The Diagnostic and Therapeutic Challenges Associated with UTUC - Sam Chang

April 9, 2019

Alicia Morgans and Sam Chang discuss the diagnostic and therapeutic challenges of upper tract urothelial carcinoma (UTUC).  UTUC is relatively uncommon compared to urothelial carcinoma, accounting for 5-7% of all cases.  The disease can be quite insidious and present a challenge to diagnose.  Dr. Chang discusses the use of CT urograms in the diagnosis and how size, grade, and stage of the tumor is used to inform treatment decisions, balancing renal preservation with oncologic treatment.  While the gold standard for patients with high grade disease has been nephroureterectomy, patients with lower grade disease may be candidates for a nephron sparing approach.  Both approaches still have challenges including the use of adjuvant or neoadjuvant chemotherapy with nephroureterectomy while nephron sparing approaches present an additional therapeutic challenge as currently there are no treatments available to prevent recurrence, requiring life long observation of patients due to the high risk of recurrence.


Sam S. Chang, M.D., M.B.A. Patricia and Rodes Hart Endowed Chair of Urologic Surgery Professor Department of Urology at Vanderbilt University Medical Center, Department of Urology 

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi. I'm thrilled to have here with me today a friend and colleague Dr. Sam Chang, the Patricia and Rodes Hart Distinguished Professor of Urologic Surgery at Vanderbilt. Thank you so much for being here. 

Sam Chang: It's great to be here, Alicia. Great to have a chance to talk to you about different things. 

Alicia Morgans: Oh, of course. Today, I wanted to focus on upper tract urothelial carcinoma. Really a diagnostic and therapeutic dilemma in many cases. I'd love to hear your thoughts. 

Sam Chang: One of the banes of our existence for sure. When you said the diagnostic dilemma, that's really the problem with upper tract disease because sometimes it can be so insidious, so difficult to find and other times it's more obvious. Ironically enough, sometimes when it's the most obvious, it's actually the most treatable. It's other times when it is difficult to find, difficult to find and then before you know it, it ends up being a metastatic and much more problematic issue. It's one of those things where we don't see that often compared to bladder cancer. 

For urothelial carcinoma, it's probably 90 to 95% are bladder cancers and only about 5 to 7% are in the upper tract, in the ureter or up in the kidney and the renal pelvis. 

Alicia Morgans: When you see an abnormality on imaging, how do you think about going about approaching that? I think at the end of the day, you want to try to spare the kidney if you can. 

Sam Chang: You're right. 

Alicia Morgans: How do you think about diagnosing that? 

Sam Chang: I think that's really the balance of trying to save kidney function, but at the same time taking care of the oncologic problem. That's the true dilemma. I guess that's the dilemma with most of the cancers we treat. But I think the first thing you said in terms of how you find it diagnostically, it used to be the IVP. The urologists, that was their favorite X-ray. Now, the vast majority of the time it's CT urogram. That's important because the delayed images on the urogram are really the most sensitive way that we have now to help define these small filling defects in the ureter. 

Once we have that, now with the capabilities of our small telescopes and ureteroscopes, we're able to endoscopically really then be able to identify the tumors. Once we identify a tumor, it's a combination of size and grade and stage, all those things that are similar to bladder cancer in terms of how these tumors act. We really like to get a biopsy of them to give us an idea is this a low grade or a high grade lesion because that helps to dictate what we do next. 

Alicia Morgans: Absolutely. You know, I talk to my fellows all the time when I talk about bladder cancer though about muscle invasion. That's really what kind of drives our differences in our approach to therapy. In the upper tract, that's not really something we can get at, right, because ...

Sam Chang: You're exactly right. It's a sampling issue as much as anything. When I talk to our residents and our fellows and actually more commonly with our patients, I describe the fact that the ureter is like the diameter of the end of the pen that I'm working on and to get any sample there is very difficult. We do have a real difficult time to determine the stage of tumors when we do biopsies because the biopsy samples we get are just a few millimeters usually in size, but that can help us in terms of grade, which is very important, and the appearance of a tumor not only on radiographic imaging, but by endoscopic visualization. 

That helps us to give us an idea, but there are certain characteristics that make these tumors lower risk and certain characteristics that make them higher risk that help then decide what we end up doing next. 

Alicia Morgans: What do you think about in terms of risk? 

Sam Chang: One of the first things you said is trying to save the kidney, trying to save the renal function. I think our knee jerk reaction probably a decade or two ago was the entire kidney and ureter needed to be removed if anything involved the kidney or in the upper part of the ureter. When it involved the lower part of the ureter, we many times would do what's called a distal ureterectomy and remove the lower part and then reconnecting it up to the bladder. We very rarely do just a ureteral or just taking a small section of the ureter out for many different reasons, including not as good a result in terms of structure formation and different things like that. 

What we've learned though is that lower grade tumors, just like lower grade tumors in the bladder, are more of a nuisance type tumor or can be and that they can be treated successfully endoscopically. With the laser technology we have, different ways to basically then with our scopes be able to get to these tumors, that these can be treated then adequately with laser ablation. The issue is we don't have anything at this point that helps prevent recurrence. As you know in the bladder, we can give different types of intravesicular treatments, either chemotherapy or immunotherapy like BCG that help prevent recurrence. With BCG, maybe even help prevent progression. 

We don't have that in the kidney. If we do nephron-sparing, if we do laser therapy, we really have to do a lifelong follow-up because these patients still have a high chance of recurrence. But if you weigh that against, especially in patients with any kind of renal insufficiency, you're going to lose a lot of your renal function for a small tumor that's really unlikely to metastasize, patients 99% of the time will say, "Well, do whatever you can to save the kidney. Keep me off dialysis and keep me safe." 

Alicia Morgans: Certainly when you're trying to figure out if it's high grade/low grade when you're trying to get that first biopsy, it's important to try to spare the kidney as much as possible. When you figure it out, if you do find a high grade upper tract, a lot of times you still have to do a nephro-u. 

Sam Chang: Yes. Yes. 

Alicia Morgans: What do you think about the lymph nodes? Because sometimes I see surgeries that are done ... Maybe they don't realize it's going to end up being a cancer surgery. The nodes aren't necessarily addressed. What are your thoughts there? 

Sam Chang: I think of all the urologic tumors, any cancer that involves the kidney either being a kidney primary, such as a renal cell carcinoma or an upper tract urothelial carcinoma, not only the template, in other words, what lymph nodes are removed, but actually the need for removal is a little bit under debate, as opposed to bladder cancer. When we do a cystectomy, basically it's absolutely necessary for adequate staging even with therapeutic benefit. The problem with the nephroureterectomy is the numbers are so small, the series are retrospective. But in anyone who has a higher grade lesion that we're doing this, we tend to do a lymph node dissection.

The lymph node is drainage is variable. Upper tract, upper part, drain in a different area compared to the lower tract. Where you remove those lymph nodes is a little bit under debate, but we tend to be more aggressive with higher risk lesions. Your point though about being accurate, you're right though. 25-30% of the time we're wrong in terms of the grade, perhaps even higher. Even with low grade lesions, honestly we tend to not do the lymph node dissection as often, but in reality, a lot of those times those patients are in fact high grade. If you want to be oncologically the safest, we do recommend doing a lymph node dissection at the time of the nephroureterectomy. 

I think the biggest debate now is whether or not these patients should get neoadjuvant or adjuvant chemotherapy for their tumors. As you know, there is a large trial presented at GU ASCO last year looking at the advantages of adjuvant chemotherapy following a nephroureterectomy. The majority of those patients were in fact node negative and had upper tract disease. That study showed a 50% chance of decrease in the likelihood of disease recurrence. There was no overall survival benefit yet shown, but it's still early. That hasn't been published yet. 

Alicia Morgans: Yeah, interesting. 

Sam Chang: The big debate that people have is that when you take out a kidney, you lose renal function. When you lose renal function, you're less likely to be able to give cisplatin. If you give cisplatin, the thought is, well, if you carboplatin, the thought is this is a regimen that's not as effective. Despite a prospective randomized trial with level one evidence that's been presented, I think most medical oncologist would say for a high-risk cancer that they would give or prefer to give neoadjuvant chemotherapy as opposed to adjuvant chemotherapy. I think that's really an unanswered question. 

Alicia Morgans: I agree. But as a medical oncologist who worked with you for many years, I could say that I did and we did. I would always try to give cisplatin to eligible candidates because, by the time you remove that kidney, I don't have as good of a chance of getting that patient-

Sam Chang: No. That has been ...

Alicia Morgans: ... what he or she needs. 

Sam Chang: That's absolutely been our bias to despite our call for high-level evidence. It's just that ...

Alicia Morgans: It's a practical thing. 

Sam Chang: It's a practical thing. The ability to handle that pre-surgery as opposed to post I think is better. In terms of kidney removal and ureter removal and how you address the bladder, there's a variety of different surgical techniques. The most important thing just like a robotics cystectomy versus an open cystectomy is that you follow the oncologic principles. Taking the kidney and the ureter and then taking a proper amount of the bladder are all essential parts of the surgery that we do. 

Alicia Morgans: Absolutely. Before we close up, I wanted to get your thoughts on whether we should start thinking more routinely about genetics. That's really a big thing in oncology now, changes in prostate cancer recommendations, considerations in bladder and upper tract. What are your thoughts there?

Sam Chang: Absolutely. Probably one of the things that we are learning the most about in a most rapid fashion. I would say 10 years ago, you would ask any urology resident, perhaps even a medical oncology fellow, "Tell me about the relationship of Lynch syndrome with upper tract disease," a few people would know. I would say now we have board questions about it now and 85-90% of the residents get it right. They understand that relationship. Vast majorities of these tumors are still sporadic. Vast are still associated with smoking. If you do have any type of ...

Especially with high degree microsatellite instability or mismatch repair deficiency, that right away increases your likelihood of having Lynch syndrome obviously. Then that likelihood in terms of not only upper tract urothelial carcinoma, but you're looking at endometrial and ovarian and sebaceous type of cancers, as well as prostate cancer. That recommendation now is not only to look for that but then to also then look at the patient's family, have them undergo genetic screening and counseling. 

I think excitingly for those types of tumors, especially with Lynch syndrome, would be the possible even better benefit of the new immunotherapy options that are out there. Before with upper tract urothelial carcinoma, you treated it like an upper tract cancer or urothelial cancer. Now, we have I think a real opportunity to be even more effective with therapies, especially in understanding the genetic and molecular subtyping. 

Alicia Morgans: Absolutely. I so appreciate that you brought up the cascade testing of family members. I think we as oncologists, urologists focus so much on the patient, but we are broadening that view I think now to be so thoughtful about family members as well. 

Sam Chang: Oh, absolutely. I mean the understanding that ... Obviously, the individual patient is still our number one priority, but understanding that for the family members, their offspring, their siblings are obviously almost as important to those individuals. Honestly, we were ignorant. I think that we are getting better and better with understanding the scope of the problem, but also understanding how we can better educate our patients and their families. 

Alicia Morgans: Really pushing the envelope in urologic oncology. 

Sam Chang: Trying to. Trying to. Trying to. 

Alicia Morgans: I always appreciate talking to you. Thank you so much for your time. 

Sam Chang: Thank you, Alicia. I appreciate it very much.