Ashish Kamat: Hello, everybody, and welcome to your today's Bladder Cancer Center of Excellence. I'm Ashish Kamat, Professor of Urologic Oncology in Houston, Texas. And it's a pleasure to welcome to the forum today from France, Dr. Constance Huck, who's joining us from the Institute Bergonié. Dr. Huck, a pleasure to have you here, and it's really great to have you join us for a topic that comes up all the time, and we're talking about radiotherapy for patients with bladder cancer. Even in the recent IBCG recommendations, CIS is a relative contraindication if it's multifocal and present in the bladder, and we face this when we are counseling patients. So really excited to see what you have to present and your opinion on this.

Constance Huck: Thank you very much, Dr. Kamat, for the invitation and to speak about a topic that is currently highly debated and often discussed in the multidisciplinary tumor board. So the role of carcinoma in situ in muscle-invasive bladder cancer. And the question is, is CIS still a strict contradiction to bladder preservation? So, historically, we know that radical cystectomy has been the gold standard for treatment of MIBC. However, despite the absence of randomized phase III trials, several prospective studies have shown that trimodality therapy that combines transurethral resection of the bladder followed by radiotherapy with concurrent chemotherapy, can achieve oncological outcomes similar to cystectomy. If we take a look at the comparative analysis by Zlotta in 2023, for example, he demonstrated no significant difference in metastasis-free or overall survival, and even a small benefit in OS for a TMT when compared to cystectomy in carefully selected patient.

So TMT is now recognized as a valid alternative to cystectomy, but the main challenge is the patient selection based on tumor stage, prognostic factors, and patient preference of course. And among these, one of the most debated issues which we try to review in our paper is the presence of CIS. So, is CIS always a contradiction or only when it's multifocal or extensive? Well, in the current guidelines, there's this controversy. If we take the last consensus statement from the EAU, they consider the absence of CIS as a key eligibility factor, making CIS as a relative contradiction.

If you look at the NCCN, it's less restrictive, excluding only extensive CIS. And for the IBCG that you talked about previously, it also views CIS as a negative prognostic factor, but not an absolute contradiction to TMT. So these recommendations, however, are mainly based on retrospective data, and patients with CIS are often excluded from clinical trials, which limits the strengths of available evidence.

So, in our paper, we first looked at the older radiotherapy alone studies, so without radiosensitizers, and the results were quite inconsistent. Some found no clear impact of CIS while others reported worse local control and survival, but we know that radiotherapy alone is no longer a standard and should not be considered as a curative intent.

Now, if we look at the trimodality studies, we found that the complete response rates were generally similar with or without CIS. But when we examine overall survival and disease-specific survival, the outcomes are quite inconsistent across the studies and these results are often influenced by the use of what we call split-course radiotherapy protocols. So in these regimens, the assessment was done after only part of the radiation dose leading to lower complete response rates. And because dose was delivered at that time, it's probably insufficient to eradicate disease and the presence of CIS. So by contrast, we know in the meta-analysis that continuous course regimens meaning that patients go through the entire radiotherapy protocol, it has shown that it achieves higher complete response rates and better disease control, particularly in patients with aggressive disease.

There are several key discussion point in our paper. The first one is the wide heterogeneity of radiotherapy regimens between the doses, the fractionation, split versus continuous course, or overall treatment time, or even adding radiotherapy boost to the tumor. That leads to quite a difficult comparison between these studies, and most of them are obviously a retrospective analysis. There's also this challenge in CIS detection because in many of the studies that we reported in our paper, the diagnosis relied on only visual inspection without systematic biopsies or mapping. So this raises the need for precise mapping to distinguish unifocal from multifocal CIS or extensive CIS, and so we need a close collaboration with the urologists.

It raises another point. It's the lack of universally accepted definition of extensive CIS. Guidelines like the NCCN clearly states that TMT should not be offered to extensive or multifocal CIS, but there is still no consensus definition of what extensive means.

Another important limitation is a limited use of modern image-guided radiotherapy, what we called IGRT, in published studies, historical series often relied on 2D or 3D techniques without daily verifications, so it's raising the risk that multifocal CIS areas were underdosed when booster gated only the visible tumor. So currently in our current practice with IGRT, now standard, bladder coverage is more accurate, suggesting that all those studies may have underestimated the true potential of radiotherapy in CIS.

Another key aspect is the role of moderate hyperfractionation, so usually 55 grays in 20 fractions, it's now standard for bladder radiotherapy and this schedule has shown super-invasive local-regional control compared with normal fractionation, but it has not yet been specifically evaluated in CIS patients, so we need prospective evaluation in this subgroup. And finally, the development of novel systemic and intra-physical agents is likely to impact the field. Immunotherapies and agents such as pembrolizumab, nadofaragene, or TAR-200, they're already effective in BCG-unresponsive NMIBC and they may be incorporated into bladder-preserving strategies, including the patients with CIS.

And looking to the future, there's also great interest in evaluating radiotherapy in non-muscle invasive disease, including CIS. If we take for example, the BRACE trial, who is almost ongoing, is going to test moderately hypofractionated radiotherapy combined with a radiotherapy in patients with BCG-unresponsive NMIBC and CIS. And the primary input is complete response at six months in line with the IBCG recommendations. And similarly, there's also the TRAIN trial who will investigate the integration of radiotherapy with systemic therapies including immunotherapy in high-risk and NMIBC with or without focal CIS. So these studies are important because they extend the use of bladder-preserving radiotherapy beyond MIBC into earlier disease stage and may reshape the way we think about CIS management in the future.

So, to conclude, my key message is that CIS should probably not always be considered as a strict contradiction to bladder preservation. We need accurate mapping and a close collaboration with urologists for proper patient selection. And we also need prospective studies using modern, continuous, and not split-course radiotherapy, and usually using hypofractionation and not normal fractionation. And the integration of novel agents as we talked previously, that may further expand bladder-preserving opportunities for patients with CIS. Thank you very much.

Ashish Kamat: Thank you so much, Dr. Huck. I mean, that was a very, very nice presentation and a tricky topic. And as you recognize, when we were sitting down and coming up with the recommendations for the IBCG manuscript, that was a hot topic of debate because many of us recognize that CIS detection nowadays is a lot more common because we're using newer tools when we're diagnosing CIS. And sometimes you'll pick up a small focus of CIS and is that really a contraindication? It shouldn't be, but some guidelines will say any CIS should not use TMT, and that's why it's a relative stop. Think about it, see how it goes.

And one of the things that I wanted to ask you in the research and the work that you've done is this issue of patients that get TMT in the background of CIS. When you have persistent residual disease, how do you counsel your patients on the management? Is that something that you handle on your own? Do you automatically refer to your urologic oncology colleagues? How is that handled in your practice?

Constance Huck: You mean after TMT, after chemotherapy and the entire course, right? It's not the split course.

Ashish Kamat: Exactly.

Constance Huck: Yes. After the long-course radiotherapy, usually I address my patients to their urologist every three months, the first year and the second year to do a cystoscopy and eventually biopsy to see the complete response or the local response.

Ashish Kamat: Yeah, no, but my question was now we're seeing a lot of bladder preservation with systemic therapy and patients get downstaged from say, T2, T3, T4, to TA, TIS in the bladder. And after systemic therapy, if they don't have a complete clinical response and they have say, TA or CIS in the bladder, we can go in with local treatment. You mentioned some of those that are currently not approved, some of them are approved, etc. In your practice in TMT, say a patient has T2 disease, gets your full course and has CIS, what are your recommendations?

Constance Huck: Well, usually we discuss the case in tumor board and usually the patient goes through cystectomy.

Ashish Kamat: Okay. So currently presence of residual CIS after T2 or invasive disease is a indication cystectomy at your institution, but hopefully with the trials that are being done and the newer technologies, we might be able to save more bladders, right?

Constance Huck: Yes. Yeah, I hope so.

Ashish Kamat: Well, always thank you for taking the time. It's a pleasure. Any closing thoughts you want to leave the audience with?

Constance Huck: Well, no, it was more about the key... I just wanted to say there is a key message of this paper because it's not always clear for the rheologist or the radiotherapist, is that the key message is not to say that we need to do bladder preservation for all these patients, but it's to really select correctly and not just say, "It's always a contradiction to trimodal therapy" when we've got CIS at diagnosis. So it's just want to rewind on the current guidelines to say that we don't really know because it's retrospective data and we don't really know what it's better for the patient's cystectomy or preserving treatments. So that was the key message.

Ashish Kamat: Great. No, excellent point. And then I really appreciate you taking the time because it's important, as you said, to recognize that CIS does not mean absolute contraindication, but it's something that you have to factor in and discuss with the patient. Once again, thank you so much for taking the time.

Constance Huck: Thank you. Thank you very much, Dr. Kamat. It was a pleasure.