomy in that setting. So if you get all the tumor out and margins are good and the outcomes long-term are the same, whether you performed a partial or radical.

[Dr. Aditya Bagrodia]
Do you have any strong opinions on enucleation versus formal partial nephrectomy in these types of cases?

[Dr. Vitaly Margulis]
Again, this is something that you look at radiographically if it's an infiltrative tumor or there's concern for tumor infiltration, not a well-defined capsule, this may be a tumor that I would probably not attempt enucleation on and would probably lean towards a more standard resection. But this is actually a minority. And I think I've switched over the years to doing more of something called a nuclear resection, probably, where you stay very close to the tumor capsule.

And it's been very beneficial from several perspectives. Number one perspective is that when there are contouring irregularities, if you stay close to the tumor capsule, it can actually recognize a nodule of the tumor extending somewhere and get around it. I've seen that happen multiple cases. It actually has helped me to get a negative margin when you stay close to the capsule because you follow the contour of the tumor. Not all the tumor is exactly spherical, so you can avoid getting into a nodular extension.

The second thing is, I think you end up cutting across fewer vessels this way. And so if you do a true partial nephrectomy, you probably do a lot more damage that way, end up sewing a lot more and probably with longer ischemia times, et cetera, et cetera. Certainly there's plenty of data to suggest that oncologically whether you do enucleation or radical nephrectomy, as long as you're good at what you're doing, I think the oncologic outcomes are similar.

(7) Robotic and Laparoscopic Approaches to Tumor Resection

[Dr. Aditya Bagrodia]
Yeah. And I think that leads me into one of the other things that I just wanted to quickly touch on which globally, I'm going to guess that we agree that really use the tools that you're comfortable with and most adept with, but robotic versus open, you'd mentioned thrombus cases, those are pretty much going to be open. I think that's the case at most centers, other than a few select centers. Tumor size, lymph nodes, what are some of the factors that are going into whether this might be a reasonable patient for a robotic or minimally invasive approach?

[Dr. Vitaly Margulis]
Again, as we have all gotten more and more comfortable with the robotic/laparoscopic approach, I think more and more cases now, I do robotic that I was doing open in the past. The main factor here is the size of the tumor. Will it be able to get good retraction on the tumor, on the kidney and still be able to see the structures that I need to see? And if that's the case, and that's my judgment then I usually do those cases robotically.

I think robotic platform allows you to do an additional lymph node dissections, even venous reconstruction, and that's something that I think most of us were not comfortable doing that with pure laparoscopic approach. So the bottom line is that a tumor's small and in even the presence of lymph node disease, as long as it's not super bulky and encasing the vessels, a lot of these tumors, I would do it with robotic approach.

[Dr. Aditya Bagrodia]
Good. Yeah, I would wholeheartedly agree. And you talked about encasement of the vessels. I think even over the course of my five years as an attending, that has shifted outside of massive transfusion-dependent hematuria, significant symptoms, et cetera, to a case where I'd really potentially like to get some systemic therapy on board before jumping in. I think those can be dangerous cases and the chance of actually getting a R0 resection are very, very small. Any comment on that?

[Dr. Vitaly Margulis]
I would say that it's a double-edged sword. A lot of these cases with these bulky lymph nodes encasing the great vessels, these are generally systemically metastatic cases, they probably should be treated with systemic therapy. But you have to realize that if there's any chance of resection, when you come back both systemic therapies, the tissue planes now have changed tremendously, and it doesn't have plastic reaction that you will have to deal with, whatever may negate the little shrinkage that you have achieved. Okay. So you have to really think about this.

And if you plan to come back and patient does have some bulky disease that perhaps was resectable, you really have to make that decision. I think for me using systemic therapy in those settings is driven by the fact that these are generally patients with systemic disease.

(8) Adjuvant Therapy for Locally Advanced Kidney Disease

[Dr. Aditya Bagrodia]
Good point. And Vitaly was a senior author in one of the first papers looking at cytoreductive nephrectomy after induction checkpoint inhibitors. And I think it's safe to summarize that with carefully selected patients, there's a lot of nuances, single agent, double agent, timing from initiation to surgery, but in experienced hands, that patients can do quite well. How about adjuvant therapy? What are your thoughts on adjuvant therapy once you've got your pathology back, patients have recovered from surgery?

[Dr. Vitaly Margulis]
Well, again, as we sit here today and talk, there's no adjuvant therapy that I use in my clinical practice. As you know, there've been multiple trials for every agent in the history of systemic therapy that've been tried in kidney cancer. If you go back years, chemotherapy, immunotherapy, interferons, targeted therapies have been tried. We know that Sutent has actually been approved by the FDA as an adjuvent treatment for post-surgery for locally advanced kidney cases.

But while Sutent in this setting has afforded delay in tumor recurrence, it really has not changed survival. So the OS end point was not met, and so basically you're giving a patient a pretty toxic therapy, I would say for a year or so, and all you're doing is really just delaying their recurrence, but not making them live longer. So, that's not an acceptable strategy in my hands. And I think most people don't use these therapies at this point. Now, there has been a recent new development as you may know that Keytruda has shown significant met... the trial of adjuvant Keytruda met this primary endpoint of recurrence free survival in an adjuvant setting.

I think we will see approval of checkpoint inhibitors in an adjuvant setting. The difference here is that we know the mechanism of action of checkpoint inhibitors actually allow for sterilization of metastatic disease, which we'll almost never see with TKIs. And so I think that this is a game changer and I think the targeted therapy... sorry, the checkpoint inhibitors immunotherapy will be a major paradigm shift in an adjuvant setting.

[Dr. Aditya Bagrodia]
Perfect. And I think there's so much that's exciting and coming through the pipeline, novel agents, theranostics, improved imaging, selection of patients that may or may not have had a complete response to checkpoint inhibitor, local therapy of metastasis, the role of cytoreductive nephrectomy. I think we're really on the cusp of a very, very exciting time in the management of kidney cancer.

As we conclude, Vitaly, I would maybe just ask you to share some of your perspective. You've been doing this for some time now, over a decade, on what's coming through the pipelines, what's on the horizon to really help these patients out.

[Dr. Vitaly Margulis]
Yeah. I mean, I think so kidney cancer is finally entering the era of really, truly personalized medicine. I think with some of the diagnostic and therapeutic technologies that you've mentioned, things like circulating tumor DNA, tumor profiling to understand which patients are at that high degree probability of relapse, and if they do relapse, how to treat them. And I think we finally have the tools that may allow us to deliver therapies that would likely impact the biology that the patient possesses.

As of now, we treat this by oncologists' preference. Somebody gives TKI, somebody gives this, somebody gives that, we don't have a rational strategy of how to address this disease. But I think that the tools are there, I think the data is exciting. Some of the newer PET imaging that actually can help us understand whether, for example, the metastatic site is immunoprivileged or not. And then we have actually some data to suggest that using radiation, for example, can convert somebody who has an immune privileged metastasis to somebody who will respond to immune therapy.

And so this is, again, a truly, truly an exciting era where we are now combining multiple specialists, specialties, we're utilizing predictors of response in form of circulating tumor cells or circulating tumor DNA. We're finally entering the personalized era in management of kidney cancer.

[Dr. Aditya Bagrodia]
Yeah, I wholeheartedly agree. And I think we both would agree that we're extremely lucky to be at UT Southwestern that has such a robust kidney cancer program, including a spore where all complex cases are discussed in a multidisciplinary film format. And the nuanced care that Vitaly's alluded to multiple times is extremely obvious. And the thoughtful discussion of these patients from A to Z, I think really has a massive impact which we've shown here across stages is the output and I think something that I would encourage all urologists to spearhead at their own institutions.

Well, Vitaly, a true wealth of information, really appreciate your time. If there's anything you'd like to add, by all means. Otherwise, I thank you for sharing your knowledge and your wisdom. I've certainly learned a lot and hopefully our audience and listenership would as well.

[Dr. Vitaly Margulis]
Thank you Aditya. Not much to add, but thank you for the expert moderation. And it's always good to hang out with you.

Podcast Contributors

Dr. Vitaly Margulis discusses Management of Locally Advanced Kidney Cancer on the BackTable 10 Podcast

Dr. Vitaly Margulis

Dr. Vitaly Margulis is a Professor of Urologic Oncology at UT Southwestern Medical Center in Dallas, Texas.

Dr. Aditya Bagrodia discusses Management of Locally Advanced Kidney Cancer on the BackTable 10 Podcast

Dr. Aditya Bagrodia

Dr. Aditya Bagrodia is an associate professor of urology and genitourinary oncology team leader at UC San Diego Health in California and adjunct professor of urology at UT Southwestern.

Cite This Podcast

BackTable, LLC (Producer). (2021, July 1). Ep. 10 – Management of Locally Advanced Kidney Cancer [Audio podcast]. Retrieved from https://www.backtable.com

Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.

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