MR: Dear colleagues, welcome to this ecancer platform and I’m happy to share the discussion today with Professor Nick James from the UK who is a team leader in prostate and bladder cancer research at the Institute of Cancer Research. My name is Morgan Roupret, I’m a urologist working at Sorbonne University in Paris, France. The ESMO, the last ESMO congress, took place in Paris ten days ago and we have the opportunity to discuss a very important topic today which is bladder cancer, but specifically preservation of the bladder reservoir in the situation where there is, indeed, muscle-invasive bladder cancer. But today if in the guidelines it’s mentioned that you should take out the bladder, there are many, many options on the table and many situations where you can discuss the possibility to preserve the bladder reservoir. We had new data from this ESMO event so thank you, Nick, for being there. Maybe we could start, if you don’t mind, with the ANZUP trial which was pembrolizumab with chemoradiotherapy as treatment for muscle-invasive bladder cancer. It was a phase II trial with some data on analysis and safety and efficacy. Which takeaways, take home messages, did you take from this trial? 

NJ: There’s a growing theme of using immuno-oncology agents and pembrolizumab is, of course, a very well-studied one of these. They’re very attractive to study in bladder cancer because they are known to be active in metastatic disease, there are also a lot of good basic biology reasons for thinking they will function as radiosensitizers and there’s a very big literature on radiotherapy plus/minus radiosensitization with chemotherapy, which is one of my main research interests. So one of the questions with these trials is if you add an immuno-oncology agent to radiotherapy, a) is it safe, b) what does the efficacy look like, and c) do you end up over-radiosensitizing, particularly bowel because bowel toxicity is one of the rate limiting things, it’s one of the key toxicities for these agents. So this trial is important because it confirms feasibility and safety for adding pembrolizumab to radiotherapy. 

There is a phase III trial with pembrolizumab, adding it to chemoradiotherapy, which I’m involved with; it’s a licensing trial. That trial is well into its recruitment without significant safety signals but there’s no data released but it has got ongoing recruitment. There were other trials in the conference as well, for example there’s one with nivolumab with a more restricted dose of radiation but, again, showing safety. So we can be pretty confident, with appropriate dose fractionation and so on, that we can add these agents to chemo-RT or RT. What we don’t know is whether it adds efficacy – that data is still to come. 

Then the second very interesting question is the nivolumab trial that I mentioned is a neoadjuvant therapy trial. So it wasn’t a full dose of radical radiotherapy, it was done prior to cystectomy. So, as you said, there’s the question of if you do a pre-op treatment with either chemotherapy, radiotherapy, IO agents or any combination of those and you get a CR, complete response, should you then take the bladder out? 

MR: Yes, that’s an interesting point because this CR endpoint has been initially criticised. We are used to dealing with trials at the metastatic phase where we display overall survival or disease free recurrence. So initially CR, I would say people were a bit dubious around it. But I think it’s quite meaningful because you have some data immediately after the initiation of the drug; the assessment from the pathology is extremely interesting. We all know from the experience that we have that patients who are undergoing cystectomy and who are pT0 because they had neoadjuvant chemotherapy have a good outcome. They don’t have 100% survival but have a better outcome than the others. 

Now, I think that CR is meaningful and, going back to what you mentioned with the nivolumab, I think you were emphasising the trial RACE IT, which is the German trial with 31 patients with muscle-invasive bladder cancer, they were even cT3, cT4. So usually the patients that you select for the trimodality treatment are unique tumour, not that very bulky, quite limited. I have the feeling from the RACE IT trial that they expanded a little bit the indication and were not afraid to include patients who would be suitable for a cystectomy. What do you see in the selection of the patients?

NJ: I think the selection of the patients is interesting. As you say, US and often in mainland Europe trimodality therapy i.e. TURBT, chemotherapy, radiotherapy, tends to use those criteria. In the UK, as with a lot of things, we do things rather differently. So that chemo-RT is the predominant form of therapy for muscle invasive bladder cancer in the UK – more than 50% of patients do it and we don’t view any of those things as contraindications. So trials like my BC2001 chemo-RT trial has plenty of T3, even completely resected patients, and it has patients with hydronephrosis and so on. We know that you’ll get… those are prognostic factors so if you have them you’ll have worse outcomes than if you have a smaller tumour, the same as with surgery. So the data from that trial are very interesting because, as you say, they included patients that are often in Germany and France and so on not included in radiotherapy.

So we’re starting to see a sort of convergence between bladder preservation with radiotherapy plus chemotherapy and some sort of neoadjuvant therapy. What we know from chemo-RT series like my own is that if you have a pathological CR post-chemo RT, as with the neoadjuvant chemo data, you have very good long-term outcomes. So we maybe need to take a very hard look at this – if you get a pathCR after your initial treatment can we omit surgery and just save it for salvage surgery? We know you can do salvage surgery safely later from post-radiotherapy, there’s plenty of data on that. So it opens up a lot of very interesting management possibilities for patients that allow them to keep their bladders.

MR: Yes, I think we could move forward into the direction of keeping surgery as an option on the table but only for palliative situations. I’m keen to think that many urologists are not reluctant to preserve the bladder. It’s not something that we should consider as a dead end. The only thing is that if we are in a palliative situation after trimodality treatment we know that sometimes the morbidity is a bit increased. So the question I would like to come with is with the nivolumab, or the new kids on the block, let’s say the immunotherapy [inaudible], we don’t know if we will increase the morbidity and let the possibility to have room for surgery. We don’t know what is going to be the impact of these drugs on the surgery.

NJ: That’s very true and the experience with chemoradiation, there’s the Christie, Noel Clarke’s group and others in Manchester have published data on about 800 patients having either primary or salvage cystectomy post-radiotherapy showing, in their hands, very similar morbidity, an indistinguishable morbidity from the cystectomy procedure. But I think if you talk to them they’ll say that the operation has to be different. Because of the much higher use of chemo-RT in the UK, British surgeons have much more experience with it than in mainland Europe or North America.

Our experience with that and chemo was that it didn’t increase late morbidity in terms of radiotherapy related late morbidity and we’ve published that. Of course, we have to wait for the same data to come out from adding the immunotherapy on top. So, yes, that’s something that will have to be watched carefully. If you end up with a dysfunctional bladder if you add too much radiosensitization then clearly that’s not a good way of preserving the bladder.

MR: One last point I would like to discuss, going back to the ESMO and what you presented there, I was very interested in your BladderPath trial which explored two possibilities, two strategies let’s say. What we do usually when we discover a bladder tumour, we go for the trans urethral resection of the bladder and then you have some theoretical path where you will use first the MRI to select or sub-stratify the patients. Can you explain a bit what you had in mind and what’s the outcome?

NJ: Thank you very much for the opportunity to talk about it. So TURBT is a very unusual procedure – you could take a surgeon from a hundred years ago and drop him into your operating theatre in Paris and he’d be quite at home with a rigid cystoscope, it doesn’t look very different. It’s a very strange way to stage a tumour – obviously you get a tissue diagnosis but mostly nowadays we biopsy people and then we image them and then we decide what the treatment is going to be. 

So essentially we wanted to test that as a pathway. There’s a lot of data on the sensitivity and specificity of MRI in terms of distinguishing invasion from non-invasive tumours and there’s now a classification scheme called VI-RADS which a couple of my co-authors on this paper are authors on the VI-RADS paper as well. So, although we didn’t use VI-RADS scoring in my trial, we were kind of using it informally but the trial predated the VI-RADS thing. 

There were two parts to it. The first was we asked the urologists if they thought the tumour might be muscle invasive or if they thought it was probably non-invasive. If they thought it was probably non-invasive we registered them in the trial but they all got TURBT because essentially if it’s non-invasive you’re going to end up with a TURBT anyway. Essentially, 98% of the patients who they thought were non-invasive were indeed non-invasive. Now, of the other 50% where they thought it might be muscle invasive, on the control arm they all got TURBT and on the experimental arm they got an MR and a biopsy. Around half of the patients each side of the randomisation were scored as non-invasive so, again, on the MR arm they went from MR to TURBT and 15 out of 16 of the patients scored as non-invasive on the MR were non-invasive at the subsequent TURBT. So you could say it was a bit pointless doing the MR in one sense because you just added a procedure. 

The other half were scored as muscle invasive and we’re still pulling in the data to look at the pathology and so on and we’ll re-score all of these patients on the VI-RADS thing as well to see if that improves the accuracy. But in this case we weren’t trying to assess the accuracy of MR because that’s already well established and published, what we were trying to assess was the impact on time to treatment. So we said, right, if you’ve got non-invasive disease then the time to treatment is the time to the TURBT. If you’ve got invasive treatment, the time to treatment you don’t count the TURBT, the time to treatment is the time to cystectomy, chemotherapy, radiotherapy or a decision to do palliative care. 

What we found was that the typical time to get to muscle invasive correct treatment was around 98 days on the control arm which is fairly typical. I know people always say, ‘Well, in my centre we do it faster,’ but actually if you look at audits internationally that’s a pretty consistent figure because you have multiple hand-offs. You have a flexi in one place, you have a rigid cystoscopy somewhere else, you have your chemo somewhere else and people keep shunting and you have to re-resect if you’re not sure, a lot of the time, whether it’s invasive or not. But it came down from 98 days to 51 days with the MR-directed pathway.

The time came down for the non-invasives as well. We think what was happening was that a patient who you thought might be muscle invasive has an MR who then shows as non-invasive. You know that’s a bad non-invasive tumour so you prioritise them. So they were getting treatment faster even with the extra procedure. So we think that putting an MR upstream of your TURBT gives you more accurate staging and allows you to make better decisions. We didn’t try and influence the subsequent decisions – people did chemotherapy, radiotherapy, whatever. So we think that we should look at revising the pathway because a one-size fits all doesn’t work, it doesn’t fit all people. In particular, if you’ve very confident that somebody is locally advanced, you can see tumour going into perivesical tissue on the MR, for example, which you can see very clearly if you haven’t done any procedure, you know you’re going to go down the surgery, chemotherapy, radiotherapy type route. So you’re just adding time, and we very clearly showed you add time, by putting a TURBT in as well. I appreciate these are controversial findings but I think the pathway is long overdue.

MR: Not really, not really. We need to see the outcomes of the patients included in your experimental arm, that’s very interesting because it will be meaningful. On top of that it’s the question of organisation and you have a point – to have access also to the OR, to the theatre, could be difficult to schedule a useless TURBT. When you do a biopsy you can do it for a patient who is not asleep or as a daycare patient. So it’s something in terms of organisation which can impact very favourably the organisation of the hospital.

One of the key questions behind is whether or not we are in a situation to offer as many MRIs as we want because when I see the situation in France there are discrepancies according to areas and catchment areas about the access of MRI. So if we can demonstrate that this is the way to go at some point there is such an exponential number of MRIs which are done for so many indications that I’m afraid that the radiologists are going to be in a difficult situation. 

NJ: Yes, a bit upset. So one of the reasons we built in the initial decision thing, it was very clear that urologists are very good at spotting things that are definitely non-invasive. So there was no point in MR scanning those and that was 50%, roughly, of the patients that we consented were very clearly non-invasive at flexi and were confirmed as non-invasive when we went on to the… So out of the 55 patients who were scored at flexi as probably non-invasive, 54 were actually non-invasive. So straight away you lose half the patients from your MR. Then of the MR ones, yes that is a workload, but if you’re in a centre where you’re doing MR routinely for prostate, as all UK centres have been for some years now, the number of extra bladder cancer patients you add is quite small as a proportion of your workload. As you say, yes, you’re increasing your MR workload but you’re potentially decreasing your TURBT workload. And an MR is much cheaper than a TURBT as well – it doesn’t involve an in-patient stay and so on and you’re substituting a flexi biopsy. Plus you’ve got the gain in time to treatment. So we think there are potential gains and the organisational challenge is not that big if you’re already doing MRs for your prostates which, by and large, people are nowadays, aren’t they?

MR: Yes, I think it’s a good way to revisit the way we treat the bladder cancer which, at some points, is much more eminence-based than evidence-based. So we need to open trials and propose the possibility to evolve on that. 

Nick, listen, it was very good to have the opportunity to catch up just after Paris on the ecancer platform to exchange on the preservative management of muscle invasive bladder cancer. Thank you very much for this discussion.

NJ: A pleasure. Thank you very much indeed.