The CISTO Study: Radical Cystectomy or Bladder-Sparing Therapy for Recurrent NMIBC

Guest Dr. John Gore and host Dr. Davide Soldato discuss JCO article, "12-Month Results from the CISTO Study Comparing Radical Cystectomy Versus Bladder-Sparing Therapy for Recurrent Non-Muscle Invasive Bladder Cancer," which compares radical cystectomy and bladder sparing therapy for patients with recurrent high-grade non-muscle invasive bladder cancer. Dr. Gore and Dr. Soldato focus on the study's patient-centered approach, eligibility criteria, and quality of life after treatment.

TRANSCRIPT

The disclosures for guests on this podcast can be found in the show notes.

Dr. Davide Soldato: Hello and welcome to JCO After Hours, the podcast where we sit down with authors from some of the latest articles published in the Journal of Clinical Oncology. I am your host, Dr. Davide Soldato, medical oncologist at Ospedale San Martino in Genoa, Italy.

Today, we are joined by JCO author Dr. John Gore, urologist at Fred Hutch Cancer Center and professor of urology at University of Washington School of Medicine. Today, we will be discussing the article titled, "Twelve-Month Results From the CISTO Study Comparing Radical Cystectomy Versus Bladder-Sparing Therapy for Recurrent High-Grade Non-Muscle-Invasive Bladder Cancer."

Thank you for speaking with us, Dr. Gore.

Dr. John Gore: Thank you so much for having me.

Dr. Davide Soldato: So, I just want to jump right in. We know that patients who are diagnosed with recurrent high-grade non-muscle-invasive bladder cancer can be treated with two different approaches. So, one is radical cystectomy, and the other is bladder-sparing therapy. I just wanted to understand: what was the gap that you were trying to fill with this study? In particular, one point that is very important is that this study is very centered on the preference of the patients. Why did you choose this endpoint instead of going for more solid oncology-based endpoints?

Dr. John Gore: Yeah, so CISTO was a study that was derived really organically from patient engagement. I think as a clinical gap in care, making a decision about when to pursue radical cystectomy for patients with non-muscle-invasive bladder cancer is a tough decision for us as clinicians. We did some engagement work partnered with the Bladder Cancer Advocacy Network and my partner Angela Smith, and found that it is also a huge gap for patients. You know, they are very anxious about recurrences, and the decision about when to take out the bladder is a very difficult one. We did an evidence synthesis and found that evidence guiding this decision is fairly limited.

The reason we chose more of a patient-reported endpoint is several-fold. One is that we, as part of our engagement work, also worked with our patient survey network to identify outcomes that were important to patients. Some of those are the same outcomes that we care about as clinicians - recurrence-free survival and metastasis-free survival - but several outcomes came out that were more patient-centered. These were patient-reported outcomes such as the burden on my finances, the burden on my caregiver or loved one, and the ability to return to physical activities that are important to them.

Part of what is unique about CISTO is that this was a contract with PCORI where we knew we would only have about 12-month outcomes for the majority of our patients. That is too early to really derive a lot of the clinical outcomes, but we are able to answer that patient-centered question of, "Am I going to be able to return to physical activities that are important to me?" And that was the genesis of that as the primary endpoint.

Dr. Davide Soldato: So, who were the patients that were eligible to participate in the CISTO trial? What were the key eligibility criteria? This is very particular to this study because this was actually an observational study. Why did you think that such a pragmatic approach still can inform us on what is the best treatment approach for these patients?

Dr. John Gore: The intent of CISTO was not necessarily to focus on the tightly defined BCG-unresponsive patient population. That is a clearly important patient population, but every day we are all faced in our real-world practice with patients with challenging, high-grade recurrences that don't fit neatly into that BCG-unresponsive box.

The reason we chose a broader inclusion was to help doctors and patients answer these same questions they have when it doesn't fit nicely into this BCG-unresponsive category. You know, maybe their BCG exposure was two years ago, but now they are having a recurrence after intravesical chemotherapy. That is no less challenging a clinical conundrum, and we wanted to be able to enroll those patients. Other key inclusions were that all of the patients in CISTO had to have BCG at some point, and they had to have recent exposure to some adjuvant instillational or intravenous therapy like pembrolizumab. We also had some exclusions that were important. They couldn't be participating in a phase 2 clinical trial, and they couldn't have had a prior upper tract urothelial cancer.

The other point about the observational trial design is I think a really important one. Part of our engagement work also asked patients about their willingness to randomize. There is a ton of literature in our history of trials that failed to accrue well when they were comparing a large-scale surgical intervention with a more conservative management strategy. What we found is only about 10% of patients would be willing to randomize when the clinical comparison is between radical cystectomy and bladder-sparing therapy. So it was very clear that an observational study design was the only way we were going to get evidence to inform clinical care when one of the key comparators was radical cystectomy. And so that is why we utilized the observational trial design.

Dr. Davide Soldato: Starting to go deeper into the results, you mentioned before that the endpoint you chose for this trial was really centered on what patients thought was more important to them. In particular, the primary endpoint of the study was physical function as measured by the EORTC QLQ-C30 questionnaire. I just wanted to understand: first, did you have a solid hypothesis regarding how physical function could be impacted by either radical cystectomy or bladder-sparing treatments? And second, what were the key results of the study?

Dr. John Gore: We figured that at 12 months after enrollment, given the burden and morbidity of a radical cystectomy, that patients in the radical cystectomy arm would have worse self-reported physical functioning than patients in the bladder-sparing therapy arm. We did hypothesize that some of our secondary outcomes might potentially be better after radical cystectomy, such as recurrence-free survival and potentially some other cancer-specific outcomes, because it is a more definitive management strategy. For our primary endpoint, however, we hypothesized that it would be worse.

What we found, and the key finding of our study, is that at 12 months after enrollment, physical functioning was not different between patients undergoing radical cystectomy and patients undergoing bladder-sparing therapy, which is just important in terms of clinical counseling because it just means that you can tell your patients, "Gosh, if we could fast-forward your life six to nine months after this procedure, your physical functioning would be similar to as if you had been able to keep your bladder."

Dr. Davide Soldato: And you mentioned that there were some key secondary endpoints of the study, which included both other dimensions of quality of life and also hard clinical outcomes. We mentioned metastasis-free survival, for example. Going a little bit into the key secondary quality of life outcomes, we know that radical cystectomy can impact physical functioning, but we also know that bowel, sexual symptoms, and also genitourinary symptoms might potentially be impacted by this type of treatment. We also know that, especially in a system like the US, financial toxicity can be a significant burden for patients. Considering the two different approaches, was radical cystectomy better also in other key secondary quality of life outcomes, and was financial toxicity different between the two arms?

Dr. John Gore: Thank you for highlighting some of the really important secondary outcomes that I think are really important to trying to figure out what's best for your patients. Some of the main ones were some of the bladder cancer-specific quality of life outcomes you highlight. Urinary quality of life was worse at enrollment in patients in the radical cystectomy arm but was no different 12 months after. What is unique about how we measure that is we used an instrument called the Bladder Cancer Index because we're comparing a population of patients who have lost their bladder with a population of patients who have retained their bladder, and there are different considerations by gender. And so that instrument is agnostic to urinary diversion status and gender.

We found that bowel function and sexual function were worse in the radical cystectomy arm. It appeared that bowel functioning was getting better to the point of near equivalence at 12 months in the radical cystectomy arm but was still inferior to bladder-sparing therapy, and that probably relates to the fact that we use the bowel as part of the urinary diversion, and that causes some transient disruption in bowel function.

Financial toxicity is an outcome we weren't initially planning on having as part of the CISTO study, but based on that patient feedback, we made that one of our key secondary outcomes. That actually demonstrated superiority in the radical cystectomy arm. I think it's important that we remember that when we do bladder-sparing therapy, those patients are predisposed to a number of visits to our office, whether they're for instillational therapies or cystoscopy surveillance visits. Sometimes that involves the patient themselves, and sometimes that involves a caregiver. We live in an area with a very large geographic catchment, so sometimes that involves overnight hotel stays and airfare. It can be a particular burden, as you made mention, especially in our healthcare system.

Dr. Davide Soldato: Going back to the quality of life dimensions and especially considering the different treatments, 50% of the patients received radical cystectomy with robotic surgery. Did you look a little bit into whether the type of surgery that they received might potentially impact on these dimensions of quality of life?

Dr. John Gore: These are some questions that a lot of urologists have asked us in the surgical arm, related to surgical approach, so robotic versus open, and urinary diversion type. We sometimes reconstruct the urinary tract with an incontinent diversion called an ileal conduit where the urine drains tonically into a bag, and we sometimes do a continent diversion where someone typically will have a neobladder, where you reconstruct a sphere reservoir out of intestines and sew it to the urethra. About 20% of patients in the radical cystectomy arm in CISTO had a neobladder.

We have not yet looked at specific surgical factors and some of those outcomes. That is one of the secondary analyses that we have planned, but we have not drilled into how different surgical approach factors can affect some of our outcomes. Fortunately, we have about 200 patients in the radical cystectomy arm, so it's enough patients that hopefully we can look at some of those factors in the future.

Dr. Davide Soldato: Going back to the clinical endpoints, you mentioned that several of these were measured. There was metastasis-free survival, cancer-specific survival, and progression-free survival. We now have the data at 12 months. I am just wondering if you can comment on those when comparing the radical cystectomy with the bladder-sparing techniques.

Dr. John Gore: I think importantly, bladder cancer-specific survival was very high in both arms, over 95% at one year. So both patient populations do very well in terms of cancer-specific and overall survival at one year. You know, when you take out the bladder, you're taking out a big source of recurrences. Not surprisingly, there was a marked reduction in recurrences in the radical cystectomy arm, so they had better recurrence-free survival.

There actually was worse progression-free survival in the radical cystectomy arm, but there is a big asterisk to that. As you noted, it is an observational study, and one of the areas of imbalance in the study is that we had higher cancer severity in the radical cystectomy arm. So there was about a 20% rate of progression at the time of radical cystectomy to muscle-invasive and node-positive disease. Of those progressions, the overwhelming majority of them were progressions at the time of radical cystectomy, which I think speaks to a couple of important factors. Number one is the challenge in staging these patients. Our staging of non-muscle-invasive bladder cancer is very reliant on our resection. And so there is this risk of understaging our patients. Number two is just the challenge of decision making, that we fear losing our window of cure in this patient population, which is why we try to steer some patients toward radical cystectomy, and that progression figure kind of speaks to that.

Dr. Davide Soldato: Also, one of the factors that was most common in the patients who received radical cystectomy was the presence of other high-risk features. For example, non-urothelial histology, which I think is something that in clinical practice we tend to fear a little bit in terms of recurrence, and so it might potentially bias a little bit towards proposing more strongly radical cystectomy to the patient.

Another thing that I wanted to have a comment on, so this is not really in the paper, but I think it speaks a little bit to how the data will evolve over time. Do you imagine these clinical outcomes changing over time, and do you think that with higher maturity of these endpoints, this study might be even more informative when counseling patients regarding what they are obtaining with a radical cystectomy versus the other type of treatments?

Dr. John Gore: You know, I think in this cancer universe, 12-month outcomes are great, but I think we all want to see two-year and five-year outcomes. We're very fortunate to supplement the work that we've done in the initial CISTO study, we’re very fortunate that we've gotten supplementary funding from the National Cancer Institute to get long-term outcomes in this patient population. So we are continuing to follow all of our CISTO study patients to get two-year and five-year outcomes.

What we expect to find is the accrual of new events in the bladder-sparing therapy arm. About 7% of patients in the bladder-sparing therapy arm underwent cystectomy in the first year, but that number will probably go up either as they have recurrences or progression events. We definitely expect the recurrence-free survival to continue to have superiority in the cystectomy arm, but we probably will see the progression events equilibrate as more progression events accrue in the bladder-sparing therapy arm. Maybe by five years, we hypothesize that we'll see clinical superiority in the radical cystectomy arm. By then, we might also see mortality events that separate bladder cancer-specific survival and overall survival between the two arms potentially. But we don't know. Hypothetically, cystectomy has its own downstream risks. It is a major reconstruction with some metabolic sequelae and renal functional sequelae, and so there may be some general medical events that accrue in the cystectomy arm that are also impactful.

Dr. Davide Soldato: One other thing that I think should be complimented on this study is that you also looked at several other endpoints that might be important for patients. For example, anxiety symptoms and depression symptoms.

Dr. John Gore: Yeah, I think one of the other key secondary outcomes we looked at were mental health outcomes. We utilized the PROMIS domains of anxiety and depression. Not unexpectedly, our radical cystectomy arm patients exhibited higher anxiety symptoms and higher depression symptoms at enrollment. What we found is at 12 months, they actually had significantly lower anxiety and depression than patients in the bladder-sparing therapy arm.

We hypothesized in this paper that that actually relates probably mostly to cancer-specific anxiety. You know, when you experience this cavalcade of recurrences, it just breeds an anxiety about adverse cancer-specific outcomes, and by taking out the bladder, you kind of eliminate this prevalent source of anxiety. We followed up the study with a qualitative piece where we interviewed 50 patients and 20 caregivers. Based on those interviews, and that's just a sample of the patient population, it did seem to be cancer-specific anxiety that was driving a lot of those responses.

Dr. Davide Soldato: I would like to end with a methodological consideration on your part because we said that this was an observational study. Frequently we tend to think that observational studies come with a lot of bias, and so we tend to downgrade a little bit the results. But I think that a lot of the merit that goes in the CISTO study that was published in the JCO, and I think it also speaks to the fact that this is very high-quality data, comes with the fact that the methodology behind this study was really robust in terms of informing us. Even with this observational study that, as you said, was the only one that we could perform considering the patient population. So just a comment on your part also to speak to the solidity of the data that was published.

Dr. John Gore: Importantly, you know, if you look at ClinicalTrials.gov or other sources, CISTO is the only trial that has radical cystectomy as a major comparator. In many ways, this study is our only source of evidence for radical cystectomy. So we'd rather have flawed observational evidence than no evidence at all. We all experience flaws of our RCTs as well. They tend to be these narrowly defined patient populations that may not match the patient in front of you. So I think there are unrecognized flaws on the other side as well.

The way that we try to counterbalance that, and none of these techniques are perfect, but we used a strategy called ‘targeted maximum likelihood estimation’. Like many methods, such as propensity scores or instrumental variable analysis, what we're trying to do theoretically is coax randomization from non-randomized data. And TMLE, which is the technique we use, tends to be pretty robust to that. So it's the best available way that we can try to counterbalance the bias based on age and clinical severity between the two patient arms. I also think what's important about this is that even when there are biases, I think we are able to infer those out and still extract meaningful details from the data. So even with the biased data, I think we all glean some really important clinical learnings from it.

Dr. Davide Soldato: Absolutely, but I would also say that in terms of observational data, the work that you have done is really something that makes us quite confident about what you found in the CISTO study.

So with this, I would like to thank you again for joining us today.

Dr. John Gore: Thank you so much, and thank you for highlighting the CISTO study. We are very excited about the data.

Dr. Davide Soldato: So Dr. Gore, we appreciate you sharing more on your JCO article titled, "Twelve-Month Results From the CISTO Study Comparing Radical Cystectomy Versus Bladder-Sparing Therapy for Recurrent High-Grade Non-Muscle-Invasive Bladder Cancer."

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Guest Disclosure

Dr. Gore:
Consulting or Advisory Role: Astellas Pharma