Systemic Therapies in Upper Tract Urothelial Carcinoma - Srikala Sridhar

Kala Sridhar provides a state of the-state in the contemporary understanding of upper tract disease, recent clinical trial findings and the impact of those trials on clinical practice treatment. Upper tract urothelial cancer (UTUC) accounts for approximately 5 - 7% of all urothelial cancers. At presentation about 60% of patients demonstrate invasive and/or locally advanced disease compared to about 25% of bladder cancer. Therefore UTUC has a high risk of recurrence despite agressive treatments. This is a dynamic area of research demonstrating significant progress in this field. In 2018, A Phase III Randomized Trial of Peri-Operative Chemotherapy Versus sUrveillance in Upper Tract Urothelial Cancer (POUT) trial which assessed the added benefit of using platinum-based chemotherapy in the adjuvant setting in patients undergoing a radical nephroureterectomy reported results. Further, treatment in the neoadjuvant setting has been reported. Dr. Sridhar discusses the importance of these prospective trials and the ongoing research in UTUC. This is a field where benefits are demonstrated from multidisciplinary approach to the care of patients.

Biographies:
Srikala (Kala) Sridhar MD, MSc, FRCPC is an Associate Professor within the Department of Medicine, Division of Medical Oncology at the University of Toronto. She is head of the genitourinary cancers medical oncology site group at the Princess Margaret Hospital and treats primarily bladder, prostate and kidney cancers. She has an active research program in the area of bladder cancer, evaluating new therapies and imaging modalities; and is currently the international study chair of a National Cancer Institute of Canada (NCIC) phase 2 clinical trial. In 2011, she was recognized for her teaching excellence with a University of Toronto teaching award.



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. Kala Sridhar, who is an Associate Professor and a medical oncologist at Princess Margaret Cancer Center in Toronto. Thank you so much for coming to talk with me today. 

Kala Sridhar: Thank you for having me, Alicia. 

Alicia Morgans: Of course. I wanted to talk with you about systemic therapies in upper tract urothelial carcinoma. You're certainly an expert, you've given talks recently at the EAU and have such a well-rounded perspective. I'd love to hear what's the latest and greatest, what should we be thinking about in terms of systemic therapy? 

Kala Sridhar: Okay. Let me start by just giving a little bit of background on upper tract disease. It's a rare type of cancer. It's about 5 to 10% of all urothelial cancers are located in the upper tract. There are about two new cases per 100,000 people in the Western world, but in China and Taiwan, the incidence is higher because of a compound called aristolochic acid which is found in many Chinese herbal remedies, and there's a link between that and upper tract disease. 

Traditionally, we thought upper tract and lower tract or bladder cancer were similar, and histologically they seem to be, but we're starting to realize that there are other phenotypic and genotypic differences between them including mismatch repair, there's hypermethylation. Perhaps the biggest differences at the time of presentation, 60% of upper tract disease is invasive as compared to only about 25% with bladder. That means that this disease has a high risk already of recurrence. 

The standard treatment has been a radical nephroureterectomy where they remove the kidney and the ureter. Despite this pretty aggressive procedure, the outcomes are pretty dismal. Five-year survivals for patients with pT2, pT3 disease is low. Patients with pT4 disease have perhaps less than 10% five-year survival. We understand that this is a very aggressive disease. 

At the same time, we have data from bladder cancer saying that urothelial cancers are sensitive to chemotherapy. In fact, we have level one evidence for neoadjuvant chemotherapy in muscle invasive bladder cancer as you know. If we put these two concepts together, one, the fact that this is an aggressive disease often presents in an invasive state, and the fact that it's a chemosensitive disease, it then goes to say that maybe we should be doing chemotherapy in these patients. 

One of the challenges, of course, is because it's a rare disease, we really haven't had a lot of large prospective trials, it's hard to get that many patients all together to draw conclusions in the context of a trial. More recently, however, there's been a lot of activity, a lot of really great collaborations which I think have moved the field ahead forward. 

The original trials that we're looking at adjuvant chemotherapy. After surgery, patients would get platinum-based chemotherapy or even other chemotherapy regimens suggested a benefit in the group that were getting chemotherapy compared to the group that didn't. 

I think on the basis of several retrospective studies, a prospective study was initiated and this was the POUT trial as you know. It was a randomized Phase 3 study where patients who had upper tract disease who were within 90 days of surgery, were randomized to receive either chemotherapy or surveillance. The choice of chemotherapy was based on the degree of renal function.

If their renal function was good, then they would go on and get gemcitabine and cisplatin which is our standard chemotherapy. If their creatinine clearance was not as good, they would then get gemcitabine and carboplatin. The only reason that they would adjust the dose is for creatinine clearance. Patients who could not receive gemcitabine and cisplatin for poor performance status, that did not come into the equation at all. These were the two groups of patients.

A couple important things from this study that we learned. One in terms of adverse events, they were what we expected, so it's a chemotherapy trial, you're going to see toxicity. We also found that about 60% of patients, only 60% of the patients give or take, could actually get the gemcitabine and cisplatin. Of those, only about another 60% or so finished treatment, and about 13% switched from gemcitabine, cisplatin to gemcitabine, carboplatin. 

I think a large reason for that is because many of these patients after surgery, have had a drop in their renal function. There's at least five studies that are looking at the change in renal function after surgery and they're all showing a drop in renal function. Although we look to the adjutant setting to give chemotherapy, we may be limited because of the drop off in renal function. That's an important consideration.

I think then that opens the door to consider, well, what about the neoadjuvant setting? What about before patients lose their kidney function? What about before they have surgery because their fitness to receive chemotherapy is probably better? Again, there've been a few retrospective studies looking at neoadjuvant chemotherapy. There were some sort of more recently one that was presented by a Dr. Hoffman-Censits that really looked at patients with upper tract disease.

There were two groups, one received neoadjuvant dose-dense MVAC, and the other group received gemcitabine and carboplatin, and that difference was based on the creatinine clearance. Unfortunately, the gem-carbo arm for a number of reasons, you know, including physician preference, or sort of concerns about carboplatin didn't accrue very well. But the dose-dense MVAC arm did meet its accrual target, so about 30 patients. Again, not a large trial. 

What they showed was that the pathological complete response rates were about 14%, but importantly there was also a significant number of patients that were downstaged to less than pT1 or so. I think interestingly, there's emerging data that perhaps downstaging is really impactful as far as overall survival is concerned. We don't need to necessarily just rely on pathological complete response, but maybe we can look at downstaging as that might be a benefit as well. 

Again, on this study, about 80% of patients got the prescribed treatment, which is again better than what we saw in the adjuvant setting where about 60% only could get the gem-cis. Again, in this neoadjuvant setting, the renal function is likely preserved. I think it's good news that we saw encouraging pathological complete response and downstaging rates, I think it's also good news that patients were able to actually get the treatment that we wanted them to have.

On the basis of these two trials, that POUT Phase 3 randomized trial and this prospective neoadjuvant trial, I think there's a renewed interest in studying this disease, in studying the role of perioperative chemotherapy and perhaps answering that question. There are at least three, there's probably more because it seems to change all the time. 

Trials looking specifically at chemotherapy in the neoadjuvant setting, so gemcitabine and cisplatin. There's an interesting study that's looking actually at comparing neoadjuvant therapy to adjuvant therapy which will give us some interesting answers. Part of that trial is really based on how many patients can get the treatment that they're supposed to get, which is I think an important feasibility type question. 

As you know in the field, there's been a lot of developments in the area of immunotherapy, in advanced disease with encouraging response rates, and those drugs are moving very quickly, earlier and earlier in the treatment paradigm. As far as upper tract is concerned, we may see an actual benefit in that setting for a few reasons. One, we know we can probably give immunotherapy to patients who have compromised renal function, we've seen that in the cisplatin unfit studies. Patients who've lost a kidney due to surgery may fit into that group.

We know that upper tract disease can have mismatch repair, which might again increase the likelihood of mutations, increase the likelihood of response to immunotherapy. Again, another reason why immunotherapy may play an important role in upper tract disease.

There are studies now underway including there's three fairly large registration studies looking at the adjuvant setting, giving immunotherapy where upper tract disease is included along with bladder cancer. They're not dedicated upper tract studies, but they are including upper tract patients. Also, recently, they've announced the POUT II study which is a follow-up on POUT I which is looking at a combination of chemotherapy plus or minus immunotherapy. That'll be an interesting study, that is a dedicated upper tract study.

Beyond the adjuvant studies, there are a few neoadjuvant studies as well in upper tract. We've seen some data in bladder with neoadjuvant studies showing encouraging activity, so similarly we're starting to see trials creeping into this space as well in the neoadjuvant setting. 

Finally, in terms of other treatments on the horizon, targeted therapies such as FGFR inhibitors may play a role as well in upper tract disease. We've looked at perhaps FGFR mutations in upper tract and they may have a different expression profile than they do necessarily in bladder, which might make them, again, a good target for treatment in upper tract disease. Those trials are in development and hopefully will change what we do. 

I think that the progress in this field has been really, really exciting, and I think it reflects a really large scale, multidisciplinary collaborations across countries, across people, across disciplines. It's a really positive step in this disease and I think it'll be great for our patients to have not only standard treatment options but also trial options in the future. 

Alicia Morgans: Absolutely. It's really exciting to me that systemic therapy plays such a role. We talked earlier about how I agree with the approach of trying to use systemic therapy with chemotherapy at this point unless it's on a clinical trial in the neoadjuvant setting. I know that one thing that people might take from the POUT trial is this is really a trial of adjuvant therapy. Should I go right to surgery based on the POUT trial and save my systemic therapy for after that nephroureterectomy?

I already know your answer but I'm curious if you could talk to the audience about what your thoughts are there and how we actually use the data that we have in clinical practice in a way that's kind of practical.

Kala Sridhar: In my practice, I try wherever possible to use neoadjuvant chemotherapy, and I'm pretty consistent both with upper tract and with the bladder. I'll start off by saying that. I think the reason I do that is really because of the two issues. One being a loss of renal function post nephroureterectomy, and second being the patient's performance status and how they are in the postop setting is often not what they are preoperatively.

I have many patients who, where the plan would be to get adjuvant chemotherapy but they never end up getting it. Sure, maybe there is a benefit to adjuvant, but that really only applies if a patient can get the drug and hopefully at the doses that we want them to. I think that what the POUT trial does is it tells us that chemotherapy in the adjuvant setting is better than no chemotherapy at all, but it doesn't tell us if adjuvant chemotherapy is equivalent, if it's better or if it's worse than neoadjuvant chemotherapy. 

I do worry because we'd have to compromise a little bit on the doses we saw in the POUT study. Patients weren't all getting gemcitabine and cisplatin, and they weren't all completing the cycles, I worry about the impact of that on the overall response. If I can get the chemotherapy in before surgery, I think I'm doing the patient a benefit. 

I think though you need to be smart and you need to be watching the patients closely. If you feel that they are progressing for some reason, then you have to be ready to stop, call the surgeon and say, "Look, I think I need this, you know, surgery to happen sooner rather than later." That really speaks to having a really good relationship with your surgeon and having a really good multidisciplinary team around you. 

Alicia Morgans: Absolutely. What if you can't use a cisplatin-based systemic therapy? What are your thoughts there? 

Kala Sridhar: I mean I think that that comes into the situation where, you know, on the neoadjuvant trial that a Dr. Hoffman-Censits presented, that there was hesitation to use a drug like gemcitabine or a combination like gemcitabine and carboplatin. In that setting, if you can't give cisplatin-based chemotherapy up front, I would not hesitate to consider doing the surgery first and then planning treatment after. I think I'd also be looking for a clinical trial if there was one available. That's always where I try to go 'cause I think that's how we're going to learn and how we're going to go forward.

Alicia Morgans: True. I don't know that the subgroup that received the carboplatin in the POUT trial necessarily seem to have the same benefit as the cisplatin patients. 

Kala Sridhar: You're absolutely right. 

Alicia Morgans: More evidence that this might not be the best way to go even in the adjuvant setting to use a carboplatin-based regimen. I completely agree with the clinical trial approach. 

Kala Sridhar: Absolutely. On the forest plot, you did see a pushover in favor of gemcitabine and cisplatin regimens over the gemcitabine and carboplatin regimen. I think that sort of fits with what we have always felt in the field, that cisplatin tends to be superior to carboplatin. The message that's important here is that with upper tract disease, I think perioperative therapy is essential. I tend to lean towards giving it in the neoadjuvant setting because I think I can get the drugs in, but I think if the patients don't get it in the neoadjuvant setting, they should be getting it in the postoperative or adjuvant setting. 

Alicia Morgans: Absolutely. Well, thank you so much for sharing such a wealth of information today and for your own guidance in really applying these studies in a practical way in our clinics. I appreciate your time and thank you. 

Kala Sridhar: Great. Thank you
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