Ananya Choudhury: Thank you so much for inviting me to talk.
Leslie Ballas: You are here at the GU ASCO symposium and presenting an educational session on radiation in non-muscle-invasive bladder cancer. Tell me, where are we with that?
Ananya Choudhury: Yes. I'm really excited that the organizing committee have invited me to talk about the role of radiation for non-muscle-invasive bladder cancer. It's something that's a little bit different. We know how important radiation is for muscle-invasive bladder cancer. And I know, Leslie, you and I have been banging that drum right across the world for many years now. And it feels like sometimes we're getting somewhere. So we've decided to pivot and look at the role of radiation in non-muscle-invasive bladder cancer. And I think this is really interesting because if you look at the data that's out there, people have been interested in whether radiation could be used to treat non-muscle-invasive bladder cancer for many, many years.
In fact, there is data from a randomized controlled trial done in the UK in the 1990s where they took people who had non-muscle-invasive bladder cancer, some of whom were BCG naive, others were BCG unresponsive. So a real mishmash of patients and randomized them to standard of care, which wasn't surgery, but any other standard of care versus radiotherapy alone. The answer from the study wasn't definitive. What it showed was that the Kaplan-Meier curves were actually banged on top of each other, which suggests that for people who haven't had BCG, that even radiotherapy alone could be a potential treatment option.
But the study took a long time to accrue. It ended up being underpowered for the primary objective. And so radiotherapy didn't become any sort of standard of care in either population. And I think that's where it was left for a long time. And the challenge then was that whenever we discussed the role of radiation, we had to look at small studies or subgroup analyses from clinical trials or retrospective theories, which just are full of confounders. And so I think this has been an area of debate between people like us who are advocates of radiation for patients who are going to benefit from it, and potentially our surgical colleagues who obviously need to be convinced sometimes of the role of radiation.
There's been a growing interest in the more recent years with phase two studies being published showing, again, that modern radiotherapy. So what I mean by modern radiotherapy is modern techniques, but also the use of radiosensitization alongside the radiotherapy. And that the use of these modern techniques could actually be helpful for people with non-muscle-invasive bladder cancer. So tomorrow I'm going to review all the historical evidence, bring people up to date and make the case for why we should be revisiting radiation for non-muscle-invasive bladder cancer.
Leslie Ballas: The non-muscle-invasive bladder cancer space has exploded in terms of different treatments. It's not just BCG. There's all sorts of other options for patients. Where do you integrate radiation in that timeline of all the different potential options?
Ananya Choudhury: So that is a really pertinent question, Leslie. And I think it's a very difficult one to answer. Whenever you get an explosion of treatments in an area, how do you sequence them? How do you compare different results and cross-correlate different studies to try and work out the best paradigms for patients is a real minefield. I think it's important for us to explore radiation because first of all, it's been around a long time. We're very comfortable with knowing what we can do, but also what we can't do. I think people who have experience of using radiation in bladder cancer are able to select the right treatment for the patient. And we all know that there are no treatments that are suitable for every single patient who walks into our clinic. So it has been tried and tested and we know about it. We know what the long-term consequences are. We know what the short-term consequences are.
The other thing about radiation compared to a lot of the newer agents is it's actually cheap compared to a lot of the agents that are being promoted for non-muscle-invasive bladder cancer. And although maybe in some healthcare systems or to some people, cost is not the most important thing, I think those of us who do clinical trials, we want our treatments to be suitable and available right across the globe. I know that you feel very strongly and I feel very strongly that the research that we do is not just applicable to high-income countries, that people in low-middle-income countries, people in different healthcare settings where maybe cost-effectiveness is as important as efficacy should be able to have treatments for their patients as well. And I think radiation does that. I mean, don't get me wrong, there's still plenty of the world that should have access to radiation and doesn't.
So by no means is this going to be a panacea, but there are definitely going to be some healthcare systems and some patients who will not be able to access many of the new pharmacological treatments that will end up being very expensive and also have unknowns about their toxicity. I mean, checkpoint inhibitors, I think are a great example. We've been using checkpoint inhibitors in other disease sites for many years, but most commonly we've been using them in the non-curative setting. So what the long-term consequences are of using them in a group of patients who should not only be cured of the disease, but where the disease should affect their overall survival is quite an unknown. And I think maybe sometimes we should be mindful of that. So radiation is going to be something that if it works, we can give everywhere and anywhere.
Leslie Ballas: Non-muscle-invasive bladder cancer commonly coexists with CIS. And there is sort of this classic teaching based on reanalysis of RTOG and MGH bladder preservation trials showing that perhaps radiation is not as effective in patients with CIS. Should those patients be excluded in the non-muscle-invasive space from getting radiation?
Ananya Choudhury: I don't think they should be excluded. I think when you do a deep dive into the data, even though the data is as good as the data can be, it is still not prospectively acquired robust data from an adequately powered phase three clinical trial, which we would all say is the gold standard for the evidence we use to practice. If you look at the data closely, then actually it's made up of small subgroup analyses. Much of the data is retrospective. It's very heterogeneous. A lot of it is very old and therefore doesn't take into account either modern diagnostic pathways or treatment pathways. And I have to admit, it isn't something that I think we should be fully convinced of. I think we need data in this area, and the best way to get data in this area is to do prospective randomized controlled trials.
Leslie Ballas: Which is a great segue into the fact that there are... Now in the US, we have an NRG trial in the non-muscle-invasive space, the PARRC trial. It is randomizing patients to either chemo radiation or immunotherapy radiation in patients who have non-muscle-invasive bladder cancer where the next step would be cystectomy. What's going on on your side of the Atlantic in terms of non-muscle-invasive bladder cancer trials?
Ananya Choudhury: So I think this speaks to the fact that there is now a reemerging interest in the role of radiation. So we have the US study that is effectively a randomized phase two study in the BCG and responsive setting. In Europe, the EORTC is opening a single-arm phase two study, asking the question is chemo radiation efficacious in, again, BCG and responsive non-muscle-invasive bladder cancer. But in the UK, we've decided to really take the bull by the horns. So we will be opening, in the next couple of months, a phase three randomized controlled trial in BCG-responsive disease. So our patients will be randomized to BCG versus radiotherapy with a radiosensitizer, and it's been designed as a superiority study. So if we can recruit to this trial and you invite me back in a few years time, then hopefully, rather than talking about the paucity of data and whether we should be treating non-muscle-invasive bladder cancer with radiation or not, I'll be able to give you data that answers that question once and for all. And then we can put to bed all of the urban myths and move on to other things.
Leslie Ballas: Well, I hope to hear about that soon. Thank you so much for joining us today. This was very educational.
Ananya Choudhury: Thank you very much.