The Evolving Treatment Landscape of Low-grade Upper Tract Urothelial Carcinoma
In this companion article, Sandip M. Prasad, MD, MPhil, from the Morristown Medical Center in New Jersey discusses the historic use of radical nephroureterectomy and provides an overview of his clinical experience using kidney-sparing approaches for LG UTUC.
In this new Urology Medical Perspectives series, The Evolving Treatment Landscape of Low-grade Upper Tract Urothelial Carcinoma (LG UTUC), experts in the treatment of this disease reflect on key advancements in the current armamentarium. Historically, UTUC management has involved the surgical removal of the tumor through a radical nephroureterectomy (RNU). However, this approach has been associated with significant postsurgical challenges related to the loss of a renal unit, prompting clinicians to consider kidney-sparing approaches for cases of LG UTUC that may be difficult to resect. Here, Sandip M. Prasad, MD, MPhil, provides an overview of the challenges related to historic treatment approaches for LG UTUC and shares key insights into his clinical experience using kidney-sparing treatments such as endoscopic resection and mitomycin gel.
Urology Times®: How does the anatomical complexity of the upper tract influence your treatment decisions?
PRASAD: The upper tract is really a different beast than the bladder in terms of the complexity of the anatomy. In many ways, that really limits our ability to treat the upper tract as effectively as we treat urothelial cancer in the bladder. In the bladder, we have easy access through the urethra. We can use large instruments, [and] we have a number of tools. In general, the bladder is spherical, so we’re able to visualize and access all its different aspects.
[To treat] the upper tract, you have to get instruments all the way up to the kidney, so the ureteroscopes are much longer and much smaller. The ergonomics of manipulating the camera—once you have this very long, small instrument all the way up in the kidney—becomes much more complicated. Visualizing the entirety of a tumor is much harder because the cameras are smaller. The flow of fluid to be able to clear the screen so [that] you can visualize clearly if there’s any bleeding, for example, is much more difficult. For us to introduce instruments all the way from outside the body, through the bladder, up the ureter, and into the kidney really necessitates utilizing all of the flow of fluid to be able to introduce these instruments. Once they’re up in the kidney, the ability to flex and get into different parts of the kidney [is] limited because the more instruments we introduce into the scope, the less flexible it becomes. Tackling disease in the upper tract of the kidney is a completely separate disease, surgically, than trying to treat these diseases in the bladder.
Urology Times®: Which patients are typically candidates for RNU?
PRASAD: Historically, a large group of patients met [the] criteria. I think all patients [with] high-grade UTUC are still candidates for RNU. Sometimes we’ll be giving these patients chemotherapy before or after their treatment, but I think all patients with high-grade upper tract disease were, and still should be, candidates for an RNU. Historically, many large low-grade tumors were also treated this way as well, because we just couldn’t reach those tumors with our scopes. As I previously discussed, getting to a tumor can be really difficult in the upper tract. So, while you might be able to get your scope up into a lower pole calyx where you can see the tumor, by the time that you introduce equipment like a laser or biopsy forceps to try and actually treat the tumor itself, you can’t get back into that same location. [For] tumors [that] we deem to be unresectable because we can’t get our instruments in there to treat them, these patients often went to an RNU, even if they had low-grade disease or even, to some degree, small-volume disease, because we didn’t really have a lot of tools to get to the tumor. I think, to some degree, that was really overtreatment of a disease [that] is generally low-grade with a pretty low metastatic potential simply because we could not ergonomically get in [to] treat a tumor. I think, in those patients, the improvements that we’ve seen in both [the] technology of our ureteroscopes—to be able to flex and obtain access into areas that we couldn’t before—as well as novel topical therapies that are kidney-sparing, like Jelmyto [mitomycin gel], really offer us an avenue away from RNU in low-grade disease and toward kidney-sparing options.
Urology Times®: What other treatment approaches might you consider for the management of high-grade disease? How does this differ from your approach for low-grade disease?
PRASAD: Typically, you’ll need a biopsy, which will help you understand whether a tumor is high-grade or low-grade. Patients with high-grade tumors in the upper tract will generally be managed with surgical resection with removal of the entire kidney and ureter: an RNU. For patients who have adequate kidney function, there [are] data to support using chemotherapy before surgery, and there [are] data to support using chemotherapy or immunotherapy after surgery, if needed based on the pathologic findings at that time. For low-grade disease in the upper tract, there is nothing else that we need to do that’s systemic, and that’s because these tumors rarely metastasize; they’re growing in place. The trick is to try to treat them completely within the kidney before we give them a long enough period of time to cause trouble, get outside the kidney, or bleed.
Urology Times®: How often are you performing RNUs on patients with LG UTUC in your practice?
PRASAD: For patients with LG UTUC, I try my best to avoid performing an RNU unless my hand is forced. [In] patients who have very large tumors [for whom] the biopsy comes back as low grade, I will have some concern or suspicion that there may be high-grade disease in that specimen [as well]. I’ve seen that before when I’ve done an RNU on very large tumors, but I think I can also assess at the time of ureteroscopy whether or not there’s some degree of mixed high-grade and low-grade disease.
While I don’t think size is a strict criterion, I think, for very large tumors where I do a low-grade biopsy, I may be more inclined to potentially treat that patient with the RNU. Otherwise, I’m trying everything I can to perform kidney-sparing approaches to preserve renal function. These patients are often older, [and] they carry other comorbidities. They’re often smokers, [and] they [often] have [chronic obstructive pulmonary disease], coronary artery disease, [or] impaired renal function, and the ability to preserve a kidney unit for these patients has tremendous implications, especially in regard to overall survival. It’s worth working a little bit harder to preserve and maintain a renal unit. I try my best to avoid an RNU unless I have some suspicion that there’s also high-grade disease in the specimen.
Urology Times®: How do you counsel your patients prior to performing an RNU?
PRASAD: For patients [who] require an RNU, we have to discuss both the perioperative course, which will be the surgery [and] recovery, and the long-term implications, which are important. As I mentioned previously, these patients are often older, [and] they [often] have other existing comorbidities.
Many studies have demonstrated that of patients who undergo an RNU, the majority actually have stage III, IV, or V kidney disease even before they have their kidney removed. For these patients, getting them through an operation requires appropriate preoperative consultation to ensure that their cardiologist or pulmonologist has cleared them for surgery and optimized them. [We] then talk to the patients about a surgery that does involve a general anesthesia. In most people’s hands, nowadays, we can do this type of surgery with a minimally invasive approach, which has significantly changed the operation. Historically, it was done with 2 counter incisions, one up in the flank to remove the kidney and another through the abdomen to remove the ureter and then the [bladder cuff]. Historically, it required 2 very large incisions, and patients [often had] significant postoperative issues with recovery. Nowadays, we can do these operations, typically laparoscopically or robotically, through small incisions that are about the width of my pinky. A small incision is made to extract the specimen in a place that’s more comfortable for patients [and] allows them to breathe easier and [experience] a faster recovery.
The majority of my patients who have this operation now just stay overnight in the hospital and can generally be discharged home on pain medications like [acetaminophen or ibuprofen] rather than taking narcotics for several days, as was historically the case. I think the operative experience for patients is generally pretty good in terms of getting home fairly quickly. They’ll typically need a catheter for several days after the operation, which I remove in my office, and then they’re generally fairly comfortable. But the big implications are for what happens when you lose a kidney, and for renal function, [and] for the requirement to get in your dialysis, which for some of these patients is a very practical concern. [There are also] implications on overall heart disease with impaired kidney function. I think that we’ve done a good job of making the perioperative course in terms of hospital stay, discharge, and pain requirements much, much better over time, but the fundamental implications of losing a kidney are the same whether we do it through a big operation with big incisions or through a small-camera approach. The long-term implications of losing a renal unit are significant.
Urology Times®: What factors do you consider when deciding whether to use a kidney-sparing treatment approach?
PRASAD: Initially, you have to determine if a tumor is high grade or low grade to determine whether a kidney-sparing approach is appropriate. In the case of high-grade tumors, I believe very strongly that the entire kidney and ureter should be removed, so RNU remains the standard of care for that. I would also argue that, for low-grade disease, we should do everything we can to preserve the kidney. These are cancers that generally have a very low malignant potential and generally do not cause significant complications, although they can cause bleeding. We should do everything in our power to maintain that renal unit to preserve renal function and avoid big operations.
From my perspective, there [are] 2 mainstays to kidney sparing that I think can be effective. The first is endoscopic resection, using a ureteroscope and the tools within that ureteroscope, to try to remove a tumor in its entirety. That may include a basket, a laser fiber, a [cauterization tool]. Many of us have different tools and approaches we use, but fundamentally, these are all pretty difficult challenges for urologists. When we look at large series across a time span of 2 decades, even with improvements in instrumentation, we see that the recurrence rate for endoscopic resection is [such that] about two-thirds of patients will recur over the timeline of any study. That’s not a great result in terms of our ability to say that we’ve removed a tumor effectively. In truth, some of these patients probably are recurrent patients in whom the tumor was cleared initially and then it came back, but I think for many of these patients, this was just simply an primary resection that was incomplete because of the challenges and ergonomics of working in the upper tract. Many of these tumors are very difficult to reach. If you have a small papillary tumor on a stalk, right at the ureteropelvic junction in the renal pelvis, you’ll be able to attack that tumor very effectively, I think, with a ureteroscope, and potentially clear that patient.
However, that’s not how many tumors present in the upper tract. Many tumors are spilling like a carpet into different calyces, or they’re in places where we can’t easily reach them. I think the approach has become to use topical agents, and the product that’s approved right now for this is [mitomycin gel], which came out a couple of years ago, and I’ve had fairly significant experience using this product which has [overall] been positive. This provides the same ability of renal preservation with a success rate that’s well over 50%, and [it reaches] tumors that can’t be reached or treated [by ureteroscope because] you couldn’t get the ureteroscope in there to resect the tumor. The gel can really cover any surface, and it’s very easy to instill and can really reach any part of the kidney. That’s the really amazing part of this. For those unresectable tumors that I had mentioned earlier—those that unfortunately we would often do an RNU on because we could not remove the tumor or couldn’t reach it—[mitomycin gel] now allows us to treat those patients diffusely throughout the kidney, really in any location as long as we can get the gel there, which is basically every surface of the kidney. Kidney-sparing approaches should be the mainstay and should be the first-line [treatment] for low-grade upper tract disease now that we have a new tool in our armamentarium for this.
Urology Times®: What factors help inform your treatment decision-making among the kidney-sparing approaches that you mentioned? In what clinical scenarios might you use one approach over another?
PRASAD: In general, my approach will always be that, if a tumor is easily resectable ureteroscopically, I’ll do that. I’ll be able to ascertain at the time of the initial biopsy, [when] I go up, if I see a tumor that’s very amenable toward being resected. I think that [describes] the minority of tumors that we see in the upper tract. I’ll go and make sure I get a very good tissue biopsy. I almost universally use [backloading biopsy] forceps, which I think are a really powerful tool to use in the upper tract to obtain a very high-quality biopsy. That’s something that I think all of us as urologists struggle with, whether we use a basket or a [ureteroscopic biopsy forceps]: It’s very difficult to get anything more than a little speck of tissue. The [ureteroscopic biopsy forceps] allow us to get a biopsy that’s really the size of a cold cup biopsy in the bladder. I actually just used the [ureteroscopic biopsy] forceps yesterday, and I was able to send a frozen section right from the operating room [to the pathology lab] to know if I had a low-grade or high-grade tumor, [and] to understand if I needed to do any more work at that time.
If I’ve determined that a patient has high-grade disease, I’m done: That patient will get an RNU. I don’t do anything else. If they have low-grade disease at that time, [if] it’s easily resectable and I can see that ergonomically, I will go ahead and try to do that [as] my first approach. Historically, I used to keep doing that no matter what because I didn’t have any other tools besides ureteroscopy. I might [have] worked and continued to work even if I couldn’t see that well. I think many urologists can identify and empathize with the idea that you’re seeing little white bits of tumor that are floating in the fluid, and then it starts to bleed, and we don’t have great flow. All of a sudden, you just get out of Dodge because it’s really not an effective procedure after a period of time.
Now, if I know that the tumor is not easily resectable, I won’t labor on because now I have [mitomycin gel], [which is], in my opinion, the primary strategy to treat upper tract disease that’s not easily resectable. Once I know that I have a low-grade tumor, I do my measurements to measure kidney volume so I know how much [mitomycin gel] to give, and then I take out the ureteroscope, and then I initially treat with [mitomycin gel]. [Mitomycin gel] is very easy to use. It can either be instilled [with] a retrograde approach, like the way we do a retrograde pyelogram, just running it through an existing catheter, or you could put in a nephrostomy tube in the patient and administer this in the office. So the technology is really quite nimble.
Mitomycin [gel is something that], as urologists, we’re all very familiar with in the bladder, but this is a different way of treating [LG UTUC]. It’s actually primary chemoablation, which is a really exciting way to think about treating tumors. The gel itself eradicates tumors, and that’s what was demonstrated in the clinical trial that got [mitomycin gel] its approval. They actually left tumors in place in the upper tract, put the gel in, and then looked back 3 months after the gel was administered, and those tumors were gone in a majority of patients. For those patients [who] were responders, there was a durable response in many patients that was up to a year, so I really believe this is a proof of principle that chemoablation works. What I like about this is it does not rely on my being able to see and eradicate all the tumor that’s there because it’s really hard to both see and eradicate tumors in the upper tract. [Mitomycin gel], because it covers every surface, to me is a more comprehensive way of treating LG UTUC.
I use endoscopic recession at the very beginning if it looks straightforward, but then my mainstay of treatment—if it’s not straightforward and simple—is to go to [mitomycin gel] and use that. If, for some reason, [mitomycin gel] is not successful, [which] I have seen in 1 or 2 patients, it [nonetheless] significantly decreased the tumor burden and left me with much less disease that I needed to treat. In the majority of patients [who] I’ve treated with [mitomycin gel], there are no existing tumors when I go back and look 3 months later. I feel like that’s a higher success rate than what I’ve seen with endoscopic management alone, and [it’s] a higher rate than what’s described in the data, in which durable cure rates for endoscopic recession are around 33%. I think of [mitomycin gel] as my first-line agent; that is [followed by] endoscopic management, if it’s a very, very large tumor and I’ve [had] no success, or [I may] consider an RNU, in patients [who] may be candidates. However, in the time since [mitomycin gel has] been improved and I’ve utilized it, I’ve not had to take a patient to an RNU yet.
Urology Times®: How has the availability of kidney-sparing approaches affected the overall treatment landscape for LG UTUC?
PRASAD: Some other historic approaches are worth discussing, although they they’re quite uncommon. Percutaneous resection, [for instance], has been described for a long period of time. I think that works well for very large tumors that are in the renal pelvis. With improved ureteroscopy and now with [mitomycin gel’s] availability, I don’t think that most people will do percutaneous resection, although I think that was a good alternative to RNU for the right tumor.
I think, as our technologies continue to improve, we will be able to offer more and more patients a way away from RNU for low-grade disease. I hope, as we start to chart the rate of use of this procedure, [which is a] major surgery for LG UTUC, we should hopefully see this continue to decline as more and more urologists become aware of products like [mitomycin gel] and more and more patients are able to advocate for kidney-sparing approaches for the management of their low-grade disease.
Transcript has been edited for clarity.