Sam S. Chang, MD, MBA

The Evolving Treatment Landscape of Low-grade Upper Tract Urothelial Carcinoma (LG UTUC)

,” thought leaders in urology and oncology offer special insight into key advancements in the treatment landscape. Emphasizing the role of kidney-sparing treatment approaches, these experts reflect on best practices for optimizing outcomes for patients with low-grade disease. In the following question-and-answer session, Sam S. Chang, MD, MBA, professor of Urology, Patricia and Rodes Hart Professor of Urologic Surgery, and chief of the division of urologic oncology at the Vanderbilt University Medical Center and chief surgical officer at the Vanderbilt Ingram Cancer Center in Nashville, Tennessee, shares his perspective on the role of mitomycin gel for LG UTUC.

How does the design of mitomycin gel lend itself to the structure of the kidney?

This is a gel that starts off as a very thick liquid. It's kept at a cold temperature, and, once it reaches body temperature, it then solidifies. By going in as a thick liquid, it's able to interconnect within the geography or the layout of the kidney itself. As it approaches body temperature, it solidifies, and, as a result, [it] is able to stay on the kidney for a period of time.

How do the response rate and the duration of response for this mitomycin gel technology compare with classical treatments for LG UTUC? How has its approval affected the overall treatment landscape, especially for patients with unresectable disease?

For LG UTUC, our treatment options [have ranged] from removing the entire kidney and ureter to doing endoscopic laser treatments, fulguration, [or] biopsy removal, where … tumors would return. And they can return quickly: in a few months, within 6 months, [or] within a year. The impressive thing about this agent is [its] ability to not only treat tumors that are already there and obliterate the tumor, but [it can also] help prevent them from coming back. The data regarding long-term 1-year responses are quite good. At this point, we have a significant treatment alternative where we never had one before. We're able to give a medication that spares the kidney [and] decreases the number of required therapies, treatments, or invasive procedures. As [a] result, you have a [noteworthy] change in terms of being able to treat these patients in a way that avoids loss of the kidney [and] loss of kidney function but, at the same time, decreases the number of interventions required.

In your practice, what has been your experience with mitomycin gel in your patients? How often are you using it in patients with unresectable disease or in patients who have had previous resections? Are there any advantages to using it in conjunction with resection?

We have utilized a technique that more recently [was] described as putting a small nephrostomy tube into the kidney directly and then injecting the medication in the clinic without requiring any type of anesthesia. This has gone quite well. Patients are tolerating it well, and we have had good responses. These aren't very, very common patients. At this point, we really follow the FDA [United States Food and Drug Administration] indication for these patients. This is [for] low-grade disease, not high-grade disease. This is [for] disease in the renal pelvis as opposed to any lower [area] within the upper tract, such as the ureter. For those patients [who] fit the criteria, I'd say [that] more than half have proceeded to receive this medication in the antegrade route in an attempt to treat the disease and prevent recurrence. I don't know if we're attempting to basically use it simultaneously [with resection] like we would for those patients [who] we treat with chemotherapy agents in the bladder. The big advantage of using this following treatment with laser ablation or with biopsy and removal is the real decrease in recurrence rates. As [a] result, by decreasing that recurrence rate, we then decrease the number of interventions required.

How do you identify patients with LG UTUC who would be appropriate for this treatment? What types of patient characteristics do you look for?

These [are] clearly those patients [who] have any degree of renal dysfunction or who have the bilateral disease where radical nephroureterectomy (RNU) or loss of nephrons would significantly impact the quality of life for those patients. [For] patients with any type of renal dysfunction or bilateral disease, who tend to have lower-volume disease, [we will] attempt to avoid RNU. Those are patients [who] are likely to get benefit from using the mitomycin gel. The question is whether we should be expanding the treatment [to include] those patients [with] smaller high-grade lesions or, perhaps … patients with tumors in the proximal ureter. We haven't yet expanded our indications at this time, but, clearly, we think those patients are very good candidates to proceed with the mitomycin gel.

What circumstances affect your decision to administer mitomycin gel in a retrograde vs antegrade approach?

As I discussed before in terms of our approach, we have, for several reasons, used the antegrade approach exclusively. [One of] the main reasons [is that], within our clinic, it's quite difficult to have fluoroscopy available to perform a retrocatheter. We don't have that ability in our clinic. Secondly, our access to a surgery center has made it difficult to also do this in a way that is accessible not only to the patient but for the physicians doing this treatment. Finally, we do have some concerns regarding the possibility that repeated ureteral catheterizations may lead to a higher chance of ureteral stenosis, which is a well-recognized possible adverse outcome for these treatments. We haven't seen that in our small series, just in those patients we have treated and in discussion with other physicians. There seems to be, perhaps, a decreased rate in ureteral stenosis when using the antegrade approach, but more studies are going to be needed to do that. Finally, using the antegrade approach with a nephrostomy tube, we are working now with our advanced practice professionals in [administering] the agent, so we are expanding the ability and capability to offer this to patients beyond just [a doctor]-supervised procedure. The ability to do that, where patients are then not required to have a cystoscopy and have that type of invasive procedure, is quite attractive. For all [of] those reasons, we've tended to just use the antegraded approach at this point.

What are some of the advantages and limitations of using mitomycin gel vs RNU?

If we focus on the limitations first, you clearly have a very tight indication given by the FDA in terms of when this medication can be used. It's for low-grade tumors within the renal pelvis, so there are issues with accurately diagnosing patients. [Accurate] sampling [of] these tumors can be difficult, so, as a result, we are still quite careful with the indications at this point. We may be undertreating some patients, [and] we may be overtreating some patients. Clearly, being able to follow the FDA indication is something that can really limit who we can treat and how we treat [them], but, for patients, when you consider the possibility of having a significant surgery where half their kidney function (at least) is removed with an RNU, it is something that can be quite life-altering. It clearly moves patients closer to renal insufficiency, perhaps even dialysis dependence. As a result, a huge advantage of using the mitomycin gel is the fact that you have a treatment that is nephron sparing. You have a treatment that can avoid a major operation. You have a treatment that can decrease interventions.

What are the benefits of using mitomycin gel in patients who have a solitary kidney?

That goes back to the emphasis on avoiding a procedure that can lead straight to dialysis. If you have a solitary kidney, and we don't have good treatment options, we're talking about RNU, and that would equal dialysis for a patient with a solitary kidney. Obviously, nephron-sparing [treatment] is the most important thing [to] avoid an RNU and avoid dialysis. Secondly, for patients with a solitary kidney, you want to try to avoid as much manipulation and [potential] damage in procedures as possible, especially for someone with a single kidney. You also decrease that by using a mitomycin gel. [The] combination of nephron-sparing [treatment and fewer] interventions [will] hopefully keep these patients off dialysis, [and], yet, safely and effectively treat their cancer.




Transcript has been edited for clarity.

Articles

In this companion article, Sam S. Chang, MD, MBA, offers his expert perspective on the use of mitomycin gel as a kidney-sparing approach to the management of low-grade upper tract urothelial carcinoma.

EP. 3B: Mitomycin-containing Reverse Thermal Gel Technology as a Kidney-sparing Treatment Option for Patients with LG UTUC 

For LG UTUC, our treatment options [have ranged] from removing the entire kidney and ureter to doing endoscopic laser treatments, fulguration, [or] biopsy removal, where … tumors would return. And they can return quickly: in a few months, within 6 months, [or] within a year. The impressive thing about this agent is [its] ability to not only treat tumors that are already there and obliterate the tumor, but [it can also] help prevent them from coming back. The data regarding long-term 1-year responses are quite good.

At this point, we have a significant treatment alternative where we never had one before. We're able to give a medication that spares the kidney [and] decreases the number of required therapies, treatments, or invasive procedures. As [a] result, you have a [noteworthy] change in terms of being able to treat these patients in a way that avoids loss of the kidney [and] loss of kidney function but, at the same time, decreases the number of interventions required.

We have utilized a technique that more recently [was] described as putting a small nephrostomy tube into the kidney directly and then injecting the medication in the clinic without requiring any type of anesthesia. This has gone quite well. Patients are tolerating it well, and we have had good responses.

These aren't very, very common patients. At this point, we really follow the FDA [United States Food and Drug Administration] indication for these patients. This is [for] low-grade disease, not high-grade disease. This is [for] disease in the renal pelvis as opposed to any lower [area] within the upper tract, such as the ureter. For those patients [who] fit the criteria, I'd say [that] more than half have proceeded to receive this medication in the antegrade route in an attempt to treat the disease and prevent recurrence.

I don't know if we're attempting to basically use it simultaneously [with resection] like we would for those patients [who] we treat with chemotherapy agents in the bladder. The big advantage of using this following treatment with laser ablation or with biopsy and removal is the real decrease in recurrence rates. As [a] result, by decreasing that recurrence rate, we then decrease the number of interventions required.

You clearly have a very tight indication given by the FDA in terms of when this medication can be used. It's for low-grade tumors within the renal pelvis, so there are issues with accurately diagnosing patients. [Accurate] sampling [of] these tumors can be difficult, so, as a result, we are still quite careful with the indications at this point. We may be undertreating some patients, [and] we may be overtreating some patients. Clearly, being able to follow the FDA indication is something that can really limit who we can treat and how we treat [them], but, for patients, when you consider the possibility of having a significant surgery where half their kidney function (at least) is removed with an RNU, it is something that can be quite life-altering.

We’re avoiding a procedure that can lead straight to dialysis. If you have a solitary kidney, and we don't have good treatment options, we're talking about RNU, and that would equal dialysis for a patient with a solitary kidney. Obviously, nephron-sparing [treatment] is the most important thing [to] avoid an RNU and avoid dialysis. Secondly, for patients with a solitary kidney, you want to try to avoid as much manipulation and [potential] damage in procedures as possible, especially for someone with a single kidney. You also decrease that by using a mitomycin gel. [The] combination of nephron-sparing [treatment and fewer] interventions [will] hopefully keep these patients off dialysis, [and], yet, safely and effectively treat their cancer.

Videos

In the third interview of the series, Sam S. Chang, MD, MBA, from the Vanderbilt University Medical Center shares key insights into the role of mitomycin gel as a kidney-sparing approach to the treatment of low-grade upper tract urothelial carcinoma. 

EP. 3A: Mitomycin Gel for the Treatment of Low-grade Upper Tract Urothelial Carcinoma

Sam, make a couple of comments about nonmetastatic muscle invasive muscle cancer. As urologists, the go-to is radical cystectomy. We’ll do selective bladder preservation with radiation and chemotherapy traditionally, but what is the urologist view on the immuno-oncology [I/O] agents in bladder preservation?

 As with almost every disease process that we treat—prostate cancer, renal carcinoma, bladder cancer—we need to go beyond just resection and removal. It took us a long time to get on the neoadjuvant chemotherapy train, and we’ve improved with that. But with trials that have shown a benefit to adjuvant therapy, the nivolumab following cystectomy in patients with or without chemotherapy beforehand, clearly, we’ve involved our oncology colleagues in not only a neoadjuvant but also an adjuvant setting. Importantly, there are trials that are open, looking at I/O therapies either by themselves or in combination with chemotherapy, that perhaps would give us benefit in addition to therapy afterward.

There are also combinations of such things as enfortumab [vedotin] and pembrolizumab that are being looking at neoadjuvantly. Then cystectomy and therapy afterward. Unquestionably, radical cystectomy as the single modality and curative—for certain patients that’s still the truth, but the majority of patients will benefit from this combined therapy. This will give me a chance to give a shout out to you, Lenny, because the folks at Thomas Jefferson [University] have laid out an algorithm and a process in terms of setting up a multidisciplinary clinic, which you guys have done for prostate cancer and bladder cancer. It’s served as a model for a lot of academic institutions.

Sam, thank you. That makes my day, so thanks for that comment. That comes from a center of excellence for GU [genitourinary] oncology, so thanks.

The role of adjuvant therapy in nonmetastatic muscle invasive bladder cancer, and an overview of promising novel therapies in the treatment pipeline.

Emerging Novel Therapies for Nonmetastatic Muscle Invasive Bladder Cancer

With that broad introduction what we’d like to do in the next couple of minutes is now get into first-line treatment of non-muscle invasive bladder cancer and non-metastatic muscle-invasive bladder cancer. Sam, we’re going to have you comment at first about the interaction between urologists and oncologists, following guidelines. We have guidelines from NCCN [National Comprehensive Cancer Network], AUA [American Urological Association], ASCO [American Society of Clinical Oncology], other organizations. How do you think guidelines play into the daily care of patients with bladder cancer?

I think they are becoming increasingly used by the urologists in terms of non-muscle invasive disease. Honestly, for invasive disease and for metastatic disease I think the guidelines put out by the NCCN are widely used or at least referred to by our oncology colleagues. Urologists probably aren’t as familiar with the NCCN guidelines but all of them are honestly pretty similar in terms of what they’re outlining and what their strategies are. In fact, the AUA guidelines are actually AUA, ASTRO [American Society for Radiation Oncology], SUO [Society of Urologic Oncology], ASCO guidelines all combined for invasive disease and I think they provide a good framework for urologists and are becoming increasingly used because the landscape is really changing, and there are many more options than there used to be even just a decade ago.

Yes. I think in our training programs I think we’re increasingly trying to follow guidelines and not sort of shooting from the hip so I do think these guidelines are becoming very, very important. I know our oncology colleagues here at the Sidney Kimmel Cancer Center are very regimented on following NCCN guidelines as you pointed out.

An overview of treatment guidelines available to support urologists and medical oncologists who manage patients with bladder cancer.

Sam S. Chang, MD, MBA

Articles

EP. 3B: Mitomycin-containing Reverse Thermal Gel Technology as a Kidney-sparing Treatment Option for Patients with LG UTUC

EP. 3A: Mitomycin Gel for the Treatment of Low-grade Upper Tract Urothelial Carcinoma

Emerging Novel Therapies for Nonmetastatic Muscle Invasive Bladder Cancer

Current Treatment Guidelines for Bladder Cancer