Christopher Wallis: Hello, and welcome to this UroToday Journal Club. Today, we're discussing a recently published paper from the BRAVO feasibility study looking at radical cystectomy against intravesical BCG for high-risk high-grade nonmuscle-invasive bladder cancer. I'm Chris Wallis, a Fellow in Urological Oncology at Vanderbilt, and with me today is Zach Klaassen, Assistant Professor in the Division of Urology at MCG. So this is a citation published in JCO recently by Dr. Catto and colleagues.

By way of background, most UroToday readers and viewers will know that nonmuscle-invasive bladder cancer is the most common category of bladder cancer, comprising a variety of different stages, including carcinomas in situ, Ta disease, and T1 disease, where the stage distribution has demonstrated on the right there with a predominance of Ta disease.

On the basis of a variety of characteristics, you can categorize nonmuscle-invasive bladder cancer based on the risk for progression and recurrence, and so the EAU and AUA use slightly different criteria, but in short, high-risk tumors are those characterized by high-grade histology, T1 stage, CIS, as well as other criteria, including multifocality, recurrence, and size.

Now, based on work from Dr. Kamat and the International Bladder Cancer Group, we can see that these risks categories are strongly associated with rates of recurrence and progression, and so in patients with high-risk disease who are BCG-naïve, TUR with repeat TUR, as needed, and BCG and maintenance is associated with not insignificant recurrence rates up to 30% at 24 months, and progression rates of up to 10% at 24 months.

And so this leads to this section of the EAU guidelines, looking at the management of patients with high-risk tumors. And again, here they're highlighting these are patients with T1 disease, CIS, high-grade histology, or multiple and recurrent and large low-grade Ta disease. For these patients, we should explain the nature of radical cystectomy and consider it as a treatment option, as well as also offering intravesical BCG. However, there's not clear evidence to guide the decision for preference between these two choices, particularly in patients with highest scores of tumors.

And so, the BRAVO study group planned a randomized control trial comparing radical cystectomy and intravesical BCG in patients with high-risk nonmuscle-invasive bladder cancer. This was initially planned as a feasibility study, and so this here gives you a bit of the study schema from their publication looking at their protocol, and this just emphasizes a multi-center, parallel-group, mixed-methods, randomized feasibility study, which was performed in seven networks within the NHS in England.

Patients were included if they were adults with newly diagnosed high-grade nonmuscle-invasive bladder cancer, they had to have at least one high-risk feature, which the authors defined is CIS, lymphovascular invasion, residual higher grade disease on repeat TUR, more than three tumors, age less than 65 years, tumor size greater than 3 centimeters, or T1 disease. Patients, following enrollment, were randomized in a 1:1 fashion to radical cystectomy or BCG stratification according to age, sex, center, stage, presence of CIS, and a prior history of low-risk nonmuscle-invasive bladder cancer prior to their diagnosis of high-risk disease.

Patients received treatment in the BCG arm with at least four induction doses of the recommended six, and an additional 12 months of maintenance therapy. At any time during their maintenance period, the presence of high-risk disease or muscle-invasive bladder cancer required substation of maintenance BCG and conversion to more invasive forms of therapy. Cystoscopy with biopsy and cytology was mandated at the first follow-up and then subsequent follow-up was as per local protocol. For patients who underwent radical cystectomy, a surgical approach was undertaken with lymphadenectomy for all patients.

The authors importantly provided some detailing of the surgeons involved in the study. And so they required at least 10 years of surgical experience performing radical cystectomy, or for those with less than 10 years, they had to have at least 2 years with reported outcomes for greater than 10 patients per year and outcomes of length of stay less than 16 days on average and 90-day mortality rates, less than 10%. So this provides some form of benchmarking in terms of the adequacy of surgical intervention.

In terms of follow-up for patients who received BCG, cystoscopy was performed according to local protocols following the initial cystoscopy biopsy and cytology. Clinic visits and imaging were performed every 3 months for 1 year, and health-related quality of life was assessed at baseline 3 months and 6 months. Adverse events were assessed up to 12 months following enrollment.

The primary outcome was an assessment of the feasibility of randomization, so they looked at the number of patients screened, number eligible, recruited, and then randomly assigned. And secondarily, they looked at the acceptance rates of study enrollment, the 12 months maintenance BCG compliance, the feasibility of collecting health-related quality of life data in this population, and they, in a qualitative way, assessed reasons for declining recruitment to the trial.

Now, given the feasibility nature of this study, the sample size was designed in order to inform a planned Phase III trial assessing cancer-specific survival. And so for this Phase III trial, the authors estimated that they would require just over 500 patients to demonstrate superiority with a hazard ratio of 0.626 over a 3-year accrual and 5-year follow-up with 80% power. And so in their pilot, they aimed to assess whether it would be possible to accrue and randomly assign 25% of eligible patients, and they felt that if they were able to accrue 60 patients from seven centers over 18 months, this would prove feasibility.

The authors performed quantitative analyses looking at descriptive statistics of the population and summaries of screening eligibility to recruitment random assignment, as well as summaries of the uptake of allocated treatment and compliance. And then qualitatively, they interviewed involved nurses, doctors, and patients to understand issues related to trial conduct.

At this point, I'll pass it over to Dr. Klaassen to talk us through the enrollment and random assignment, as well as the results of this trial.

Zachary Klaassen: Thanks, Chris. So, as Chris mentioned, they figured they'd have to screen a lot of patients to be able to get down to a feasible number to randomize. And indeed, they screened 407 patients. There were 215 patients that were suitable for participation and 185 that were approached for participation. At that point, there were 134 patients that did not consent to the study, including patients that had a maintenance BCG preference or radical cystectomy preference. And subsequently, they consented 51 patients, randomizing 50 patients, 1 patient was randomly assigned, but then changed their mind due to maintenance BCG preference. So in total, 50 patients were randomly assigned and consented.

In terms of allocation, you can see here that 25 were randomly assigned to radical cystectomy and 25 to maintenance BCG. On the radical cystectomy side, which is on the left side of the screen, there were 5 withdrawals that subsequently wanted maintenance BCG, and so 20 patients ultimately underwent radical cystectomy and 25 patients in that arm were included in the intention-to-treat analysis. Moving to the right side of the screen, there were 25 patients that were randomly assigned to maintenance BCG arm, of which 2 patients withdrew and subsequently decided they wanted a radical cystectomy, so 23 patients received maintenance BCG. And once again, 25 patients on that side were included in the intention-to-treat analysis.

So, looking at the baseline characteristics for this trial, you can see this table on the left is the different variables. The second column is radical cystectomy, the third column is the maintenance BCG patients. As I mentioned, 25 each were randomized to each arm, not surprisingly. Quite representative of the bladder cancer population in terms of age and predominantly male gender. In terms of patients that had their diagnostic procedure, about half underwent initial TURBT, and then they were diagnosed on re-resection and the other half. Tumor stage at the first TURBT was predominantly Ta, followed by T1. And on re-resection, we see that there were 32% of patients that had T1 disease. At the bottom of the table, you can see that there were 31 patients that had CIS concomitantly, and that was slightly higher at 68% in the maintenance BCG arm compared to 56% in the radical cystectomy arm.

Continuing with the baseline characteristics, you can see here that most of these patients were high-risk at bladder cancer, 92% of patients in the radical cystectomy arm and 96% in the maintenance BCG arm. Not surprisingly as well, the majority of these patients were either current smokers or ex-smokers. And surprisingly, to a degree, 84% of patients had industry-associated exposure to carcinogens, including 92% in the radical cystectomy arm and 76% in the maintenance BCG arm. Roughly 80% of these patients had an excellent performance status of category 0, with the remainder of them being a 1 and 2.

And finally, to sum up, the baseline characteristics in this third slide, you can see that they also categorize the diagnostic setting as to when the patients were diagnosed, and in the NHS 54% of patients were in the district hospital and 46% were in the cancer center, with the majority of patients having an excellent estimated GFR at the time of study enrollment.

This table here looks at the treatment compliance and events, specifically in the maintenance BCG arm, so for those 25 patients. You can see that they break this down by cycle as well. So, not surprisingly, the majority of patients underwent one cycle, 92%. Subsequently, 18 patients underwent cycle two. And this drops off to only 6 patients undergoing three cycles. In terms of whether the administration of BCG took place within the times specified in the protocol, all of these patients had this in the first cycle, and then you can see the compliance within the protocol decreases in cycle two and in cycle three. Cytology was normal in about three-quarters of patients in cycle one, and just over 80% in cycles two and three. The majority of patients did not have tumors at cycles one, two, and three. And you can see the pathology results by stage. In the patients that did have tumors, the majority of these were Ta, CIS, and T1.

In terms of if the patients permanently discontinued BCG, 78% did not. The reasons for discontinuing BCG included toxicity and intolerance in 40% of patients, local recurrence, and progression in 40% of the patients. The majority of patients did have CT scans on time at 88.9%, and the majority of these, at three-quarters of the patients, had normal upper tracks.

So, switching over to the treatment compliance and events in the radical cystectomy arm, in this first column here, you can see that 20 patients, or 80% of patients, did undergo a cystectomy, and this did take place within the 8 weeks of random assignment in 90% of patients. As I mentioned previously, these patients had normal BMIs, they had an essentially normal kidney function. The majority of these patients did undergo an open radical cystectomy at 85% compared to 15% robotic. Majority of patients underwent level 2 lymph node dissection, with only 1 patient having a concomitant urethrectomy. The majority of operations lasted between 3 and 5 hours, and a majority of these patients underwent an ileal conduit, and most patients lost between 300 and 500 or 500 to 1,000 ccs of blood.

This is the second half of this table. On the right, you can see the majority of patients did not require a blood transfusion, there was no return to the operating theater, and a majority of patients did not receive a postoperative radiological intervention. In terms of the histology by stage, you can see that 2 patients, or 10%, had T2 or above at the time of cystectomy, 15% had T1, 10% had Ta, 40% had CIS, and 25% of patients were T0. Looking at the lymph node count, about 70% of patients had more than 10 lymph nodes. There was concomitant prostate cancer diagnosed in several patients, the majority of which was a Gleason group 1, and the majority of patients did have a CT scan at the 12-month mark, in terms of 90% of the patients in this arm.

This figure on the right looks at the health-related quality of life as measured using the EQ5D and the EORTC QLQ-C30, and basically, here I've summarized the important findings on the left. There were few changes in the EQ-5D-3L that we're seeing between the radical cystectomy and the BCG arms, however, in the QLQ-C30, we see that radical cystectomy patients had a reduction of quality of life at 3 months compared to the maintenance BCG arm. However, this recovered to baseline sometime between 6 and 12 months.

In this figure here, we're looking at bladder cancer-specific EORTC patient-reported outcomes. And once again, I've summarized these figures in the bottom with several bullet points, including that, in the maintenance BCG arm, there's a small increase in urinary symptoms scores at 6 months, as well as a small reduction in future worry scores with subsequent time. In the radical cystectomy arm, most of the symptoms that patients experience improved from 3 to 12 months except for sexual dysfunction, which did not improve over the course of that first 12 months.

So, several discussion points for the BRAVO study. The authors in the trial should certainly be congratulated for performing this feasibility study, as these are challenging as we've gone through the last several slides, and given the suspected challenges of recruiting to an RCT of maintenance BCG versus radical cystectomy, a feasibility study was certainly a reasonable approach.

This RCT reveals several important insights into the disease and does challenge several preconceptions. The first preconception of challenges is that BCG is a default first-line treatment because clinicians feel patients are unfit for radical cystectomy. The authors note that 80% of the considered population in this study were deemed fit for either treatment in BRAVO. As we saw in the previous slides, the performance status was 0 in the majority of these patients with excellent kidney function, so they were deemed fit for either treatment.

The second preconception is that clinicians often manage high-risk nonmuscle-invasive bladder cancer as a non-lethal disease. And in this study, BRAVO, they found that most new high-grade nonmuscle-invasive bladder cancers are at risk of progression, and in fact, the 10% of patients that had T2 or higher disease at cystectomy do have potentially lethal disease.

And finally, the third preconception this study challenged was that patients fear radical cystectomy as they perceive a low health-related quality of life, and BRAVO showed that within the first 3 months, indeed, the health-related quality of life may be slightly better with maintenance BCG compared to cystectomy, but as those previous figures showed, these differences tend to disappear by about 12 months, with the exception of sexual dysfunction.

So in conclusion, an RCT comparing maintenance BCG and radical cystectomy will be challenging to recruit to, and approximately 10% of patients with high-risk nonmuscle-invasive bladder cancer do have a lethal disease and may be better treated by primary radical treatment. However, as the majority, these patients do not have lethal disease, many are still suitable for bladder preservations and may retain their pretreatment health-related quality of life. The BRAVO authors do note that these findings should be used as a platform to inform patients about the relative risks for each approach and recommend the use of an individualized risk-adaptive approach to treating these patients.

Thank you very much for your attention to the BRAVO Journal Club. We hope you enjoyed it, and thank you for attending.