Read the Full Video Transcript

Ashish Kamat: Hello, everyone, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, a urologic oncologist at MD Anderson Cancer Center. And it's a pleasure to welcome Professor Yair Lotan, who's a urologic oncologist up at UT Southwestern, to join us for an ongoing series on his work and the database that he's essentially led, looking at patients with BCG unresponsive disease and digging down into the details of what happens with these patients when they're treated with different treatment modalities. And in this particular instance here, we're really looking forward to seeing what you have to share with us on the impact of tumor stage on the outcome of patients undergoing bladder-sparing therapies.

Yair Lotan: Great. Thank you so much. Again, this is a multi-center collaboration, so obviously, I want to thank all the institutions and authors who helped contribute to this effort, especially when we're dealing with a disease such as BCG unresponsive bladder cancer.

It's very hard for any single institution to have sufficient patients to do subanalyses, which are still important for us to understand how to treat individual patients. And so it's nice when we can do a large collaboration where we can try to get some information about some of these questions. So this analysis focused on the impact of tumor stage and oncologic outcomes of high-grade BCG unresponsive nonmuscle invasive bladder cancer patients, specifically those undergoing bladder-sparing therapies as opposed to immediate cystectomy. These are my disclosures.

So the current "real-world" data on oncologic outcomes for BCG is largely limited to single centers and doesn't differentiate outcomes by clinical stage very well. And a greater understanding of prognosis based on tumor stage at the time of BCG unresponsiveness could improve the ability to counsel patients, especially patients who don't want to undergo cystectomy and prefer to pursue bladder-sparing therapies. So this was essentially a study to really try to compare the impact of tumor stage.

And so we know that you can be BCG-unresponsive with papillary A disease, patients with papillary 1 disease, or CIS, a combination of the two. We know about 20% of high-grade patients have concomitant carcinoma in situ. And it's important because the clinical trials, primarily for this disease, have focused on patients with carcinoma in situ. And the papillary arms tended to be smaller arms that were not powered for efficacy outcomes.

As you know, carcinoma in situ is considered not to be cured with TURBT. And so, we can assess drug effect better if you have a patient with carcinoma in situ than a patient who had a papillary-only disease where you resected the tumor and then gave a drug as an adjuvant. And then, all you can do is assess recurrence-free survival.

So we collected data on 401 patients with BCG-unresponsive disease at 10 centers. This was a large cohort, but over a 20-year period. And after TURBT, about a third of patients had high-grade T1 with or without carcinoma in situ, a quarter had high-grade Ta alone, and about 40% had carcinoma in situ with or without Ta disease.

And so we compared these patients with Ta alone or carcinoma in situ with patients with T1 disease, whether or not they had carcinoma in situ. And we found that any patient with T1 disease was more likely to progress, metastasize, or die of bladder cancer. And this was statistically significant in each case.

When we did a multivariate analysis looking at the independent factors, we found that tumor stage and the type of treatment for BCG unresponsiveness both affected independent predictors of progression-free survival. Only tumor stage was predictive of metastasis-free survival. For cystectomy-free survival, again, it was—T1 was more likely than CIS to undergo cystectomy. Treatment, again, did have an impact. And for cancer-specific survival, again, patients with T1 disease or those who received gem/doce had some differences in terms of cancer-specific survival. T1 was worse. Gem/doce versus BCG alone was better. And there were differences also whether or not you had T1 versus carcinoma in situ with or without Ta disease for overall survival.

Here are the curves looking at high-grade recurrence-free survival. And what you can see is that Ta alone had fewer recurrences than any patient with CIS, whether or not they had T1 or not. But it wasn't statistically significant because we had three groups comparing. But if we were just comparing anybody with CIS to Ta alone, the Ta group had fewer recurrences. For progression-free survival, though, now you have a separation where T1 is clearly worse than anybody who didn't have T1, whether or not they had CIS or Ta disease.

Again, for cancer-specific survival, the T1 group, with or without CIS, had worse cancer-specific survival. But for overall survival, there was more overlap between the groups in terms of statistical significance. But again, the T1 group was definitely worse than the CIS group or the Ta alone.

So in the summary, the presence of CIS demonstrates worse psychological outcomes for many forms of bladder-sparing therapy compared to Ta and CIS alone, which have less aggressive features. And a trial of bladder-sparing therapy and Ta alone or CIS, with or without Ta, may not compromise oncologic outcomes, but it's possible that T1 patients may have worse outcomes. And the current practice of linking patients with T1 and Ta into a singular papillary group for clinical trials is probably inappropriate, given the differing outcomes between T1 and Ta disease. In fact, because Ta disease is more common in some of these papillary arms, it may mask the worst oncologic outcomes of T1 in clinical trials. And so really, that practice probably should end, or at least we need to report outcomes differently for those two groups. Thank you.

Ashish Kamat: Thanks so much, Yair. I think you actually highlighted the point that I wanted to highlight, which is there's so much of a difference in the behavior of patients with T1 disease, that, clearly, a lot of the current trials that have a small proportion of T1 patients and report everything all together—we can't really understand what the impact of the treatment is on those T1 patients when you want to translate that into the clinic.

With that in mind, but then with the limitations of what we have currently, how do you use this data, which again, just reinforces what we know about T1 disease? But how do you use this data coupled with what's been published on the currently approved agents and those that are coming out to counsel your patients in the clinic when you see someone in front of you that has T1 disease, CIS, BCG unresponsive and is looking to you for answers?

Yair Lotan: Yeah, I think in this era where we're going to have multiple available treatments for BCG unresponsive disease, the temptation will be to avoid cystectomy. And in fact, it's possible that people will almost suggest that cystectomy is unnecessary or it will be viewed upon so negatively as a failure in management because the patient didn't respond to one of these treatments, that it will be pushed out too far. So for example, right now, at least five years ago, you and I were practicing, and we had very few options.

And we told patients you're probably going to get a cystectomy, and we can try a clinical trial, but if it doesn't work, we're going to give you a cystectomy. And that was usually the discussion you had with the patients. And the patients accepted that cystectomy was a high-ranking choice of treatment and the best chance of cure.

But if you have a conversation with a patient, and you say, well, there are four or five different options, people will view cystectomy as a last resort. But it probably shouldn't be a last resort. It should probably be second-line or third-line preferred therapy because we know that eventually, patients, even with CIS, might metastasize or progress, and their outcomes will be worse. So that's my biggest fear, is that people will say we have four or five options, so naturally, cystectomy is option number six. But in fact, for patients with T1, I think a serious conversation should be with the patient—so this should be number one, and if you try anything else, you're taking a significant risk.

Now, is it a huge risk for one other treatment? Maybe not. Maybe not for 3 to 6 months. And if you get fortunate, you have a good response. Then you don't need your cystectomy.

But I think very much we still need to say cystectomy is still the best chance of cure for organ-confined disease. And for T1 disease, I think we have to have a very significant emphasis early on when we present the options that that's still probably a good chance they're going to end up there. And it's probably the best chance of cure. And we might give one drug a chance, maybe two. But at that point, if they still have invasive disease, they're going to need to have their bladder removed.

Ashish Kamat: Yeah, and you made a key point there. Calling T1 invasive disease, I think, is the best way to remind people that it is invasive. It's just not muscle-invasive yet.

And that's the other point because now we have multiple lines of therapy. And it's probably safer in a Ta patient and a CIS patient to try one or two or even three different lines of therapy. But in a T1 patient, every time they're T1. You and I know this. Our clinical staging itself is not as good as we'd like it to be. And we might be missing that window of opportunity of cure, not just progression, but of actual cure, as you showed from the data, metastasis-free survival, cancer-specific survival. So I like that message that you're putting forward.

Yair, let me play devil's advocate a little bit. And again, I believe everything that we're talking about. But what about the counterargument saying, well, in today's day and age, T1 is not the same as RT1? I can see tumors better. I'm going to do a Re-TUR. This data probably didn't have enough patients with Re-TUR. It's the old scopes. How do you counter that and caution people that say, hey, today's T1 disease is not the same as what you and I were treating?

Yair Lotan: I think the answer is we need more data on that. It's nice to say we have retrospective data. You and I are both going to have a prospective registry. And I think we need to get more data. The CISTO trial is going to be published. There are many hundreds of patients, probably a decent proportion of T1. And we're going to have to see whether or not that's true. But no matter what, a patient with T1 disease still is always at a lifelong risk for recurrence, potentially progression and metastasis. And we know that about 5% to 10% of those patients have micrometastatic disease, even when we first diagnosed them.

So as a patient advocate, as a patient, you might be completely right. It may not be the same. But it's clearly worse than T1 or CIS alone. And it has to be treated differently and probably more aggressively. And whether or not that—I'm not suggesting that every one of those patients should have upfront cystectomy, but I do think that we need to be cautious with patients who have persistent high-grade T1 disease.

It's not the same disease as a patient who has Ta disease or CIS. And we need to look at the trial data carefully because these are small arm B's with maybe 50 patients, of which maybe 10 or 15 have T1. And we can't just lump them together. And maybe that's the only message I can give, is that until we have more data, we just have to be extra cautious. And certainly, we shouldn't generalize the data we're getting from trials right now and apply them indiscriminately.

Ashish Kamat: Yeah, no. Well said. And I think the key message for us to send to the audience that's listening and our younger members of the urologic oncology field is that it's not acceptable to have even a single patient die of nonmuscle invasive disease. And if you keep that in mind, it's a good trigger to remind us as to when the cystectomy is actually appropriate. Don't wait for metastases. Don't wait for it to become an incurable disease, even with EV, pembro and all of that we have nowadays. Yair, thank you again for taking the time. I'm looking forward to seeing you at an upcoming meeting, and I'm sure we'll hear a lot of exciting things coming out of this database and the prospective registry that you have planned. Thanks again.

Yair Lotan: Thank you so much.