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Leslie Ballas: Hi, I'm Leslie Ballas. I'm a radiation oncologist at Cedars-Sinai in Los Angeles, and I am very excited to welcome Gautier Marcq, who is an Associate Professor of Urology at the University of Lille, to discuss his recent publication in the JCO on whole pelvis versus bladder-only radiotherapy. Thank you so much for joining us today.

Gautier Marcq: Thanks for having me.

So I'm going to walk you through our study that was done. Those are my conflicts of interest, sorry.

This study was done in Canada, from out of ten academic centers. So a bit of background to start first.

When talking about radiation fields in MIBC, pelvic lymph node irradiation is under debate. We know from surgical cohorts that up to 20 to 30% of patients will harbor lymph node invasion at the time of cystectomy. So as TMT is offered and radiation therapy is also offered to patients with higher-risk MIBC where patients may have more CIS, LVI, or hydronephrosis, we asked the question of PLNI being more pertinent in that regard. So our aim was to compare whole pelvis and bladder-only RT for patients with MIBC and compare the complete response, cancer-specific survival, and overall survival.

So we included about 600 patients from, as I said, ten academic center databases, including patients with MIBC, cT2 to cT4 disease, cN0 to cN2 disease, from 2001 to 2018. All those patients received a curative-intent radiation-based therapy. The median dose for radiation therapy was 50 Gray in 23 fractions. The median follow-up time for that study was 54 months.

I'm not going to go through all the details of the unweighted population. What is important to note is, in the weighted population, the baseline characteristics were well-balanced between the two populations.

The main findings that I'm reporting here are the cancer-specific and overall survival benefits with the use of whole pelvis RT. If you look at the median CSS of 84 months, or the median OS of 71 months in this cohort, it's interesting to report.

So there are a couple of ways to skin the cat, and we also used an MVA to look at the benefit with the use of whole pelvis radiation, and we again show a benefit, and no less benefit with the use of whole pelvis radiation.

The other parameters influencing overall survival in this analysis were advanced age, advanced ECOG status, the presence of hydronephrosis, or the use of NAC. And the use of NAC was actually the sole parameter that decreased the risk of death, basically.

We also, obviously, performed some sensitivity analyses in patients that were lymph node-negative on CT imaging prior to therapy. And again, whole pelvis RT was associated with improved survival. We did also a sensitivity analysis in patients having a strict TMT protocol or a hypofractionated regimen. And again, whole pelvis RT was improving the overall survival. We also did a cause-specific hazard model when looking at CSS. And again, this cause-specific hazard model showed a cause-specific survival benefit for patients receiving whole pelvis RT.

When we look at the data, it's important to know that there is only one randomized trial in that space, looking at the benefit of whole pelvis radiation. And actually, this trial was negative, reporting no benefit with the use of whole pelvis radiation. Although, we have to take into account that in that trial, patients receiving bladder-only had a two-centimeter margin around the bladder, which is an important margin to have.

The grade three and four acute toxicity was about the same, but almost significant with whole pelvis radiation having slightly higher toxicity. But this is a reason why some people were doing bladder-only, but we have to be very careful with this data because an editorial of concern was published regarding that RCT.

So in summary, pelvic lymph node irradiation for MIBC may improve survival. I think it's fair to say. Prospective validation is required, although it's unlikely to happen. And our study is, obviously, limited by the retrospective design and the multiple RT regimens.

With that, I'm happy to share the QR code for the viewers to see our article. Thank you.

Leslie Ballas: Okay. Thank you so much for sharing this. This is a really wonderful and timely study. The question of whole pelvis versus bladder-only radiation for bladder cancer is sort of one of these age-old questions which has varied in terms of how people practice. The classic RTOG trials always included a small pelvis radiation field, whereas in the UK, they've done a little bit more bladder-only. So this is wonderful. Thank you for sharing.

So to start our discussion, I have a couple of questions for you. I guess first, I noticed the actual patient population before weighting—it was younger, healthier patients that got whole pelvis radiation. And so I'm wondering, do you feel like IPTW can really correct for that? Obviously, there's some selection bias that's causing whole pelvis to be given to younger, healthier patients.

Gautier Marcq: Right. That's a great question. And it's important to note that when we compare those two populations prior to the IPTW analysis, patients with whole pelvis RT had higher-risk disease also. They had a higher risk of LVI. They were more prone to have neoadjuvant chemotherapy prior to TMT. And it's fair to say that there might be unmeasured bias, but the IPTW analysis is not perfect. But we did account for age, ECOG, so this was weighted in the analysis. So obviously, there might be unmeasured bias; it's important to note, and we actually highlight that in the limitations of our study.

Leslie Ballas: Yeah. I guess one thing that you point out, which is also an important thing, is neoadjuvant chemo on multivariable analysis was also significant in terms of outcomes. And certainly, it's got to be patients who are younger and healthier who are also getting neoadjuvant chemo. So that confounds it also a little bit. I understand that you weighted accordingly, but yeah, I mean...

Gautier Marcq: Yes, obviously. And we also reported recently in another paper that neoadjuvant chemotherapy is associated with improved survival also in patients getting radiation. And I think it's timely that we work on this. I do believe there is a fair amount of patients that demand bladder preservation. And right now, looking also at the use of immunotherapy in the adjuvant space, this is something that we have to work on altogether to make sure that patients can choose and can still benefit from also IO peri-local treatment. So whatever the treatment is, the important thing is the patient getting a good treatment, and a treatment that can make him live longer.

Leslie Ballas: Agree. Agree. Very well stated. I guess in conjunction with your study this month, there was also a publication in European Urology, the RAIDER trial, which was adaptive radiotherapy, looking at how to deliver radiation based on bladder filling, for those listeners who hadn't read the paper previously. And it uses our most modern technology for treatment. And in this study, they did bladder-only, and they adapted the radiation field to how full the bladder was each day. And they found that with that technology, with that treatment, there was only a 7% pelvic lymph node relapse rate after bladder-only radiation. And so I guess it begs the question—and that was a prospective trial—when you look at a prospective modern trial like that, how do you think about the benefits of whole pelvis when you're really only maybe preventing a 7% pelvic relapse rate?

Gautier Marcq: Yeah. That's a fantastic question again. And we have to take into account that our analysis was mainly on cancer-specific and overall survival. So our outcomes were looking at the use of whole pelvis on survival, and we were not able to assess the rate and the rate of local recurrence, but obviously, the aim for those patients that you're treating with them for MIBC—the aim is for them to live longer. So that's why we wanted to focus on overall survival and cancer-specific.

And if you look also at—so I cannot compare to RAIDER based on the data we have first. And second of all, if you do bladder-only, urologists have to know how radiation oncologists are doing. When you do bladder-only, you take a margin. And the margin, depending on the filling of the bladder, I'm quite convinced that if you do bladder-only, you also deliver some radiation to the nodes to some extent. So this is important to take into account. But I do believe it's a UK thing to treat the bladder only right now. As if you look at how American centers are treating MIBC with RT right now, more and more they are quite prone to do whole pelvis compared to what we do in Europe. But this is something that we have to look at. And I think as academics and doing research in academics, we have to work all together to answer all of those questions, actually.

Leslie Ballas: Yeah, I agree. Actually, interestingly, we just completed accrual in this country to the SWOG/NRG 1086 trial, looking at chemoradiation versus chemoradiation with atezolizumab in patients with clinical T2 to T4a N0 muscle-invasive bladder cancer, and they allowed sort of dealer's choice in terms of treatment field—whole pelvis versus bladder-only versus actually even a bladder tumor boost as one of the options, and they've stratified for that. So in that prospective study, we'll hopefully also get some data to help address this.

What was interesting is that at the start of that trial, when it opened—which I think was in 2020 or something, 2019—most people were doing whole pelvis radiation. And by the completion—or more people were doing whole pelvis. And by the completion of that study, I think that it was about 50/50 whole pelvis versus bladder-only. And so it will be very interesting to see how that reports as well, and kind of put that into context with your own data.

I guess that raises a question. The data that you present is very complete and has lots of patients, but it does account for 2001 to 2018. And obviously, radiation technique has changed. We now use IMRT for bladder radiation; then they were using 3D conformal. The chemotherapy has changed—the radiosensitizing chemo. So do you feel that your data is applicable to modern chemoradiation?

Gautier Marcq: Well, again, that's a limitation that we have highlighted in the article, and this is very important to note. I do believe that our centers were ten academic centers out of Canada, and in those centers, IMRT was already used mostly at that time. So I think our data are still advocating for whole pelvis RT. Although we have to acknowledge the limitation of the prolonged inclusion period, we have to acknowledge that. But I do believe it's still—in our centers, when we asked them to go and look again, many of them were using IMRT, actually.

Leslie Ballas: Okay. Well, I am, again, so excited about this terrific publication. And I just wish you congratulations on a very well-done study. Is there anything else that I didn't ask that you want to tell our viewers today?

Gautier Marcq: No, I think we submitted all here.

Leslie Ballas: All right. Well, again, thank you, Gautier. It's so nice to do this with you and have this discussion.

Gautier Marcq: Thanks for the wonderful, wonderful talk. Thank you very much.