Dr. Michael S. Cookson presented “BCG Failure: Defining and Managing Difficult Patients” at the 26th Annual Perspectives in Urology: Point-Counterpoint, November 10, 2017 in Scottsdale, AZ

How to cite: Cookson, Michael S. “BCG Failure: Defining and Managing Difficult Patients” November 10, 2017. Accessed Jul 2024. https://grandroundsinurology.com/bcg-failure-defining-managing-difficult-patients/


Dr. Michael S. Cookson, MD, MMHC, provides an update on non-invasive bladder cancer and discusses some of the treatments for locally advanced and metastatic disease.

BCG Failure: Defining and Managing Difficult Patients


We’re going to talk about BCG failure patients, and BCG unresponsive patients. I bring you greetings from Oklahoma City, the Olympic rowing team, the OU football Sooners are hanging in there.  They still have a shot at the playoffs.  We thought we were really sprucing our city up with the big three.  We haven’t done very well.  We lost last night to Denver, but we’re going to try to figure out a way to get the thunder up and running.  We’re going to focus the first half of this stuff on non-invasive bladder cancer, and once we have talked our way through that we’ll go to more the invasive and some of the treatments for locally advanced and metastatic disease.  So we know that about 80% of non-muscle invasive bladder cancer is non-muscle invasive bladder cancer of which about 70% is the Ta type tumor.  20% are T1 tumors, a special category, and about 10% are CIS.  It is difficult to predict the natural history of these tumors, especially the high-grade ones, things that we think about, and these are going to be common themes, a recurrence, the risk can be as high as 70%, and tumor progression, which can be 30, even higher, depending on the risk strata and we’ll talk more about that when we talk more about risk stratification with the non-muscle invasive disease.  

This was a study that Harry Hurr [phonetic] got me interested in early on, and it was the only study and may still be one of the only studies where they tried to show that BCG can reduce progression of disease, but it was a small study looking at TUR vs. TUR and BCG in these high-risk patients.  About 50% ultimately progressed, and 20% formed upper track tumors, and that data is pretty true today for a larger series.  About a third of non-muscle-invasive patients ultimately undergo a cystectomy, and when we follow them out for a long period of time about a third of them actually died of their disease, and that is still true today too.  So it’s sad to think you have somebody with a non-invasive, high-grade tumor contained within the bladder.  And then flash forward, and they are going to die from their disease.  So we definitely have some challenges to try and identify those patients.  They require lifelong surveillance in their bladder and periodic upper tract imaging as well.  

We know that BCG is a standard of care.  Most intermediate patients will get that, and all high-risk patients will be recommended.  It is superior to chemotherapy in the high-risk patients.  The data is supported by large, randomized trials, as well as meta analysis, and it is endorsed by the guidelines, better results with longer therapy including maintenance therapy.  This study will be debated a little bit later, but the SWOG8507 was the U.S. study that looked at the value of six weeks as compared to longer maintenance essentially every six months after you get going with three installations every six months, and showed clearly that there was benefit to the longer duration by about 20% in terms of recurrence free survival, and then it was durable out to about five years.  That kind of set the stage, but the problem is that not everybody responds to BCG.  Some patients will recur, in fact maybe up to half of the patients may if you follow them long enough and monitor them, and you can only salvage a certain percentage of them, maybe a third of them with additional BCG therapy, so if we don’t control the bladder, the bladder can be, you know, we can lose that battle, and these patients can ultimately die.  It’s even been argued with each failing therapy the risk goes up maybe as much as 10%.  What are the potential causes of failure?  They are many.  So this is just a list, but they include sometimes we think maybe it is the host.  The patient himself can’t mount the defense needed from the immune-based therapy, perhaps inadequately resected tumor or unidentified flat tumors.  What about the tumor itself?  Maybe it doesn’t have the antigenicity to stimulate the immune system.  The treatment schedules, and the way we administer the treatment can also factor in.  So there are a lot of ways that patients become BCG failed or BCG unresponsive.

Getting back to these definitions, there are—the World Health Organization and others have kind of come to some consensus on some of these statements, but it is mostly an expert opinion.  Intolerant though means that for some reason they just can’t handle the therapy.  So you are trying to give it, and they are having side effects, and so they have to stop.  A resistance is really just where they have—I just had a patient on a new Tokyo trial who developed a low-grade recurrence after his six-week induction.  That patient can then still go on to get additional therapy because the tumor itself usually disappears, and they get a response later, but it is a—they have a lesser grade or lesser stage, and it is improving.  A relapse is somebody who develops tumors in their bladder after a long time since they have seen the BCG, and then the truly refractory ones are the patients failing at the six-month mark despite usually two induction courses or induction plus maintenance.  

This is some of the information why we believe that a single six-week course of BCG is not enough.  This was Sloan-Kettering’s study where they looked at about 100 patients and couldn’t really differentiate the proportion that are going to recur with the early look at three months.  The separation of the curve really was when we looked at what was happening to them at six months, and so most of the time and the only exception is really the T1 tumor, those patients deserve more than six weeks.  Think about if you’ve been smoking for 65 years, a pack or more a day, and we give you six weeks’ of therapy.  It’s probably not enough to reverse that.  

Ultimately determining when a patient has failed is a shared decision between urologists and the patient.  So some people don’t like that, but I think it is true that we have to sit down and talk to them about when it’s not working.  Sometimes it is a judgment call.  There is a move afoot to incorporate some of the urinary markers into the treatment algorithm and perhaps they can predict the failure before we have to wait for it to recur.  So this was a study by Ashish [phonetic] Kamat and his group at MD Anderson where they looked at the role of Eurovision [phonetic] FISH testing at the six-week mark.  So they are coming in to get their last BCG.  They send the FISH test.  Many times it’s very difficult to use cytology in that setting because it’s going to be atypical.  Then the results of the FISH test were predictive of what was to happen later, and so you can see here both the top-line is recurrence, and the bottom rows are progression.  Those patients that had a positive FISH as shown in the red had a worse outcome for both recurrence and progression when they were getting near the end of their BCG.  So you could imagine that could be used as a tool.  Some people may decide, oh, well I’m going to take them to the OR because we’re going to biopsy something as opposed to just doing a surveillance cysto in the clinic.

So molecular failures are being tossed around as a possible way to switch gears.  It still to my knowledge hasn’t been used to enroll patients in a prospective clinical trial yet.  

We know that radical cystectomy is certainly an option for patients who failed intravesical therapy, BCG with high-grade disease.  However, most patients would like to avoid cystectomy due to the morbidity and the life-changing way that it affects you so we need to try and come up with regimens or treatments that may salvage some of those patients.  So the strategies can be divided up into different groupings, but generally I like to think about it like better surgery, enhanced detection, more complete fulguration perhaps of CIS.  Another option would be better agents, so if we identify that BCG is not working, how can we administer something that is more effective?  Better delivery systems, and we’re really behind on this in the United States, but it’s coming soon, better ways to deliver the intravesical chemo and better diagnostics or enhanced predictive tools so we know when to switch gears earlier rather than waiting another three to six months for things to continue to happen.  

We’ll see this throughout some of the other talks, but the use of enhanced detection with things such as photodynamic blue light.  Hexvix is the commercially available Cysview in the United States has a way to detect not only enhanced papillary tumors, but CIS, and those CIS lesions can be identified and fulgurated, and that can also in and of itself improve outcomes.  These are some of the data from the studies looking at this, and you can see for both Ta tumors, and CIS, there was enhanced detection over conventional white lite.  These were pretty well conducted studies.  There have been many of them now including the U.S. that got its registry and approval here.  

Another technique that can be used is narrow band.  So narrow band just really relies on differences in wavelength absorption of blood vessels at the capillary level.  It is shown here.  You can see that the deeper areas present more like a green, and the supervision layer, the vessels in the superficial layer are more brown, and so you might be able to pick up smaller tumors and patches of small tumors with enhanced detection over white light, and although their studies are not as robust as the blue light studies you can see that there were enhanced detection methods and high negative predictive values if you had a  negative narrow band imaging surveillance study.

Better agents include use of other treatments beyond BCG.  So unfortunately the one that has its FDA approval is a really old drug as David was alluding to earlier.  There’s really not a lot of new drugs yet in the space and valrubicin had its approval since 2000.  But initially it was a short win, a short-term win, about six months.  They had about a 21% response rate.  

As patients were followed out longer though at least with six weeks of therapy, it—the response waned.  Most people would probably redo the study with maintenance chemotherapy if they were doing it today, and the other problem with this is it’s very costly.  So with all of the agents that are out there, it is probably the most expensive one, so it hasn’t really fallen into favor for the mainstream despite the enthusiasm.  It is FDA approved for CIS, so that’s key.  If you are going to use this drug, you have to make sure you code it as CIS or you won’t get reimbursed, and the patients have to be unwilling or unfit to undergo a radical cystectomy.

Then we get into some of the other agents that are out there, so pretty much anything that has been used for systemic therapy for invasive bladder cancer has been looked at for non-invasive, and gemcitabine would also fit that mold.  The best probably gemcitabine data for BCG unresponsive patients is this phase 2 study done by southwest oncology group.  What was interesting was they sued the gemcitabine, not just the six weeks, but they used monthly maintenance.  We have patients that are on this now, and I’m not sure how long to continue their maintenance because they have done so well, and it’s very unlike Mitomycin it’s very easy for them to receive this therapy, and we don’t see sort of that chemical reaction that you get with some patients when you use Mitomycin, but this is an option for patients who are failing, and it has somewhat durability to it as opposed to the valrubicin.

Other taxanes are being looked at, and some of these studies were done early on for the BCG failures.  Docetaxol had a study with 54 patients looking at it as an option, so that may be something you would use.  We tend to use more gemcitabine, but there is no reason you couldn’t, and not only could you use docetaxol, but you could use paclitaxel too.  Similar somewhere in that 25 to 30% range for disease-free status, and some of these studies go out beyond a year.  So that is not bad for some of these salvage chemos.  

BCG interferon was kind of hyped up early on 10, 15 years ago we were a little more enthusiastic about it.  We still do sometimes add interferon to the mix, but these are the trials that were done.  The problem was in the day when these were being done, they were just putting all kinds of patients in.  If you’d had a whiff of BCG, you were BCG-failed so you would get into the study.  They tried interferon by itself as a stand-alone.  It didn’t seem to work at all, and it is expensive, so if you are going to use it, it is probably going to be 50 million to 100 million units in combination with BCG, but this large multi-center phase 2 study demonstrates the complexity.  

If you were to look at that and say, well, I’ve had more than two courses of BCG, then the response rates are going way down.  If you failed at that six-month part, the earlier you failed, then the responses aren’t so good.  So if you took all-comers, you might say that it looks like it works pretty well, but when you really ferret out the patients that are truly today’s definition of BCG unresponsive, the results look pretty modest.

So probably the best definitive therapy as I’ve talked about is to put the bladder in the bucket.  Formalin works quite well, but the problem is it is a morbid procedure, it is life-changing, and many of these patients are older, and frail, and really can’t undergo that.  So then we have to look beyond that at some other strategies, and some of the things that are evolving are these better delivery systems.  Hyperthermia I think is going to come and be an interesting addition.  It has been used a lot in Europe.  It has been slow to come forward because of the studies and things that need to take place to get it here, but it has sort of a dual mechanism of action.  It heats up the therapy, and the heat alone can cause tissue destruction.  It also enhanced the penetration of chemotherapy to get it deeper into the bladder, so that also is thought to promote tumor ablation as well as to reduce it, so this is one example of a study that was done using Mitomycin in BCG failures where they reported probably too good of results, but somewhere around 50% at two years.  There are a couple of different delivery systems out there.  The one that had the most early data was this microwave catheter that you put in that has little antennas on it to heat and to measure.  It is a little cumbersome, and I think that there have been some concerns about complications in the urethra with it.  The one that is also available that may not have that same problem is basically a recirculator like a blood warmer, and so that one is getting some traction and has a lot of studies coming forward.  And they are mounting their ability to get FDA approval in the United States looking at that.  I have no experience with photodynamic therapy, but it is used in Europe.  They use a photosensitizing agent.  I believe it’s a systemic agent, and then within the bladder you activate the light, and it destroys the tumor.  Again, no experience with it here in the United States so I think it’s on the menu, but it seems a little further out of reach than the hyperthermia.  

BCG unresponsive clinical trials are really the name of the game because we need new agents, and so many of you probably have seen or refer patients for these trials.  We have some of these agents at our place too, so there’s viral vector-mediated ways to try and enhance cytokine production in the bladder, so that is the FKD/SUO clinical trial.  There is a pseudomonas toxin.  That is the Viventia.  I am not a fan of that although we do participate in that.  It’s really cumbersome.  We have treated I think six or seven patients with atezolizumab.  We were doing some of the phase 1 studies, and now here are several other immune-based therapies that are coming forward looking at that and its role in CIS particularly in patients who are BCG failed and other trials out there, but really that is the best way to go forward with this, and if they are candidates and have access to the clinical trials, that is probably what I would recommend for them.  

Better diagnostics are on the horizon too, and it gets back to we talked a little bit about the FISH testing, but certainly we—I’ll just breeze through this pretty quick.  We know there are lots of products in the Urine available to us to assess the response to the therapy such as BCG, and so some of the work that is being done is looking at just the byproducts of that cytokine response looking at whether or not it looks like they’re getting a good response to the therapy, and one of the—this is just an example using IL-8 after the six BCG showing correlation with recurrence, but they put a whole bunch of these together into a nomogram.  I believe they are working on a commercial product for this.  That would be a little kit you kip the urine in, and you would get an answer.  The hope is that we would have some better diagnostics coming down the road.  

So the best recommendations for these BCG-failed patients are I think to repeat their TUR, to go in with some enhanced imaging to at least to the best of your ability make sure you have eradicated all of the tumor, fulgurate any abnormal appearing areas and biopsy.  If it has been more than a year since they’ve seen BCG, and they tolerated it well, certainly you can go back and re-introduce BCG.  In fact we have had to do that in a lot of patients because we—the clinical trials mandate that they have to have seen BCG within like six months or nine months of enrollment in many of these people, their ship sailed on the BCG a long time ago, and they are not written for chemotherapy.  And then we actually are seeing, you know, patients are salvaged just with the BCG alone, but if it has been less than a year, then you need to consider a more aggressive therapy.  Cystectomy is certainly something that needs to be discussed with them, and if they are unwilling or unfit to undergo a cystectomy clinical trials prefer and they can move into some of the intravesical chemotherapies like gemcitabine, Taxotere, and things such as valrubicin for CIS are available.  

This group remains poorly defined.  I think we are only at our infancy of trying to understand the disease process.  The best salvage therapy is yet to be determined with modest response rates as I showed you with some of the various agents.  Risk of progression is there, and so these people are on the clock so to speak increasing the risk with each progressive round of failed therapy, and I’ve already told you that cystectomy is an option.  

Looking forward markers to predict response or failure so we can more quickly switch gears, better strategies to eradicate it, more effective, less toxic regimens, better delivery systems, perhaps the hyperthermia will be a step forward, and then a more personalized approach, which we are trying to do for all tumors to try and tailor the therapy to the individual cancer. 


Michael S. Cookson, MD, MMHC, is Professor and Chairman of the Department of Urology and holds the Donald D. Albers Endowed Chair in Urology at the University of Oklahoma Health Sciences Center in Oklahoma City. He has authored some 240 peer-reviewed journal publications as well as more than 30 chapters of various textbooks, and he is nationally recognized for his outstanding contributions to urologic oncology. Dr. Cookson completed his Urology Residency at the University of Texas, San Antonio, and completed his Urologic Oncology Fellowship at Memorial Sloan-Kettering Cancer Center in New York. From 1998 to 2013, he served as the Vice Chairman of Urologic Surgery and Director of the Urologic Oncology Fellowship Program at Vanderbilt University. Dr. Cookson has devoted much of his academic career to the management of patients with urologic cancers, with a strong emphasis on clinical guidelines, education, and evidenced-based medicine. He was a member of the AUA/ABU Examination Committee for 10 years, serving as Oncology Consultant and Pathology Editor. He also serves on the ABU Oral Examination Committee. He is a Co-Founder of the Oncology Knowledge Assessment Test (OKAT), an SUO-mandated examination. He also served as Chair for the OKAT for 5 years. In 2011, he received the President’s Distinguished Service Award from the SUO for educational contributions. He received the 2018 AUA Presidential Citation for Outstanding Service for his role in the development of the OKAT and as Chair of the Castration-Resistant Prostate Cancer Guidelines Committee at the AUA 2018 Annual Meeting. Dr. Cookson has previously served as a member of the AUA Guidelines on Localized Prostate Cancer Committee. Dr. Cookson is currently serving out the 2019-2020 term as the SUO President.