Listen in as Joseph and Nathan talk with Professor Maurizio Brausi about his landmark paper “Final Results of an EORTC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guerin in Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 Years of Maintenance”.
Professor Maurizio Brausi completed his MD in 1976 at the University of Modena and went on to specialise in Urology at the University of Bologna, Italy. He did further specialty training at the University of Modena in Oncology (1983) and General Surgery (1988). Since 2000, Professor Brausi has held the position of Teaching Professor of Urology for Geriatric Medicine at the University of Modena as well as Teaching Professor of Urology-Oncology at the University of Novara from 2002.
He has been a member of multiple Professional Advisory Committees including National Coordinator (Italy) of the European Organisation for Research and Treatment of Cancer Gen- ito-Urinary (EORTC–GU) Group (1992–2000); International Consultation on Bladder Cancer (1992, 1997, 2004); International Consultation on Prostate Cancer (1996); Board Member European Society Urological-Oncology (ESOU) 2000 until present; and Board Member of Strategies Planning Office (SPO) of European Society of Urology (EAU) 2006 until present. He has published numerous journal articles and many book chapters.
TALKING UROLOGY podcast transcript
Talking Urology Landmark Paper – Series 2, Episode 3
I’m Joseph Ischia
I’m Nathan Lawrentschuk.
Joseph: And we’re Talking Urology where we hunt beyond the headlines of the landmark urological papers to help doctors and allied practitioners develop a deeper understanding of the literature to ensure we apply the right evidence to the right patient. Today we will be looking at a remarkably important paper on BCG, which was published in European Urology in 2013. The first author was Jorg Ottens from the Netherlands and the paper was titled, “Final Results of an EORTC-GU Cancers Group Randomized Study of Maintenance Bacillus Calmette-Guerin in Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Urinary Bladder: One-third Dose Versus Full Dose and 1 Year Versus 3 Years of Maintenance”. It must be shorter in its native Dutch or Italian! Today we will be bringing the literature to life with our international expert and man of mystery Maurizio Brausi who was second author and one of the PIs. He currently works in the Ramazzini hospital in Modena, Italy, a beautiful part of the world.
Nathan: I think this is a superb paper and a hugely important one. We all see dozens of bladder cancer patients every month, we subject lots of them to BCG but if we’re being honest, none of us are really sure what the optimal dose or duration of BCG should be. We also don’t know if we can reduce BCG’s toxicity or side effects by adjusting the dose.
Joseph: I think that’s the first time I have ever heard you say you don’t know something Nathan! Are you sure you’re feeling OK?!
Nathan: I’m serious Joseph. There’s so much we don’t yet know about BCG. But conversely, I can say that there are some things we do know about BCG. So, before we dive into the paper, which investigates whether we can reduce the dose or the length of maintenance, let’s just do a quick recap of the benefits that have been shown for BCG right after we get back from thanking our sponsor.
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Joseph: Welcome back and thanks to our sponsor whose generous support make these podcasts possible. So let’s start with a quick recap of the effectiveness of BCG. There was a very nice study by a Swedish group, Thiel et al, published in World Journal of Urology in 2018 that showed after 15-year follow-up of patients with high risk NMIBC who had undergone treatment and maintenance with BCG, there was a 60% reduction in recurrence and a 48% reduction progression. But interestingly, the authors did not find a reduction in cancer-specific mortality. It is worth noting that in this study, they did not find a significant association with BCG treatment and decrease of progression in the T1HG tumours with concomitant CIS subgroup- i.e. the highest of high risk group.
Nathan: There are some papers out there which do suggest a reduction in mortality in BCG patients, but the jury is definitely still out on this one and indeed Cochrane reports from 2003 and 2011 failed to see any effect of BCG on cancer-specific mortality.
Joseph: Huh. But at least we reduce the morbidity associated with recurrent and progressive disease. And as with all good treatments, it comes at the cost of some side effects. Side effects of BCG are quite common and can be divided into local and systemic. The incidence varies widely according to what you read. The commonest local ones are bacterial +/- chemical cystitis (30% of patients), haematuria (20%) and urinary frequency (20%). The most frequent systemic side effects are typically general malaise (15%) and fever (10%). Full blown BCG sepsis is thankfully very rare, roughly 0.5% incidence. There is a long list a rare and weird complications but we will let you look those up for yourself.
Nathan: Or you could self-administer BCG and experience them for yourself! But let’s get back to the study. This was set up as a non-inferiority trial where the aim of the study was essentially to establish the optimal dose and duration of intravesical BCG in the treatment of non-muscle invasive bladder cancer.
Joseph: That’s right. Within 14 days of TURBT, 1355 patients from 51 centres in 13 countries were randomized to one of four groups – 1/3 dose with 1-year maintenance, full dose with 1 year of maintenance, 1/3 dose with 3 years of maintenance and full dose with 3 years of maintenance. Oncotice was the strain used. Cystoscopy and cytology were repeated every 3 months during the first 3 years and then 6-monthly thereafter. The primary endpoints were disease free rates at 5 years and toxicity. Median follow up was 7.1 years.
Nathan: Before we look at the results, we wanted to ask Maurizio about the inclusion criteria and some of the methodology. Maurizio, why did you exclude patients with a solitary Ta high-grade cancer?
Maurizio: This is a very, very good question. At that time, it was 1996 when this study was conceived, and I was the chairman of the superficial cancer committee and we tried to astute Ta because at that time we didn’t know if Ta was equal to T1. That’s the only reason. But they could be included also, there’s no reason why not to.
Joseph: And Maurizio, you use the Oncotice strain in this study, do you think we can now generalise these results to the other strains?
Maurizio: There is some data showing that Connaught is better than Tice. But the data has some flaws, the number of patients included is not so high, coming from only one centre, and just to be very, very direct; I’m doing a study at my centre comparing two different strains of BCG – Connaught versus Tice. I don’t think it’s going to have different result, but in this case, I would say – at that time we thought OncoTice was our sponsor and so we decided to use OncoTice. But I don’t think there’s going to be any difference.
Joseph: In the preparation of the trial, it was decided that a decrease of 10% in the disease-free rate at 5 years was going to be a limit for non-inferiority. Therefore, if the difference between the new drug and the active comparator does not exceed a prespecified margin, noninferiority can be concluded. Now the trick is defining an appropriate noninferiority margin which is one of the most challenging aspects in the design of noninferiority trials. Nevertheless, studies looking in to this concept of the size of the allowable margin have shown that the method of determining the margin has not been mentioned in more than half of the published noninferiority trials.
Nathan: Interesting. So what do we do?
Joseph: Well, regulators have recommended that the margin should be defined based on statistical considerations and clinical judgement. And whose better judgement could we trust than the authors of this paper. So firstly, Maurizio, in your study, how did you choose 10% and secondly, after initially accruing the required patients, you and Jorg Oddens did a central review and on-sight audits that lead to the data from six centers being completely excluded. What was the issue?
Maurizio: Again, at that time it was 1996, we thought that 10% was okay. Our research investor said okay we should go for 10%, but still we needed 1300 patients, so it was big numbers.
The issue was the quality of the data. The trial randomised 1490 patients or so and unfortunately there were some centres that were visited, and the quality of the data was not very good and so we decided to excuse them.
Joseph: So it was like an episode of the Apprentice- You’re fired. Maybe that would sound better in a Dutch or Italian accent.
Nathan: I suspect not. Let’s now take a look at the results. The key finding was that the null hypotheses of inferiority of the disease-free interval for both 1/3 dose and 1-year treatment could not be rejected. i.e., they did appear to be inferior. Testing for superiority, which we remind you was not the primary objective of the trial, the differences in the disease free rate were likewise not significant for either the dose or duration of maintenance.
Joseph: Ok. So the study did show that based on the primary end point of disease free interval, the 1/3 dose for 1 year is suboptimal compared with full dose for 3 years. The authors also found that for patients with intermediate-risk urothelial cancer, that you only need to treat them with full dose for 1 year because there is no further improvement in outcome by continuing treatment to 3 years.
Nathan: That’s right. However, in high-risk patients, full dose-3 year BCG treatment reduces recurrences as compared with full dose-1 year; but there were no long-term differences in progression or survival.
Joseph: Those results are fascinating. I think they could make a huge impact in the way we now prescribe maintenance BCG. They certainly should. Blanket BCG prescribing should be reviewed and instead tailored more appropriately for the patient’s risk category. We consider reducing the dose of BCG to reduce side effects, but more recently we are using this to hekpl stretch our BCG supplies during the global shortages. This is a great study to see if this actually make a difference in the long term. So Nathan, was there any reduction in side effects in the 1/3 dose group?
Nathan: Interestingly Joseph, there were no significant differences in toxicity between 1/3 dose and full dose. A total of 103 patients (7.8%) stopped treatment due to local or systemic side effects, specifically 47 patients (7.1%) randomized to 1 year of maintenance and 56 patients (8.6%) randomized to 3 years of maintenance. Neither reducing the dose nor shortening the duration of maintenance decreased the percentage of patients who discontinued treatment due to side effects.
Joseph: Very interesting indeed. Other notable findings were that nearly 50% started but did not complete their treatment. The reasons for this were inefficacy or recurrence in 26%, toxicity in 7% and other various reasons in 17%. Nathan, we mentioned at the beginning, that BCG should reduce recurrence by around 60% in these patients. How did this study stack up?
Nathan: True to form for BCG, there was a 43% recurrence rate during the study, mostly Ta/T1 recurrences. Of the 1355 patients who were included, 91 patients developed CIS, 109 progressed to muscle invasive disease, and 67 people unfortunately developed distant mets. A total of 369 patients died, 68 due to bladder cancer. There were no significant differences between the treatment groups for the time to progression or overall duration of survival. I reckon this just emphasizes what a dangerous disease bladder cancer can be despite the best treatment in the best hands. That’s still a frightening amount of CIS, muscle progressive disease, metastatic disease and cancer-specific mortality.
Joseph: That is a very important stat there, Nathan. 13% of patients progressed to muscle invasion or metastases by 7 years in this study. Obviously, some of these were present from day one but it just took a while to become apparent. But we should also be mindful of the study we mentioned earlier that there is no benefit of BCG in very high risk T1 with CIS. These patients sound more and more like they would benefit from upfront cystectomy with extended lymph node dissection.
Nathan: I wonder if there is any evidence to the contrary. We couldn’t find any and yet we still will offer these patients BCG. But let’s move on to hear more from our expert guest. Maurizio, the final hazard ratio for a reduction in the disease-free survival was 1.15, which is more than 10%. Is that significant or is it the fact that the confidence interval crosses one make it statistically inconclusive?
Maurizio: As we state in the paper, the statistical significant differences between 1/3 dose BCG 1 year versus full dose BCG maintenance to 3 years. This is the only statistical significance we have. Already, the clear message of the study is 1/3 dose BCG for patient with this kind of intermediate high risk is not sufficient. We should use full dose BCG. And, at the end of the story intermediate BCG full dose 1-year, high risk BCG full dose for 3 years.
Joseph: That’s great to hear you say that; that really is the take home message from this paper. Maurizio, the recurrence rate was lower than you expected when you were powering the study. This is something that comes up time and time again. Why do you think we have so much trouble powering studies or predicting outcomes in these studies?
Maurizio: I don’t know really
Joseph: That is concise. I think also Maurizio you note in your discussion that the introduction of re TUR may have played a big role.
Maurizio: Yes of course. This is another very important issue. At that time very few patients received re TUR after 6-8 weeks and right now it’s going to be the standard.
Nathan: Maurizio, when you first saw the results did it change your practice?
Maurizio: Yes. As you said before, there was the tendency of using 1/3 BCG when you have some problems of toxicity and so on. But the statement was very clear – for high-risk patient you must use full dose and maintenance for 3 years, no question about it. And do not use 1/3 dose BCG because it’s not effective.
Joseph: The study specifically excluded CIS, do you think we can generalise the results of this study to CIS as well? We see quite a bit of CIS so I think this is a key issue.
Maurizio: This is another very, very nasty and important question. Actually, no. My personal feeling is, no. I don’t think there is going to be any difference because the best therapy for CIS is maintenance full dose BCG for 3 years. This is what has been done, what has been written in the guidelines and is also my experience.
Nathan: Very little wriggle room there. Let’s change direction a little bit and look at another crucial aspect of BCG treatment, namely its toxicity and tolerability. A lot of patients don’t like BCG, simple as that. In the trial there was no difference in toxicity between 1/3 and the full dose and yet, in practice, if someone is having toxicity at full dose, we’ll reduce to 1/3 dose, does this trial tell us that we don’t need to do that because there’s no difference in the toxicity between third and full dose?
Maurizio: Yes, actually you are right in certain points because some are already doing it and I think you can reduce the dose especially in this moment where BCG is not available, at least in Europe it’s very difficult to get because it BCG wasn’t produced for 3 or 4 years. So, we are trying to reduce the dose after the first course of 6 installations. So, this is a possibility.
Joseph: When we look at the SWOG data and the EORTC, only about 1/3 of patients get to 3 years of maintenance, and we always say it’s because they can’t tolerate it. But in fact, the majority of people don’t get to the end of their maintenance because they recur. We still know that around 24% of patients will suffer from toxicity or other reasons, do you think there’s much we can do to get more people through?
Maurizio: This is a very good point. BCG is toxic. This is what has been said many times, people on the podiums say I would like to have less toxic agent. However, even the first trial we demonstrated toxicity because BCG reach 30% toxicity or even more, in our trial we showed that the toxicity of 1/3 dose was not inferior to the other one. So, the question is we were better in giving BCG and explaining to patients the symptoms, so the compliance of patients was much better. This in my view is due to the experience of the urologist giving BCG and the nurses. Because the centre is very important. One of the major issues is to be in touch with the patients, ensuring patients have a number to call to get some direction.
Nathan: I couldn’t agree more Maurizio. It’s crucial for patients to have a point of contact and to know that there’s somebody out there who will listen and can understand their problems. So, in your experience Maurizio, do you have a rule of thumb for someone who is suffering toxicity? What do you do, what are your steps to get them through?
Maurizio: First of all, I see the patient personally or they see Michael Walker who is in charge of the hospital as the BCG is given in a hospital setting, and then we discuss with the patient and we have some treatments. If they have fever more than 38 for more than 1 day, we just use normal antibiotics if they have a positive urine culture. If they have a temperature higher than 38, we use Isoniazid at 300mg per day for 3 months.
Joseph: Some people are using Fluoroquinolones as sort of like a prophylactic measure, do you ever use those Maurizio, do you find them useful?
Maurizio: Yes, sometimes we use it and it’s been reported by Marco Bell in a randomised trial that if you use quinolones during installation you can reduce the side effects. That’s very important. But, in my trial on toxicity we showed that, again the toxicity of BCG is not as high as we think
Nathan: I think that finding will surprise quite a few. I reckon there’s a perception out there that BCG toxicity is rampant. Again, changing direction a touch now, we always like on this show to pick the brains of our experts on other areas in their fields of interest. So, I asked Maurizio if he had 20 years of enthusiasm for doing another big trial like this, what trial would he set up? What does he think is the key question for bladder cancer at the moment?
Maurizio: I think one of the question is do we give too much BCG, just reducing the schedule, instead of doing 3 installation every 3 and 6 months, just reducing the schedule of BCG, just studying the immunological system and immunological response of the BCG this is another one. But, in my mind I have two big issues 1. I have always dreamed of studying oral therapy for reducing recurrence.
Joseph: Do you have any particular candidate in mind?
Maurizio: Yeah, the oral therapy is a Yakult which produced a lactobacillus and this was done in China and it reduced the recurrence, this could be very nice. And 2. bladder cancer prevention program I am following because the real question is – to prevent bladder cancer. Bladder cancer must be prevented more than diagnosed early or cured with installation. Just prevent it and avoid smoking and avoid dies. So, this is the main issue for me right now.
Nathan: You mentioned a change in the regimens from the current type protocol – a lot of people are using maintenance BCG once a month. Do you think that enough to stimulate the immune system or do you think you need multiple doses?
Maurizio: I think it could be enough. However, we do not have as you know randomised trial to demonstrate this. I know for instance in Italy we have centres where they do once a month, they don’t use SWOG for BCG treatment. Really, I think it should be enough. As I said before, we have to study Interleukin, we have to study the immune stimulators in the urine in order to know what going on after BCG and we have some data from Amsterdam. For instance, the Caroline School was the first to study this. However, I think if I had to mount a trial, I would try to reduce the administration – the schedule.
Joseph: And while they were doing that trial, I know they were looking at 1, 2, 6 month intervals.
Maurizio: Yes, it could be. However, you have to have the same patients, intermediate, high risk, sometimes you include CIS, for instance SWOG trial included CIS; and it was very interesting addition in the SWOG trial. The SWOG trial, the inclusion criteria was, diagnosis, when you treat CIS if they did respond, they go to the trial. If they do not respond they are out. So, this was a criteria. Very few people know this, but this is very important in order to realise and to evaluate the results. Because they select proper patients.
Joseph: That is a fascinating point about CIS in the SWOG trial. I didn’t know that. Cheeky but does guide us to not continue with BCG in CIS failures! Unfortunately, we’re just about out of time now. Such a pity because we could talk about BCG for a lot longer. I’m intrigued by Maurizio’s thoughts. A really interesting paper. Congratulations to all involved in the study. Like we said at the outset, it’s a topic which we encounter nearly everyday in clinical practice. It’s great to now be armed with these data. Thanks so much for joining us Maurizio – you were very informative. Thanks to Nathan too – you were less informative but thanks anyway!
Nathan: Careful! So, Joseph, can you just to recap the take home messages of this outstanding trial, the ones you really need to consider incorporating into your own practice?
Joseph: Certainly. Our five fast facts:
- There were no differences in toxicity between 1/3 dose and full dose.
- 1/3 dose with 1 year of maintenance is suboptimal compared with the standard full dose for 3 years.
- Intermediate-risk patients should be treated with full dose for just 1 year.
- In high-risk patients, full dose for 3 years reduces recurrences as compared with full dose for 1 year but not progressions or deaths.
- CIS is high risk- treat it for 3 years.
Nathan: Nicely summarized, Joseph! We’ve been Talking Urology today with Maurizio Brausi. We still have some great podcasts coming up so go to the website www.talkingurology.com.au or find us on Apple podcasts, soundcloud or wherever you find great podcasts.
Joseph: Thanks for listening. We hope you enjoyed the show. You can contact us with questions, corrections, updates, or if you have a study that shows that BCG treatment is not inferior to surgery for high grade T1 with CIS, at email@example.com. This episode of Talking Urology was written by Mark Quinlan and Joseph Ischia. Spoken by Nathan Lawrentschuk and Joseph Ischia. Produced by Joseph Ischia and Cara Webb. And of course, none of this would be possible without the generous and non-interventional support of our sponsor, Ipsen.