Upper Tract Urothelial Carcinoma Highlights - Nima Almassi
August 14, 2022
Nima Almassi, MD, Urologic Oncology, Department of Urology, Cleveland Clinic, Cleveland, OH
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
Sam Chang: Hello, everyone. My name is Sam Chang. I'm a urologist in Nashville, Tennessee and we have the great pleasure of having Nima Almassi. He is an associate staff member at the Cleveland Clinic and spent some time, as many of us did, at AUA 2022 and was moderating sessions associated with upper tract urothelial carcinoma. I asked Nima to actually highlight a couple of abstracts that he thought were most exciting when it comes to upper tract urothelial carcinoma. First, welcome Nima and tell me about the first one that you found, not only exciting but perhaps provocative.
Nima Almassi: Thanks so much for having me, Sam. I really appreciate the opportunity. A couple abstracts that really stuck out to me, focused on the theme of nephron-sparing treatments for upper tract disease. And I think this is really an area of great need in our field. The first one was titled, The Final Results of a Phase I Trial of WST11 or TOOKAD, vascular-targeted photodynamic therapy for upper tract urothelial carcinoma. There are multiple different ways of organ preserving or nephron-sparing treatment for upper tract disease, one of them is VTP or vascular-targeted photodynamic therapy. And in this trial investigators from Memorial Sloan Kettering reported their outcomes from a phase I trial of TOOKAD, a short-acting photodynamic agent in the treatment of upper tract disease.
In this trial, patients with upper tract disease who were either ineligible or refused radical surgery were eligible for enrollment. That was irrespective of tumor size or grade. Patients underwent ureteroscopic treatment and in order to be enrolled on the trial had to have either recurrent or residual disease after endoscopic management. In this trial, they were assessing both the safety of this treatment but also efficacy. And in this trial, a total of 22 patients were enrolled, 18 of whom received treatment and had data for which they were able to assess these outcomes and that's what was reported in this abstract.
And patients underwent a ureteroscopic assessment of residual disease at 7 and 30 days following treatment with VTP. And of the 18 treat patients who were treated, 50% demonstrated a complete response, meaning no residual disease within the treatment area and negative ureteroscopy and cytology. 44% of patients had a partial response, which means that they did have no evidence of disease within the treatment area. And at the maximum dose of energy that was used in this trial, only two out of the 18 patients had dose-limiting toxicity, which was mainly pain. And the investigators did not demonstrate or observe any incidence of ureteral obstruction or stricture. Although this is a small trial, I think it's really exciting because this is sort of the first to show safety and promising efficacy data in the use of VTP in upper tract disease. Clearly, longer-term follow-up and more studies are needed and there's actually an ongoing phase III trial looking at this treatment in patients with upper tract disease, which I think is very exciting.
Sam Chang: Well Nima, the first thing you've got to say for any phase I to have that 50% CR rate as a first response is, wow. Because obviously, you're looking for toxicity. Tell me a little bit, and you may not know, but tell me a little bit about the logistics of getting photodynamic therapy. Is it something that could this treatment be universally applied? Or only specialized centers or specialized surgical areas that can limit lighting, et cetera? Tell me what you know about the logistics?
Nima Almassi: Patients receive the agent intravenously and then the treatment is actually delivered uretoscopically using the near-infrared laser that's delivered through a fiber going through the ureteroscope. Now in this trial, many of the patients had multifocal disease and so treatment would have to be delivered at each area, meaning the laser would have to be held at the area that you're looking to treat for 10 minutes and then subsequent areas treated. But it seemed as though, even in patients with multifocal disease, this was a feasible and potentially efficacious treatment. Because this agent is shorter acting the duration of which patients had to be sort of shielded from light was lower than with older agents. I do think it is something that could be widely applied if it is shown to have long-term efficacy and safety.
Sam Chang: You can see the appeal to patients. It's almost, even though you're invasive with the scope, but it's almost like a no-touch technique. You have the laser, the lights being dispersed, the agent is given intravenously and absorbed. Do you have any idea of the coverage area? Is it 5mm, 10mm, in terms of the actual laser? Or is it direct contact media?
Nima Almassi: That's a good question. I don't know the answer to that question. In reviewing the abstract and the Q and A with the investigators, it seemed as though for disease that required treatment in different calices, you might have to have essentially a session where you're treating in one calyx, apply the laser for 10 minutes and then move to another calyx or potentially another pole of the kidney but I'm not sure the specifics on that. That's a good question.
Sam Chang: Well, it is. You can see why there's a lot of buzz, just like you were saying in terms of the excitement of this, especially because in all likelihood, you haven't lost anything and the ability to have this response without strictures, I think is actually also very, very appealing. We look forward to phase III. I think they're enrolling through the SEO CTC so I think lots of sites will be very, very interested in this technology. And I think for sure patients would be interested in it. Very, very exciting trial. How about the second one, Nima?
Nima Almassi: Kind of keeping on the same topic of nephron-sparing treatments, as you know, the administration of intracavitary or topical treatment has been increasingly utilized since the reporting of the OLYMPUS trial, which looked at efficacy and safety of a reverse thermal mitomycin gel. Now in the original OLYMPUS trial, that was administered in a retrograde fashion through ureteral catheter. And that trial showed 59% of patients receiving treatment had a complete response to treatment. One of the main concerns reported in that trial was a fairly high incidence of ureteral stenosis. 44% of patients who were enrolled in that trial actually demonstrated ureteral stenosis. And so the abstract from this year's AUA that I wanted to highlight looks at another way of administering that treatment. And the title of that abstract is The Antegrade Administration of a Reverse Thermal Mitomycin Gel for Primary Chemoablation of Upper Tract Urothelial Carcinoma via Nephrostomy Tube.
As the title suggests, the authors looked to assess the safety and efficacy of administering this same reverse thermal mitomycin gel antegrade through a nephrostomy tube rather than retrograde through urethral catheter. They were looking to assess both safety and efficacy. This was a study that was conducted across four centers. And so in patients enrolled in this study, they first underwent nephrostomy tube placement and then similar to the OLYMPUS trial, had their renal pelvis volume measured. In this case via an antegrade nephrostogram. Patients then received once-weekly induction treatments and in this trial, they were reporting safety outcomes. And that included any patient who received at least one treatment as well as efficacy outcomes, which included any patients receiving at least five of the six induction treatments.
In total, they enrolled 32 patients of whom the majority had low-grade disease. Sixty percent of patients who are enrolled underwent complete endoscopic ablation of tumor before treatment. Whereas the remainder had some residual disease after ureteroscopic treatment. Of the 32 patients enrolled, three patients discontinued treatment due to adverse events. The majority of adverse events were grade 1 or 2. The most common of which were fatigue or flank pain. Of the patients who completed treatment, three of patients developed renal stenosis, so that was 9% of patients. Two of these three patients had this managed with endoscopic balloon dilation and subsequently demonstrated no evidence of recurrent stenosis at last follow-up. One patient was managed with a temporary in-dwelling stent and subsequently had that stent removed, again without recurrence that last follow-up. Among the patients who completed at least five of the six induction treatments, 59% of patients had a complete response and 38% of patients had a partial response.
Nima Almassi: In summary, this study does suggest that administration of a reverse thermal mitomycin gel via a nephrostomy tube in an antegrade fashion does have efficacy and it appears to be similar to that reported in the original OLYMPUS trial. Although again, longer term follow up is needed. What I found exciting about this study was that they observed a lower incidence of ureteral stenosis. In this study, it was 9% of the patients who were treated. Now again, this is a small study and more patients need to be accrued and enrolled to sort of confirm these findings and we do need longer follow-up. But if these results hold, I think this is a really exciting alternative option for again, in organ preserving treatment that appears to be both effective, in this case safe.
Sam Chang: I think that the appeal for patients to avoid the weekly cystoscopy with urethral catheter replacement, et cetera, it seems much more appealing with the replacement of the nephroscopy tube than to get a treatment that's given, and then it's basically a clinic appointment. And so at our institution, we're actually doing this antegrade method almost exclusively. And just as the report says, in terms of the abstract, tolerability is quite high. Knock on wood, we haven't had any strictures to this point. And so I think it is really appealing. What was nice about this was that the abstract results in terms of the CRs, et cetera, seemed very similar to obviously to the OLYMPUS trial. Very reassuring in terms of its safety. What do you think in terms of the long-term downside and nobody's really reported this, is there a hint that the stricture from the antegrade method may be even less worrisome than the strictures from the ureteral catheter replacement? Or is it just too early to say anything about that?
Nima Almassi: You wonder about repeated instrumentation in a retrograde manner and whether or not that influences ureteral stricture rates. Another sort of appealing aspect of this method of administering the drug is with a percutaneous access, depending on sort of how you elect to monitor a patient, antegrade assessment endoscopically is also feasible, which if you're thinking about six induction treatments and then endoscopic evaluation and potentially maintenance treatment, that's a lot of traversing the ureter if you're going in a retrograde manner. I do think that may play a role but it would be great to see sort of longer-term follow up obviously, to make sure that this is sort of a durable finding.
Sam Chang: You highlighted two exciting abstracts. Tell me what you think in terms of evaluating kind of this year's abstracts in the future. What do you think or what concepts, perhaps theoretical treatments, perhaps diagnostic tests, to you are on the rise and is most exciting when it comes to upper tract urothelial carcinoma?
Nima Almassi: One of the things that I find exciting about where the field is headed is trying to find efficacious, effective and safe treatment options that don't require radical nephroureterectomy. One of the big challenges that we run into is, ureteroscopically and with current imaging, it's very difficult to stage patients preoperatively. And one of the things I liked about the studies that we discussed is that they really did allow a wide range of patients to be enrolled, including both low and in some cases, high-grade patients but also patients with unifocal and multifocal disease. And again, the follow-up is relatively short and we do need longer term follow up but if these results hold, having treatment options that seem to be effective irrespective of unifocalilty or multifocality, I think is an exciting option because I do know that we do struggle to accurately stage these patients.
And that's one of the huge concerns with organ preserving treatments, is are we under staging the disease and potentially providing inadequate treatment? Going forward, I'd love to see more work in terms of the diagnostics that we're using for staging and assessing treatment response beyond just ureteroscopy, biopsy, cytology and as things like liquid biopsy or other urinary biomarkers come online, I think that could really help us push the field forward in terms of determining which patients really are well suited for an organ preservation technique and which patients really do require more aggressive treatment.
Sam Chang: I love those highlights and the look ahead because early on in terms of diagnostics, incredibly exciting, no question regarding some type of urine base marker that diagnoses cancer, perhaps even tells us more regarding the aggressiveness of the disease. But we're clearly making inroads with less aggressive tumors and with obviously with metastatic disease, with more advanced disease, adjuvant and metastatic therapies. Incredibly exciting times I think when it comes to a disease process that honestly, when I was a fellow, when there wasn't a lot of options out there and now actually with options, like we said early on, later on. Really an exciting time and really a time for urologic surgeons and oncologists to really consider clinical trial enrollment and development. And I think that's really, we're moving ahead in that area as well. Nima, thank you so much. I appreciate it and look forward to having more conversations in the future with you. I'm a big fan of you and all the faculty at Cleveland Clinic. Again, appreciate the time very much.
Nima Almassi: Thanks very much for having me, Sam. I really appreciate it.