Read the Full Video Transcript

Leslie Ballas: Hi, I'm Leslie Ballas. I'm a radiation oncologist at Cedars-Sinai. Thank you for joining us. I am thrilled to have Professor Robert Huddart joining us. He is a professor of urological cancer and honorary consultant in clinical oncology at the Royal Marsden Hospital, and has recently published the RAIDER trial, looking at adaptive radiotherapy for bladder cancer treatment. Dr. Huddart, thank you so much for joining us.

Robert Huddart: It's a pleasure to be invited to come and talk to you. The RAIDER trial is a trial that we ran from the UK, along with colleagues from the Tasmanian and Australian Oncology Group and Trans-Tasman Oncology Group in Australia. And it was a trial in which we looked at the role of adaptive radiotherapy and whether that would facilitate dose escalation in bladder radiotherapy.

The trial was designed as a large phase II study. And we were testing whether or not the so-called plan-of-the-day adaptive radiotherapy allows us to move towards a more tumor-directed approach for bladder radiotherapy. And so we have three arms.

We have a standard arm, which was treating the whole bladder. We had an arm which was targeted on the tumor but giving the same dose. And we had a dose-escalated arm, where the dose was increased by about 15% from 64 to 70 gray in 32 fractions or 55 up to 60 gray in 20 fractions. And we had two parallel cohorts of 20-fraction cohorts and a 32-fraction cohort, which were, for many of the endpoints, and particularly toxicity endpoints, analyzed separately because we weren't sure that the results were actually going to be crossover.

In total, we recruited about 345 patients from 46 centers. And that was slightly higher than we initially set out to do because of wanting to ensure that we had enough eligible patients to meet our primary endpoint, which was the proportion of patients experiencing grade 3 toxicity. And we were trying to look to see whether by using these techniques, we could dose escalate and not exceed a rate of 20% grade 3 toxicity in the DART arm. And we needed a minimum of 57 patients in the DART arms, therefore, to do that.

And this is essentially what we intended to do. Instead of treating the whole bladder, we had two volumes: a whole bladder volume, and we had a secondary tumor volume, which were outlined. And then for each volume, we made a set of plans: a small plan using a 0.5 centimeters CTV to PTV margin, a medium plan which used slightly bigger margins, particularly anterior and superior when it went to 1.5, and a large plan where that was increased to 2 and 2.5. And the idea was that before each treatment, the team treating the patients would do a cone beam CT scan and select the best plan for the patient each day.

And this was also taken up in over 35 centers across the UK and Australia. And we trained well over 200 radiographers and technicians who were trained to do the study. And so one of the first endpoints we had was, do we use each of these plans, or does everyone stick to a medium plan? And actually, the answer was yes.

You can see, in terms of what was used in the plan selection, there's a variety of different plans we used. Medium was still largest but also significant number of small plans and a smaller number of large plans, with a non-medium plan used in just under 60% of patients. And when we looked at what plans were used for individual patients, we could see actually a single plan was only used in a very small number of patients—less than 2%.

And actually, over 70% of patients used all three plans. Which, in my mind, shows that there is a role and a need for adaption to optimize target coverage and minimize normal tissue radiation in bladder radiotherapy. And to note that this is a study comparing image-guided radiotherapy in both arms. Because most patients in the standard arm, even though it wasn't absolutely mandatory, had cone beams used daily throughout the treatment.

So our primary endpoint was grade 3 toxicity, which was radiation-related. We were trying to exclude 20%. And we did that quite clearly with very low rates of radiotherapy-related grade 3 toxicity. In fact, there was a single patient in the dose-escalated arm of just over 115 patients who had a grade 3 toxicity. And actually, that number was no different to the other standard dose arms.

And we had strict criteria about what we call radiotherapy-related. But if you just look at any grade 3 toxicity, the rate was still very low at 8.6% in the 20-fraction arm and 3.5% in the DART arm. And both of those are well below the 20%. The upper confidence limit is well below the 20% cutoff that we wanted to exclude. So we can say that you can take these doses up using these techniques quite safely.

The second side of the coin is, does it do any good? And that is slightly more. The study was not designed to be directly comparative between the arms and wasn't powered to detect differences in outcomes.

But we did find, and this is true for a number of endpoints, but this one is bladder-intact event-free survival, which is defined as recurrence, also invasive recurrence, pelvic nodal recurrence, distant metastases, cystectomy for any reason, bladder cancer-related deaths. And it's commonly used in other studies.

And the hazard ratio in favor of the DART arm was 0.81 with 71.7% at two years in the DART and 66.3% in the standard dose arms. And importantly, in this study, with a median follow-up of about 30 months, only 4% of patients have had a cystectomy. Two at the beginning, where they switched to having cystectomy rather than radiotherapy, and 11 for disease recurrence, and none to date for toxicity reasons.

And patients tolerate the treatment well. This is just one of the samples. Health-related quality of life was little different between the arms. And certainly, there was no evidence that the dose-escalated arm had worse quality of life. And actually, the mean quality of life—and this is a symptom scale, the EORTC urinary symptoms as an example—was pretty flat across all the time points.

And some of the quality of life showed some dip. And some toxicity results showed some dip in the immediate time around the end of treatment in the first three months. But by and large, by six months, they've all returned to baseline levels and stayed there over the longer term.

So we can conclude that most people need more than one plan during treatment if you're going to optimize coverage. That grade 3 toxicity is low with these techniques of radiation in all the treatment groups. That dose escalation to the dose levels we took to here was safe and feasible and was well below the predefined thresholds.

Health-related quality of life is well maintained in patients having this form of radiotherapy. And the local control for this treatment was at least as good, if not better, than historical trial data. And by and large, the DART arm had encouraging hazard ratios around about the 0.75 to 0.8 margin for all the endpoints we looked at in terms of disease-related outcomes. And these results are now published in European Urology.

Leslie Ballas: Thank you so much for that really wonderful explanation of the RAIDER trial. And congratulations on an important trial in bladder cancer radiotherapy. I guess my first question would be, has DART become your standard of care in your patient practice based on these results?

Robert Huddart: We're getting there at the moment. We've started doing some more work using real-time adaptive therapy. So we've been working through those processes. And it's only recently we've had these results.

So we have started looking at patients who are suitable for this. We're going for that dose—we've changed our guidelines to include and allow that dose escalation to occur. It's obviously slightly difficult because of the design of the study to give those categorical. I can't tell you that doing this definitely improves. I can tell you it's safe, as long as you use an adaptive technique. But I can't tell you if it definitely improves outcomes. And though the suggestion is it might do. I think there's probably further work to consolidate and to do more work in that area.

Leslie Ballas: I noticed in the plans that you showed, you did not have fiducial markers in the bladder outlining the area of tumor for the area of boost. Is that just not common practice in the UK? That's a question that comes up here in the US sometimes is, if we need bladder fiducials for bladder tumor-only treatment.

Robert Huddart: Yeah, before we did the study, we did quite a lot of—we did some work with fiducial markers. We found them quite tricky. In the protocol, it was encouraged to use fiducials. But it's only a handful of patients in the whole study actually used them.

Partly, it's logistical, in that we're in a highly pressured public health service for most of these patients. And actually, getting patients back to put the fiducials in is quite tricky. Quite a lot of the patients are not particularly fit. And they've got through one TURBT. You don't really want to put them through operations which aren't absolutely 100% crucial. So there's a number of reasons.

And we found during the study, it became less of an issue because, increasingly, patients are getting CT scans before they've had their baseline TURBT. And in the past, we've had this issue that the patients are diagnosed, have a TUR, you're left with a thickened bladder wall with some fuzziness outside the bladder and not knowing what it is. But now, patients are having CT urograms, you're often getting the baseline imaging before anything has been done.

We've encouraged the MRI imaging as well. And we use that whenever we can. And that's often also useful for defining the tumor. But in the protocol, by and large, most patients were defined clinically according to the local practice.

And we had quite an intensive quality assurance program looking at images and reviewing what people had outlined. Before starting, they had to outline three cases that we identified, one of which had fiducials and two that didn't, to define the tumor. And quite a lot of them went back to the same case to have another go. And then we looked at the first couple of patients that were contoured in local centers. So there was a lot of quality assurance to check on the outline and contouring aspects of the study.

Leslie Ballas: Along the lines of that quality assurance piece, it was the radiotherapy technician who would choose the plan of the day at the console, not an MD, correct?

Robert Huddart: It was open. But by and large, it was done by the radiation technicians, yes. So everybody who was selecting cases in the protocol had to go through a training program. And sites were told to ask what their experience was on cone beam imaging and imaging.

And then we have a training package for everybody taking part to go through, teaching them about the anatomy, about what was expected. And then there were training cases for selection. And then there was a test, and everyone had to pass the test.

We also did on-trial, post-implementation QA. And in fact, one of the things we did find was that we had an initial stage of about 70 patients. And we did an audit of those patients compared to an offline standard done by our quality assurance group. And we actually did find a discrepancy and some discordance between what was selected on the site and afterwards.

So we had to go through a retraining program. And actually, we increased the concordance rate from something around about 76% to sort of 90%, 91%, 92% by doing so in the latter parts of the trial. So it's certainly true that some of the results—some of the selections may not have been optimal. And it was a non-random bias towards selecting larger plans, by and large, particularly in the first stage of the study.

And I think it did reflect an element of how radiation technicians, radiographers in the UK are trained, which is—I mean, the first thing is don't miss. Whereas the viewpoint, some of our clinicians, we don't really want to miss. But actually, we also don't want to treat the patient too much. So there was that sort of getting that tension resolved between not missing. And some of the advice we had maybe promoted the idea of not missing a little bit too much.

Leslie Ballas: Yes, I remember there was a quality assurance paper that came out after the HYBRID trial, showing that it does take quite a bit of retraining of the radiographers to ensure that quality assurance, as you're describing here as well.

Robert Huddart: Yeah, we've published two or three papers and had quite a few presentations about that quality assurance side. And I think the latest paper is either published or in press at the moment by Amanda Webster. And actually, the trial wouldn't have been possible without the really great work that the QA teams and the radiotherapy and quality assurance group in the UK and also the TROG group in Australia were really fundamental. And it shows that in terms of complex intervention, that quality assurance is really important. I think when I started out, I never expected it to be such a lot of work to do.

Leslie Ballas: Another sort of question that comes up a lot, at least in the United States and probably Canada as well, is the question of should we be doing whole bladder versus whole pelvis radiotherapy. I know that in the UK, it's most commonly done bladder-only radiotherapy. But within the same week or two weeks of this paper being published, there was a paper published in the JCO by Mark and colleagues from Canada, looking at bladder-only versus whole pelvis. They did a 10-center retrospective analysis of somewhere in the 500 to 700 patients and found that there was an overall survival benefit to whole pelvis radiotherapy. I just wanted to hear how you would put this trial into context with that question.

Robert Huddart: Yeah, it's a great question. And actually, one of the worries we had with doing this study was whether or not we could make matters worse by being more precise. We had looked at the data from the BC2001 trial originally. And we found that the number of patients relapsing with nodal-only relapses was below—it's about 7% or 8% maybe.

And we found the same sort of number. I'm just going to go back. It was on one of the slides I showed you, but I didn't focus on it. Yeah, so there's nine patients in the whole of 345 patients who had a pelvic-only recurrence.

So it makes me slightly skeptical because the numbers of patients—so the only patients you think would be salvaged by pelvic radiotherapy are those patients who have a lymph node-only metastatic recurrence or a lymph node and bladder recurrence. And not all of those patients are going to be long-term cures because some of those patients are going to go and get metastases. So we have looked at this issue about should we do a trial looking at pelvic versus bladder treatment. And the numbers just don't stack up in terms of the difference that you might expect to see.

And so the retrospective study seems a lot larger than you would like to do. And I am always slightly skeptical about some of these things that you can't really ever account for the biases you get in that. So all I can say is that in our study, we didn't. The results, the overall survival control rates that we report are based on bladder-only treatment. We didn't see any obvious evidence of more nodal recurrences in the adaptive arms compared to the standard whole bladder arm.

And one of the thoughts is that when you do bladder radiotherapy, you're not far off whole pelvic nodal radiotherapy as you think, particularly if you put a large margin on. And that by making the margins tighter and making the high dose more targeted, we could end up with more nodal recurrences. And we didn't see that. So I can't necessarily square that circle. I say, we tend to do that just on the basis of trying to limit toxicity without a clear benefit. There's one smallish randomized trial in the quite distant past, which didn't show any benefit for pelvic radiotherapy.

Leslie Ballas: Yeah, I mean, I think that there's a lot to be said about the fact that that's a retrospective study. They used IPTW to smooth out the differences in the patients who got bladder-only versus whole pelvic radiotherapy. And like you said, there's selection bias obviously on the treatment of choice that was used, so yes.

Another question that I have for you is, sometimes there's the question of, should we be doing whole bladder versus bladder tumor boost? This would be a common—this would be sort of a comparison of your whole bladder versus standard adaptive radiotherapy arm. And it seems from your data, there's no benefit in terms of quality of life, nor is there a benefit, and understanding the caveat that it wasn't the primary endpoint, in outcome. And so it seems, if I'm not misunderstanding, that the only benefit in doing a bladder tumor boost would be if you were to dose escalate.

Robert Huddart: I think that's probably where we are with the data. So this is the second trial that I've been involved in that has tried to test tumor boost. The problem may well be partly that with the techniques we've had, even with most people still having the medium and the large, they're still using relatively large margins. And if the tumor is anything more than a small tumor, you're still treating a fair amount of the bladder with high-dose radiation.

So it may be that to see the diff—so it may be that the volume that you treat to the bladder is less important than we thought, which is one aspect. It may be that we're just not sparing enough bladder to make a difference. It may be that the toxicity is less volume dependent than we thought it was. And it may be related to genetic and other factors or the underlying tumor. It's quite difficult picking out what's causing symptoms quite often.

So we haven't proven in here, which is one of the things we wanted to look at, was whether or not we could prove that reducing the volume would have an impact on toxicity. One of the hypotheses was by reducing the high-dose volume, that would allow dose escalation. So it has allowed it. And I don't think that we would want to necessarily take the whole bladder to 60 gray, for instance, in 16 to 20.

So it has allowed it. But it is a slight disappointment that we didn't see any clear trends at all to benefit from the boost. I'd just like to add that one of the things I didn't talk about was the patient characteristics. Just to say that in the trial, about half the patients had neoadjuvant chemotherapy. And about 70% of patients had concomitant chemotherapy or carbogen nicotinamide.

And so there was about 30% of patients who just had standard radiotherapy. One of the things we need to look at going forward is what differences we see between those different groups. Only three patients in the trial had cisplatin. Most of the patients had either 5-FU, or gemcitabine, or carbogen nicotinamide, but that was about 70% of patients. Which, I think, is all important in terms of interpreting the efficacy outcomes.

Leslie Ballas: Yes. And did you leave it up to provider discretion whether or not they use neoadjuvant chemo versus a concurrent chemotherapy?

Robert Huddart: Yeah. Well, neoadjuvant chemotherapy is recommended by our national organization to be considered in patients who are suitable for it. And they were allowed to come into the trial. So obviously, that's pre-RAIDER.

Within the trial, sites were asked to nominate a preferred, accepted concomitant therapy. And then they were allowed to choose a second one, if they wished, for patients who weren't able to do that. And some places used two different chemos.

Some patients used chemotherapy and then carbogen if you couldn't do chemotherapy. And some people just had one, and then they didn't do it. They didn't do any concomitant therapy. So there was a bit of a mixture. And it was up to investigators.

But we only accepted those that had good phase II or phase III data. So cisplatin, gemcitabine, 5-FU, or carbogen were approved for use in the trial. But in the end, not many patients had cisplatin in the UK.

Leslie Ballas: Yes, thank you.

Robert Huddart: Which I think is different to other countries.

Leslie Ballas: Certainly different than here, yeah. Cisplatin-based chemotherapy is our—sort of if patients are cisplatin eligible, would be the preferred radiosensitizing chemotherapy. Well, that's all that I have. I can't thank you enough. This was really a treat for me. And we want to just once again say congratulations on a wonderful and very well-run trial. So thank you so much.