Sari's Notes

Disclaimer: this is a very complex topic, and I do not claim any mastery of it. Also, I am not endorsing any treament over another

Table of Contents

1. Background
2. Basic terms
3. Why is BCG-unresponsive disease a big deal?
4. What is considered a successful treatment for BCG-unresponsive disease?
5. Cystectomy: The Standard of Care that no one wants
6. Intravesical Bladder-Sparing Treatments (BSTs): The Good, The Bad, and The Ugly
7. Systemic Therapy: Pembrolizumab (Keytruda) and other IO agents
8. Final Thoughts
9. Footnes

Background

Before getting into the weeds of this, I recommend checking the following links to better understand non-muscle invasive bladder cancer (NMIBC). My discussion below assumes that you understand the basic terms discussed in these resources

• National Comprehensive Cancer Network (NCCN): https://www.nccn.org/patients/guidelines/content/PDF/bladder-patient.pdf
• Bladder Cancer Advocacy Network (BCAN): https://wellprept-prod-storage.s3.amazonaws.com/migration_folder/1677489367_mgPnBUZD.pdf
  

Basic terms

• High-grade cancer means the cancer cells look aggressive and are more likely to grow or spread. High-grade bladder cancers can be papillary or CIS
• Papillary tumors progress in their tumor stage, also known as T, from Ta (superficial) to T1, then T2
  • T1 means the cancer has grown into the layer just below the bladder lining but not into the muscle. This layer is called the lamina propria
  • T2 means the cancer has invaded into the muscle, making it a muscle-invasive bladder cancer (MIBC)
• CIS is a separate type of high grade bladder cancer than can exist by itself or alongside papillary high-grade Ta or T1 cancers. It has a high risk for recurrence after treatment, and more importantly, for progression to MIBC
• BCG is the current standard-of-care management for high-grade NMIBC. It is considered an “immunotherapy”¹ because it activates the bladder’s immune system to fight cancer
  • I will not delve into the details of BCG treatment here, as you likely already know them, but here’s a helpful resource: https://bcan.org/bcg-treatment-for-bladder-cancer/
• BCG-unresponsive disease means the cancer has not gone away after treatment with BCG. This is a “consensus definition” that was established by the American Urologic Association and Society of Urologic Oncology (AUA, SUO) to make it easier to discuss and study this disease, and replace older and sometimes confusing terms like “BCG failure”, “BCG relapse”, or “BCG refractory disease”. Formally, BCG-unresponsive disease is defined as either:
  • Persistent high-grade disease or recurrence (Ta, T1 or CIS) within 6–12 months of “adequate BCG” ², or
  • T1 high-grade disease at the first evaluation following induction BCG

Why is BCG-unresponsive disease a big deal?

1. Because further BCG is unlikely to help
2. Because there is a high risk for progression to muscle-invasive bladder cancer (MIBC) – at least 10-20% within 1-2 years
   • MIBC is typically treated with surgery (radical cystectomy), usually preceded by chemotherapy, or chemo-radiation.
   • Even with cystectomy or chemo-radiation, MIBC patients have roughly a 70% chance of remaining cancer-free at 5 years from treatment (disease-free survival, DFS)
     

Treatment Options following BCG failure: An Overview

1. Radical cystectomy (removal of the bladder): The standard of care, as it is the most effective way for cure and prevention of progression (80-90% cancer-free survival at 5 years)
2. Bladder-Sparing treatments (BST): less effective than cystectomy; their rates of success – defined as cure or at least preventing high grade disease recurrence, are usually only 30-50% over 2 years
   • Intravesical therapies (bladder instillations, i.e., washing the bladder with an agent like BCG) – chemotherapy and/or biologic agents
   • Systemic (IV infusion) therapies – mostly pembrolizumab (keytruda)

What is considered a successful treatment for BCG-unresponsive disease?

• Evaluating the success rate of these agents can be difficult and confusing, and unfortunately, easy to “fudge”, i.e., make it look better than it really is
• A more technical term that we prefer over “success” is “efficacy” for these agents. We have to measure it against their “toxicity”, i.e., side effects.
• We also like the terms “response rate” (percent of patients who respond to a treatment) and “duration of response” (for how long)
• A key point here is that “efficacy” or “response” do NOT equal cure – almost none of the treatments that I discuss promise cure in the way that patients think of it. What they really promise is one or a combination of the following terms:
  • Recurrence-free survival: preventing the high-grade cancer from coming back
  • Progression-free survival: preventing progression to muscle-invasive disease
  • Cystectomy-free survival: avoiding a cystectomy
  • Combination of all of the above + death
• For all those reasons, it is very difficult, even for experts, to interpret – and more importantly, to not be swayed, by treatment data
  • For example, a trial of a new agent – let’s call it agent X, may claim a “70% response rate”, but that does not tell us if that response lasts just 3 months or two years

Cystectomy: The Standard of Care that no one wants

• Pros: this is the standard of care per all guidelines – the most effective way for prevention of progression (80-90% cancer-free survival at 5 years)
• Cons:
  • Major surgery with significant risks, with complications ranging from 30-60% in most series
  • Mortality is 1% at baseline – usually from a post-op complication, but can increase to over 5% in frail patients over 80
  • Lifelong urinary diversion – usually an ileal conduit, aka urostomy (“a urine bag”)
  • Even continent urinary diversions (no bag), usually a neobladder, carry their unique risks and issues
  • Likely drastic changes to sexual function
• Not surprisingly, almost no patient wants to go directly to cystectomy, except for patients with already severe bladder symptoms and issues, who cannot tolerate any further treatments
• More on cystectomy and urinary diversion:
  • Basic introductory video #1: https://www.youtube.com/watch?v=xqmh_4zA9YY
  • Basic introductory video #2: https://www.youtube.com/watch?v=yZWx_JDsn88
  • Urinary diversion overview: https://jamanetwork.com/journals/jama/fullarticle/2773564
  • Taking care of a neobladder: https://bcan.org/care-and-keeping-neobladder-webinar/
    

Intravesical Bladder-Sparing Treatments (BSTs): The Good, The Bad, and The Ugly

1. The Good: You get to keep your bladder and avoid the high morbidity of radical cystectomy, and the field is continuing to evolve with a new agent or trial every day
2. The Bad:
   • Generally, these agents offer a 30-50% chance of remaining free of high-grade cancer at 2 years for all comers
   • You may progress to MIBC or even metastatic disease while receiving them, even if you are getting close surveillance, due to the inherently difficult nature of diagnosing MIBC
   • Most of the newer agents are being evaluated in a clinical trial setting, meaning that they are not yet FDA-approved, and require traveling to referral centers that provide them
   • They can be very costly (at least to the healthcare system) – with price tags of $60K+ per treatment and up to $500K/year
   • They can result in serious side effects
   • They involve further treatment of the bladder, which can result in serious urinary side effects – potentially life-long, e.g., worse urgency, frequency, reduced bladder capacity. They also mean more potential bladder surgeries, imaging studies, and discussions
3. The Ugly
   • See my last The Bad point – the patients may not realize that these treatments can cause serious, potentially lifetime side effects to their bladder. In other words, while they are bladder-sparing treatments, normal bladder function is not necessarily spared
   • The bar for calling an agent or a trial successful is very low: a 20-30% chance of remaining high-grade cancer-free at 2 years is not great, but this is usually well hidden in the fine print. This is done by dividing patients to “early responders” vs non-responders, i.e., patients who did not have disease recurrence after round 1 of treatment. The percentage is usually 40-50%. Next, the trial follows the recurrence rates for these early responders over 1-2 years. The percentage, usally reported as “sustained response” is usually 40-50%. Simple math tells that for all comers, this means a ~25% response rate at 2 years, i.e., 25% chance of being free of high grade disease (including potential progression to MIBC or metastatic disease)
   • The trials are generally single-arm trials, i.e., they are not compared to cheaper or known agents, e.g., BCG or other intravesical chemotherapy agents, making it unclear if they are improving over what we already have
   • The pharmaceutical industry is in charge of almost all of these trials, rather than having them be driven by academia
     

Systemic Therapy: Pembrolizumab (Keytruda) and other IO agents

• Pembrolizumab is one of the first immune checkpoint inhibitors, a new class of agents that has revolutionized cancer care.
• There are many names and acronyms for these agents: immuno-oncologics, immune checkpoint inhibitors, or immune checkpoint blockage agents = IO, ICI, ICB. Let’s go with IO, which is the most popular acronym.
• IO agents activate the immune system against cancer by targeting checkpoints in the immune system (hence the “immune checkpoint blockade”). It’s much more complex than this, but essentially, by blocking these checkpoints, IO agents allow the immune system to better recognize and kill cancer cells. However, it can also make the immune system over-react to normal cancer cells – auto-immune reactions. These can be life-threatening compared to intravesical therapies, including death, severe lung inflammation (pneumonitis), thyroiditis, and any “-itis” that can occur. These reactions can be unpredictable and latent, i.e., may occur months or potentially years after stopping therapy
• Pros: they doe not involve any intravesical therapy, a plus for patients who are loath to catheters (who isn’t), particularly those with already sensitive bladders
• Cons: Limited efficacy – only 19% of patients treated with Pembrolizumab (KEYNOTE-057 trial) had a sustained response (remained high-grade cancer-free) at 1-year by some estimates, with relatively high rate of side effects. It also requires IV infusion, and remains quite expensive (~$250K/year)

Some popular intravesical treatments

Disclaimers:

• I am barely up to date with these treatments, so the ones I list are the ones are most familiar with. Also, I used OpenEvidence (openevidence.com) to outline some parts of the the summary below
• My goal is not to explore the technologies of these treatments nor compare them, but to help the patient understand their basic pros and cons – are they worth your time?
• I am bound to sound pessimistic when it comes to most of the novel therapies, but unfortunately, this is sometimes the necessary attitude when dealing with any potential delay in treatment of bladder cancer.
• Conflict of Interest: I am neither endorsed nor endorsing any of these treatments, and I am not involved in any trials of these treatments, but I’m an academic co-PI for PIVOT, a trial of a biologic instillation for a different type of NMIBC
  

1. Intravesical chemotherapy

• Usually sequential gemcitabine-docetaxel (patient’s bladder is filled with gemcitabine first, then emptied, then filled with docetaxel)
  • Some providers may try one of these agents individually (“monotherapy” with just gemcitabine or docetaxel), but that usually has less efficacy (closer to 20% at 2 years)
• Pros: generally the favored treatment by most urologic oncologists, because it (1) involves well-studied agents that have been used for decades with generally good tolerance, and (2) promises a high-grade disease-free rate of 40-50% over 2-years, which is higher than most of the intravesical biologic agents
• Cons: A key concern for the field is that this is not FDA-approved (it’s an off-label treatment), because it was not formally evaluated in a trial format. In other words, the above data is based on retrospective series, not a formal prospective drug trial, making its results less reliable than those of a formal drug trial. However, retrospective series with similar outcomes, suggesting that the

2. Intravesical Biologic Agents

• General issues with these agents were discussed in the above section (The Good, The Bad, and The Ugly). But a key issue is that the low bar set by the FDA³ for these agents allows them to be granted approval without a cutoff for actual efficacy rates, or appropriate comparison to an alternative, e.g., just another round of BCG induction, or older agents like Valrubicin
• I tried to avoid delving into the fine print of these agents and their all-comer response rates, but I ended up doing it a little. I also, I purposefully listed the estimated response rates only for FDA-approved agents.

• FDA-Approved agents (non-exhaustive list, as of July 2025)
  • Adstiladrin (Nadofaragene firadenovec) – bladder instillation that utilizes an engineered adenovirus to target bladder cells and activate an immune response within them. However, the 2-year success rate for all comers is approximately 20%, with high cost
    • 20% is calculated as follows: the initial response rate was 51%, and for the patients who responded, 46% sustained their response at 2 years.
  • Anktiva (nogapendekin alfa inbakicept) – evaluated in the QUILT trial series. The agent uses a special immune pathway (IL-15, activating a different subset of immune cells), but is notably given in combination with BCG.
    • The 2-year disease-free rates are a little difficult to interpret, but they seem to be about 40-50% for all comers, with close to 85% chance of remaining cystectomy-free (a mixed bag outcome, but relevant). Close to 50% is good – close to gemcitbine-docetaxel. However, this may have to do with the trial allowing “re-induction”, i.e, retrying the treatment regimen, for patients who did not respond after the initial treatment. So, in English, patients who developed a recurrence despite the initial 6 treatments were allowed to redo all six instillations all over again. Other new agent trials have not done that, so we don’t know if they would have achieved better 2-year rates if they allowed for reinduction as well .
  • Valrubicin: Old agent that is technically the first FDA-approved treatment for BCG-unresponsive disease. It quickly fell out of favor due to poor efficacy and cost.
    • However, ironically, that efficacy is actually what most other intravesical agents, as well as pembrolizumab (Keytruda) can achieve – 20% recurrence-free survival at 1 year, and its cost has been eclipsed by newer agents.
• Not yet FDA-approved agents (non-exhaustive list, as of July 2025)
  • Most of these agents use combination therapy: similar to Anktiva, these agents may combine a novel agent with a more established agent, such as BCG or chemotherapy
  • Sasanlimab (an immunotherapy agent, like pembrolizumab) + BCG. Studied in the CREST trial, this has some promising results, but continues to have the same issues I discussed before: limited/no benefit in preventing progression to MIBC or death, high risk for side effects, and likely high cost.
    • It uses a novel immune checkpoint blockade agent, which can cause similar immune side effects to pembrolizumab (Keytruda).
  • TAR-200 (aka gemcitabine “pretzel” trial): studied as part of the SunRISe trial series, which is ongoing. This is an interesting idea of placing a gemcitabine-releasing coil (GemRis) in the patient’s bladder for several days to maximize effectiveness, with or without an IO agent called Cetrelimab. The trial design is nice and their preliminary data is exciting, even for just the TAR-200 montherapy (just the pretzel, no immunotherapy), but there are caveats
    • The preliminary data is based on a tiny cohort (less than 100 patients) with 9-month sustained response rates, so not even 1 or 2 years (yet).
    • It’s a single-arm trial; it does not compare itself to any alternative management, e.g., just regular gemcitabine instillations, to see if it actually improves over them to make the cost and additional procedures needed for this treatment worth it. They are actually testing this in SunRise-5, a separate trial
    • Cetrelimab is an IO agent that can cause serious side effects
  • Gemcitabine + BCG (GAIN trial) – current trial at Memorial-Sloan Kettering that utilizes gemcitabine and BCG. I am likely biased towards it due to my training at MSKCC, but it is being conducted the right way (two-arm trial) and with inexpensive and relatively safe agents. That said, it’s still early and the patient cohort tested is small.

Now what?

• Take a deep breath: As mentioned earlier, the risk for progression to MIBC is usually 10-20% over a 1-2 year period. This is scary, but also means that there is time to think, consider your options, and potentially try some bladder-sparing treatments (BST)
• Trying bladder-sparing treatments (BST) is not a bad idea: You are not crazy to want to keep your bladder. This is normal. Very few patients want to do away with their bladder, and it’s usually patients who already have severe bladder issues at baseline – overactive or sensitive bladders, making them loath to any more treatments that may worsen their symptoms. So, I still discuss BST as a reasonable option with all my patients, and I am happy to refer them to centers where some of these agents and/or trials are available
• Talk to your family and loved ones – you need them. Bring them to your appointment
• Seek a second opinion. Even if you trust your provider, it helps to hear your situation described from a different angle, and to discuss options several times if necessary before deciding on one
• Do your research (with caution): AI has revolutionized people’s ability to study medical issues, and has helped me make this post, but a professional opinion remains critical. Do not buy the hype of many of these newer agents – the companies do a great job promoting their novel technologies (which is usually true), but obfuscate their actual all-comers success rates. If it’s too good to be true, it probably isn’t
• Please, DO NOT experiment with alternative medicine. These treatments are not well evaluated and do not meet any of the standards for FDA-approval or medical use, no matter what you read on the internet

Final Thoughts

• I started this post because I was unable to find any patient-friendly resources or videos online to show my patients. In fact, it inspired me to start this blog altogether.
• However, I realize that what might sound patient-friendly to me may remain confusing to most people. You are not alone – even my residents, i.e., urologists in training, and non-oncology trained urologists struggle with this difficult topic.
• Assuming anyone reads this, please feel free to leave comments, and I can use them to edit this post to make it more helpful. That said, I will refrain from commenting on any specific treatments beside the basic outlines above
  

Footnes

1. I used quotation marks for immunotherapy here because this term is now more used for immune checkpoint blockade agents, aka checkpoint inhibitor or immuno-oncologic agents, such as pembrolizumab (Keytruda) ↩︎
2. “Adequate BCG” is somewhat arbitrary, but it is defined as least 5 of 6 induction instillations and at least 2 of 3 maintenance instillations, or a second induction course. While both “adequate” BCG and “unresponsive” disease are based on inherently arbitrary criteria, they do reflect belief by experts that further BCG treatments are unlikely to help the patient, and that establishing a clear-cut definition for this disease would allow for standardization of criteria for clinical trials and eligibility for them ↩︎
3. This is not a snipe at the FDA. BCG-unresponsive disease is considered a high-need disease due to the limited therapeutic options, which is why the FDA generally grants priority review to its trials, and why it also allows approval to be based on single-arm trials (where the agent is not tested against an equivalent agent), and does not set a cutoff success rate to approve a new agent. However, expert opinion has recently suggested that this is now necessary ↩︎