Optimizing BCG Therapy in Bladder Cancer: Expert Insights on Managing Toxicity and Maximizing Efficacy - Badrinath Konety & Wassim Kassouf

May 12, 2023

Badrinath Konety and Wassim Kassouf discuss managing Bacillus Calmette–Guérin (BCG) toxicity and optimizing BCG therapy in bladder cancer with Wei Shen Tan. BCG toxicity can range from local bladder symptoms to systemic effects. Patient selection is crucial in reducing toxicity, avoiding BCG in cases of gross hematuria or symptomatic UTIs. Delaying BCG and using longer intervals between instillations can help manage local toxicity without compromising efficacy. Fluoroquinolones after BCG instillation can reduce symptoms, while anticholinergics have limited benefits. Severe cases may require lidocaine-antibiotic concoctions. Dr. Kassouf highlights strategies to maximize BCG efficacy, including selective treatment for responsive patients and upfront cystectomy for adverse pathology cases. Maintenance therapy with the full dose and three-year duration is crucial for high-risk patients. Lowering the frequency of BCG instillations is less effective. Ongoing research explores BCG strains, priming with BCG vaccination, and combination therapies. Patient selection and individualized approaches are vital. Dr. Konety encourages clinicians not to fear BCG and to re-induce BCG in previous responders. Dr. Kassouf stresses proper patient selection, adherence to maintenance therapy, and developing approaches for BCG availability in areas with shortages while maintaining efficacy.


Badrinath Konety, MD, FACS, MB, President, Allina Health Cancer Institute, St Paul, MN

Wassim Kassouf, MD, CM, FRCSC, Urologic Oncologist, McGill University Health Center, Montreal, QC, Canada

Wei Shen Tan, MD, PhD, FRCS (Urol), Urologic Oncology Fellow, Department of Urology, MD Anderson Cancer Center, University of Texas, Houston, TX

Read the Full Video Transcript

Wei Shen Tan: A very good afternoon. I'm Shen Tan, a urology fellow at MD Anderson Cancer Center. Today I have with me two very eminent urologists in the field of bladder cancer. We've got Dr. Badrinath Konety, who is President of Allina Cancer Center in Minnesota, and also Dr. Wassim Kassouf, who is Professor of Urology at McGill University in Montreal. Welcome and thank you very much for joining us today at UroToday. Today our discussion is going to be about managing BCG toxicity and optimizing BCG therapy in bladder cancer. We'll start with Dr. Konety. Dr. Konety, if you could brief us about how common is BCG toxicity and is there anything that we can do to reduce the risk of patients suffering from these events?

Badrinath Konety: BCG toxicity encompasses a wide spectrum. Local toxicity is very common, between 60-70% of patients who get intravascular BCG will have some sort of bladder related toxicity, usually urgency, frequency, dysuria, even hematuria sometimes. But more systemic toxicity like fever or BCG sepsis, BCG-osis, thankfully, are much less common and maybe less than about 3% or so, and BCG sepsis is under 1%. There have been about 12 deaths reported from BCG, though they're all historic. More recently, I don't think there've been any real deaths report from BCG. So there's a whole spectrum and different incidences of toxicity.

The main things we can do to prevent BCG related toxicity is all upfront, figuring out who to give the BCG to and who not to give the BCG to. So, obviously you want to make sure that anybody who has gross hematuria, you don't really want to instill the BCG that day because that suggests that there is some venous channel open, that the BCG can immediately go into the vascular system of the patient and cause systemic BCG-osis or even BCG sepsis, which you really want to avoid.

Patients that have significant local toxicity, you can delay the BCG. You can certainly intersperse intervals of maybe 2 weeks or even 3 weeks between instillations without loss of any efficacy in the long term from BCG. So it's important to do that. We want to make sure patients don't have a UTI. Sometimes it may be confusing to see if the patient has a UTI because of the related symptoms. Culture often helps, though asymptomatic bacteriuria is really not a problem. If you just have white cells in the urine, that's not an infection. That usually means sometimes that the BCG is even working because you're recruiting white cells into the local environment of the bladder itself.

So it depends on what the situation is, but certainly patients who are symptomatic who have a UTI, avoid it, gross hematuria, avoid it, and applying very sterile technique because you don't want to cause iatrogenic infections that can exacerbate the toxicity. Those are usually the commonsense steps that you can take.

There are certain other pharmaceutical interventions you can do to minimize or at least decrease BCG toxicity. The randomized trial data suggests you can use some of the fluoroquinolones 6 hours and 12 hours after BCG instillation to reduce symptoms. I routinely do this. There have been at least two different randomized trials, both suggesting there's about a 20% reduction in symptoms if you give fluoroquinolones afterwards without any loss of BCG efficacy. Older studies suggested giving INH. One dose prior to BCG instillation sometimes helps. Again, the data on that are controversial. The randomized trial did not show a benefit using anticholinergic like Ditropan have been tried as well in a randomized trial. It didn't really show much of a benefit. So there's not a lot of things you can do.

Severe cases, you can use a concoction that includes lidocaine and some antibiotics, gentamicin in particular, ampicillin, and some lidocaine that you can actually put into the bladder itself, which can reduce some of the severe local symptoms. There's one study with a small number of patients that has used this and shown good symptomatic relief. Again, this, you should reserve for somebody who's got very severe intolerable local toxicity almost, if you can. And lastly, if patients can't tolerate BCG, don't keep punishing them, just stop it. There are other alternatives now.

Wei Shen Tan: What would your threshold be before, based on adverse events, that you would say, "I'm going to give up on BCG and move to something like Gem-Doce or something else?"

Badrinath Konety: Good question. Again, it varies from patient to patient, clearly. The toxicity tends to be cumulative. Usually they do well after the first instillation, after the second instillation. Third and fourth is where they consistently get a problem. Then it depends on what the toxicity is. If it's just a little bit of fever and it goes away with Tylenol, not a problem. But usually the reasons I stop BCG is recurrent gross hematuria, intolerable dysuria that patients are complaining about, urgency and urge incontinence in particular, if they're getting in incontinent, then I typically will think hard. We'll still try up to the third or fourth dose, and if at that point this doesn't work, we just need to stop it.

Wei Shen Tan: In your experience lowering the dose, one-third dose rather than full dose, would that have any influence on adverse events?

Badrinath Konety: Yeah, I do think that there is an advantage to lowering the dose. You can go to one-third, I've even used one-tenth, and there have been literature reports of up to one-one-hundredth that can be used, but obviously there's some sacrifice and efficacy you're using. Previously, when interferon was available, we would combine BCG plus interferon in order to offset some of that potential loss of efficacy. But recently I tried to do that on a patient, apparently, interferons off the market, alfa-2B, so I couldn't get it, to be honest. So now we have to really switch, at that point, to Gem-Doce or some alternative.

Wei Shen Tan: Okay, great. Thanks a lot for that. We're going to switch now to Dr. Kassouf. Dr. Kassouf, what is your approach in terms of trying to maximize the efficacy of BCG?

Wassim Kassouf: There's a couple of things we can do. I think the first thing, we don't have to treat all non-muscle invasive diseases equally. So if we try to pick the patients who we know, they're not going to respond to BCG, for example, patients with adverse pathology. So if you look at all the guidelines, patient with T1, high-grade, multifocal large, concomitant CIS, lymphovascular invasion, variant histology, these patients, some will blow through BCG and progress because they don't respond to BCG, and some are actually are under-staged. If we can cherry-pick these patients an advocate for an upfront cystectomy, then you kind of enrich the denominator into patients who will likely more respond to BCG.

In my practice. I think the two important features that I push for upfront cystectomy is patients with varied histology, micropapillary, sarcomatoid, plasmacytoid, once in a while I see T1 with plasma. These things, I'm not comfortable treating conservatively and I push for an upfront cystectomy. Patients with lymphovascular invasion, same thing, particularly if you have a reliable pathologist, because that could be tricky depending on the expertise of pathologist.

Other adverse features I would say that are listed in many guidelines, I often dictate my management depending on the restaging of TURBT, and take it from there. I'll say, risk stratification will be an important thing to enrich the patients who will respond to BCG, then after that, there's various options on the way we administer BCG that has been shown to improve efficacy. Number one, maintenance therapy. Don Lamm's SWOG trial have showed that if you give maintenance therapy up to 3 years, you improved the recurrence-free survival and the [inaudible 00:07:51]-free survival, and became the standard of care in patients with high-risk disease.

Number two, what about dose and duration? The EORTC trial randomizing approximately 1400 patients evaluating the dose, whether it's one-third versus full dose, and evaluating the maintenance duration, whether it's 1 year versus 3 years, found that if you compare the 3-year full dose compared to the 1-year one-third dose, the 3-year full dose have a significantly improved disease-free rates. And when they looked at this sub stratification, in high-risk patients, the full dose 3 years benefited the most, and intermediate risk, the full dose 1 year, had a similar efficacy to the full dose 3 years, and hence the guidelines advocating for a 1 year rather than 3 year maintenance in the intermediate risk. So in terms of dose and duration, this trial shows for high risk, at least if you want to optimize BCG, give the full dose and three years if they tolerate it well.

Now, the tolerability, as Dr. Konety was mentioning, if you look at the SWOG trial, only 16% tolerate the full three years. But I think this is likely a low number. When you look at the EORTC trial, in those who do not recur, approximately 90% of patients tolerate the maintenance regimen. So I believe that the maintenance is much more tolerable than we thought it was in the past.

The other thing is, particularly in light of BCG shortage, people have looked at maybe decreasing the frequency. Could we do that without compromising efficacy? Well, that was answered recently by the German trial. Grimm et al, published that 2 years ago in European Urology, evaluating a similar frequency as the Lamm protocol compared to a reduced frequency. And that reduced frequency is induction course, namely 3 weeks rather than 6 weeks, and the maintenance cycles were 1 week per cycle versus 3 weeks compared to Lamm. That, actually due to the interim analysis, closed early, because showed that the Lamm frequency protocol was superior in terms of recurrence-free survival. So we should not reduce the frequency. We should advocate for a full dose and three maintenance in a high-risk patient population, and pick those patients who would likely benefit from BCG and weed out those who are likely going to be under-stage or blow through the BCG therapy.

Now, there's a couple other factors that we think about that I would say they're not answered right now. BCG strain. Historically, we've all thought that all BCG strains have similar efficacy. This is not clear at this present time. We do know there's a trial that was published back in 2014 in Switzerland evaluating the Connaught versus OncoTICE®. Now, this really evaluated those patient populations that got induction, of course, without maintenance therapy. It showed that the Connaught strain seems to be a bit more efficacious than the OncoTICE®.

Now, the Svatek trial that is awaiting readout is evaluating that question, but assessing whether the Tokyo strain is any different than the OncoTICE® strain. That will give us and shed some light in terms of the impact of BCG strain on efficacy. They're actually also evaluating the effect of priming, and that should be interesting to see if priming can yield better results or not.

Lastly, adding on BCG, the last 50 years I say, the first patient that was treated with BCG back in Kingston, Canada was actually 50 years ago. So that's the 50th anniversary of the first patient getting treated with BCG. We haven't really done a lot better beyond BCG. There's a lot of trials evaluating the impact of adding IO to BCG in the naive setting, in the exposed setting, that will remain to be seen if it's going to change the standard care. But we do know we could improve BCG efficacy, particularly if you look in the BCG unresponsive state adding interleukin-15 superagonist, the N-803 or QUILT study, have shown some efficacy in combination with BCG. However, keep in mind, if you use that alone, the interleukin-15 superagonist, their complete response is suboptimal at best. So many things left unanswered, particularly on the strain and particularly on combination with other stuff.

Wei Shen Tan: In terms of priming, I imagine, are you referring to BCG vaccination with BCG itself, and what's the data for that? Also, is there anything out there to predict response to BCG that you know of?

Wassim Kassouf: That's an interesting question. There was a nice paper by Matthew Albert evaluating it in mice, priming the mice with BCG subcutaneous, showing that the efficacy of BCG was much better when these mice were primed. These are preclinical data. I think clinical data will wait to see what the 1602 SWOG study, whether this does impact efficacy or not. There are several studies evaluating whether we can predict response to BCG. T-cell exhaustion pathways have been shown to be associated with that. All these need to be validated in a prospective fashion before we actually consider even using it in the clinical setting.

Wei Shen Tan: What are your thoughts regarding historic data that was published from Italy of alternating BCG with EMDA mitomycin? The data was quite promising, except it just never took off and no further validation trials were done in it. What are your thoughts about alternating EMDA with mitomycin or chemotherapy with BCG?

Wassim Kassouf: Conceptually, it makes sense. The data behind it is showing that an enhanced tissue penetration of the chemotherapy and durability of that as well. I think you're alluding to the Lancet Oncology paper randomizing patients to BCG versus BCG plus EMDA. We've used that, actually, in our patient population back in McGill, and the results seem good. I think the issue right now is they do need a special catheter for administration of the EMDA mitomycin and the company has ceased to produce this catheter. So I'm not aware of that approach being still utilized elsewhere.

Wei Shen Tan: Great. Finally, Dr. Konety and Dr. Kassouf, any final words on first the toxicity that you want our audience to be aware of, key points, and also, of course, efficacy? If you could summarize what we've discussed today.

Badrinath Konety: I just want to add one thing about toxicity. Historically, we've always been afraid of using BCG maintenance and the compliance with BCG maintenance, especially in the United States, was really terrible for a long time for fear of toxicity. Most of this was based on the SWOG trial and that 16% tolerability in the long term. But one thing to keep in mind is that trial also used subcutaneous BCG along with intravascular BCG in terms of maintenance, so I don't know whether that played a part in the increased toxicity or not. The EORTC trial clearly has answered that to a large extent.

I think main thing I would like people to take away is we shouldn't be afraid of BCG and BCG maintenance. That is standard of care and that's what they should do. Most people tolerate it pretty well. Actually, most recent data, there's some nice data coming out of Europe as well, follow up studies, which suggests that with maintenance doses, even if the induction has resulted in some toxicity, with progressive maintenance doses, the tolerability of BCG actually increases and patients do quite well. And we should also not be afraid of patients who have had BCG before and then have a good response, have a recurrence, and you re-induce them with the BCG, there's not going to be a risk of increased toxicity. So I think people should think carefully about avoiding BCG in some patients just because they had a little bit of toxicity and have a slightly higher threshold.

Wei Shen Tan: Dr. Kassouf?

Wassim Kassouf: I think, in brief, pick your patients properly. Patients with adverse features, discuss the merits on upfront cystectomy, and if you want to give BCG for high-risk disease, make sure you give the maintenance therapy. Don't reduce the frequency and full doses if possible. Now, in Canada, we're fortunate that we don't have BCG shortage because we have another strain available on the market, but I think the challenge is in many areas of the world where they have BCG shortage, you need to kind of develop an approach to increase the pool of patients getting BCG, while trying to assess how you can not impact on efficacy.

Now the SUO, AUA, EAU, the Canadian Urological Association have all put out guidelines in terms of how you manage this, whether you want to reduce the maintenance to 1 year in the high-risk patient population, whether you can give a full dose with induction and give a one-third dose with maintenance. All these strategies are perfectly reasonable if you want to increase the pool of patients getting BCG, because at the end, you'd rather have more people getting BCG for high risk than less people getting it, but with the maximize the maintenance regimen.

Wei Shen Tan: Great. Thank you very much you all for your time. Thank you.

Wassim Kassouf: You're welcome.

Badrinath Konety: Thank you.