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Node-positive bladder cancer treatment options are illuminated by new research - Martin Swinton

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    Leslie Ballas: Hi there. Thanks so much for tuning in to join us. I'm Leslie Ballas. I'm a radiation oncologist at Cedars-Sinai in Los Angeles, and I am so excited to welcome Martin Swinton to discuss his recent publication, "Bladder-Sparing Treatment With Radical Dose Radiotherapy Is an Effective Alternative to Radical Cystectomy in Patients with Clinically Node-Positive Nonmetastatic Bladder Cancer." Dr. Swinton is a clinical oncology registrar at the Christie Hospital in Manchester, and he has been kind enough to make time for us. So congratulations on the publication, Martin, and we're so excited to dive into some of the details of this paper.

    Martin Swinton: Thank you. Thank you very much for the introduction. So I've got a few slides here just talking about our recent publication in the Journal of Clinical Oncology. This is looking at patients who present with clinical node-positive nonmetastatic bladder cancer and looking at a multicenter retrospective analysis of one, how these patients are being treated in centers in the UK, and then also the sort of survival outcomes in those treatments. And with this data, we were able to compare patients who received either bladder-sparing treatment with trimodality therapy, with radical dose radiotherapy against those who received radical cystectomy.

    So the background to this work is there's not really clear evidence to guide the clinicians and patients through the management of clinical node-positive nonmetastatic bladder cancer. In terms of node-negative disease, historically it had always been thought that the gold standard for treatment was radical cystectomy. But then there's been a real paradigm shift towards bladder preservation and bladder-preserving treatments in this site. And the trials of radiotherapy plus radiosensitizer have shown very good overall survival rates of about 50% at five years, which are kind of equivalent to radical cystectomy series from the BC 2001 and the BCON trials.

    And then as well as this, the recent work has done things like propensity score analysis to match patients to do good retrospective comparisons between patients who had radical cystectomy against bladder preservation. And this has provided very good evidence that bladder preservation can be as effective as radical cystectomy in a setting where it's not been possible to do a randomized controlled trial.

    And actually, in the UK, we've sort of had this accepted for quite a long time, and our NICE guidelines are that all patients who are suitable for radical therapy for their bladder cancer need to go and see both the urologist to talk about surgery and to come and see an oncologist to talk about bladder preservation. But all of this kind of data and evidence has come really from the node-negative setting. So these series and these trials either excluded patients with node-positive disease or they had very low numbers of those patients.

    So I suppose currently this had been an evidence-low zone. We do know that bladder cancer patients who have lymph node-positive disease, particularly if it's pathological node-positive disease after radical cystectomy, these patients have a worse prognosis. And there's a question of how do we best manage these patients, which was leading up to why we did this retrospective analysis.

    So we looked across four UK oncology centers and we identified patients diagnosed between 2012 and 2021. And those patients who were diagnosed, they'd have to have clinical node-positive disease, so clinically N1, N2, or N3 disease and no signs of metastasis on standard staging. So that would be CT staging these patients received. These patients received a wide variety of treatment, and the way that we classify these treatments was those patients who received some type of potentially radical treatment. So that was either receiving a radical cystectomy, which there were 76 patients, or radiotherapy at a radical dose where there were 87 patients. And then the remaining patients we classified as receiving only palliative intent type treatments. So this included patients who had only systemic anti-cancer therapy, so either chemo and/or immunotherapy, palliative radiotherapy, chemotherapy plus palliative radiotherapy, or best supportive care.

    So when we looked at this whole cohort, this is rather than trial patients, this is real-world outcome, real-world patients that we are seeing across these centers. So we had 10% of patients who had performance status three/four, about 20% who had performance status two. The median age was 71, and about 80% of patients had T3-4 disease, about two-thirds had clinical N1 disease, and about a third had N2 with a small number having N3 disease.

    I'm just putting up the characteristics of the... So when we look just at the radical radiotherapy and the radical cystectomy group for the later comparisons. So the significant difference was in median age. So the radical cystectomy patients were younger than the radical radiotherapy patients, but otherwise in terms of performance status and T stage and clinical end stage at NDT, they were well-matched.

    So this is just showing some of our results. So this is showing the whole cohort of patients receiving treatment. So when we look at this whole group, including those low-performance status two and three patients, we see that actually this cohort overall does quite poorly. So the median overall survival across this whole group is about a year and a half. We had a median follow-up here for about four and a half years, and when you look at the whole cohort, the two-year overall survival is about 40% and the five-year is about 20%.

    If we separate out those patients into those who received a radical type treatment, these patients do better. So the median of survival in those patients who received a radical treatment was two and a half years with about 50% alive at two years and about a third alive at five years.

    So if we look just at those patients who received a radical type treatment and divided it into those who had radical radiotherapy and radical cystectomy, we saw that there was no difference in overall survival or progression-free survival between these two curves and no difference in median overall survival between these patients. We also looked at, so in terms of those who received chemotherapy... So there was the absolute number or the percentage of patients in the radical cystectomy group who got chemotherapy was a little bit lower than the radical radiotherapy group. There wasn't a significant difference. So we wanted to look at just selectively those patients who received both a radical type treatment and had chemotherapy, and again, we saw no difference in survival or progression-free survival between whether you had radical cystectomy or radical radiotherapy as your radical treatment.

    So in summary, overall survival in this cohort, patients with clinical and positive, but nonmetastatic bladder cancer is poor, but it is higher in those patients who get to receive a radical intent treatment. We saw no difference in overall survival, whether you receive radical cystectomy or radical radiotherapy. And so our data supports the use of bladder preservation as a treatment option alongside radical cystectomy to be offered to all patients who have clinical and positive a nonmetastatic bladder cancer.

    Leslie Ballas: Thank you and congratulations. This is really important work, and I think the question of what to do with clinically lymph node-positive patients is one that we all struggle with. Now tell me a little bit about, on our NCCN guidelines here, most of these patients would get neoadjuvant chemotherapy followed by some form of radical treatment. I noticed that not all of your patients got neoadjuvant chemotherapy. I think it was somewhere close to 70% or so that got neoadjuvant chemo? Did those patients do better, do you know?

    Martin Swinton: I suppose we haven't separately looked at a comparison of chemotherapy versus no chemotherapy. We wanted to do a comparison of... Showing that comparison of those who had chemo and to show there wasn't a difference between radical radiotherapy and radical cystectomy. I suppose in terms of typically, so some patients who didn't get chemotherapy would be due to things like not having a good enough EGFR, which might exclude chemotherapy, but we haven't done a comparison of chemo versus not.

    Leslie Ballas: So your typical paradigm in the clinical setting would be to give these patients with node-positive disease, neoadjuvant chemotherapy followed by some radical treatment, whether it's chemoradiation or cystectomy.

    Martin Swinton: Yeah. So if a patient who doesn't have anything preventing chemotherapy, they would typically be started on chemotherapy. I suppose there's a question whether we call that chemotherapy, neoadjuvant chemotherapy because I suppose there's a lot of... Some clinicians would say that... I suppose one of the reasons we put this comparison between radical and palliative treatment is some people consider these patients to be palliative essentially within positive disease. And so these patients are started on chemotherapy, platinum-based chemotherapy, but sometimes a clinician may or may not call that neoadjuvant chemotherapy. They may be calling it palliative chemotherapy.

    So I think typically these patients are started on these chemotherapies, they'll often get a CT scan after three cycles or receive six cycles, and there'll then be a decision based on if there's a response and if there's a lack of metastatic disease appearing after that chemotherapy, they might then receive a radical type treatment. And then I suppose you could then post-hoc call that neoadjuvant chemotherapy. So I suppose it highlights that in this setting it's difficult. It's difficult to define the term, so we call the primary chemotherapy to kind of cover both.

    Leslie Ballas: And that's how we would typically treat patients here and as is reflected in our NCCN guidelines, we just happen to, I guess call it maybe neoadjuvant chemotherapy. But yeah, semantics. I get it. We know in bladder cancer that there's a large difference in terms of clinical staging and pathologic staging. And so I'm wondering if you saw in the radical cystectomy cohort, if there was that same difference in terms of a clinical node-positive versus pathologic node-positive. Were you getting good and accurate readings of nodal disease in these patients?

    Martin Swinton: Yeah, we didn't put the data into the paper yet, but we did look at, because I suppose, so obviously in the patients who had radical radiotherapy, we don't have any pathological staging to compare in the surgical cohort. We could compare the clinical and the pathological node status. I suppose, so there is some upstaging and down staging at surgery of which the other complicating factor is a lot of these patients have chemotherapy. So it's difficult to know whether is the clinical node-positive disease, how accurately does it represent pathological nodal disease versus did you have true pathological disease then that's then responded?

    When we looked at correlation between clinical and pathological nodal staging, the commonest things were clinical N1 stay in clinical N1. Sorry, clinical N1 being pathological N1. N2s being pathological N2. Of the patients that were pathological N-not most of those patients were clinically N1 at presentation. I think those sort of comparisons... It's probably quite helpful if you had two surgical cohorts, you could compare how well that your clinical staging was at. You could use your pathological staging to compare how your clinical staging, but we don't have that with the radiotherapy cohort. I suppose it's a difficult comparison.

    I suppose ultimately though we have to make these decisions based on clinical nodal status. We don't think there's any reason that the kind of correlation between clinical and pathological staging will be different between these two groups. So we saw in the surgical group that something like five or 10% of these patients had N-not disease when you took it out. And I suppose we'd expect that to be the same in the radiotherapy group, but I suppose without surgery you can't prove that, but there's no reason why it would be, that we can see that it would be different.

    Leslie Ballas: And I guess your staging evaluation was based off of CT and I believe the EAU guidelines of greater than eight millimeters or greater than one centimeter. Do you ever in these patients use PET as part of the staging and do you think that would've made a difference in terms of determining more clinically node-positive patients?

    Martin Swinton: So yeah, we are not routinely getting PET scans in these bladder patients. I suppose it might change things in a few ways. So for one thing, you'd probably expect some upstaging of... Expect some metastatic disease, occult metastatic disease to be detected in some of these patients, which would take them out of this cohort because we are looking at non-metastatic patients. Again, you might have, I suppose you might improve the accuracy by when you have... So I suppose the patients that were clinically N1 and then were pathologically N-not some of those patients, the PET scan may not be avid and you might have slightly better accuracy, but I suppose. But yeah, so these patients didn't get PET scans, but again, we think between the two cohorts, the radical cystectomy and the radical radiotherapy, they had the same staging. So these groups should be similar.

    Leslie Ballas: I noticed in the paper in the table one where you define characteristics for the patient population that only about 80, 85% of patients had pure urothelial carcinoma. You've got some that have a mixed histology urothelial plus some variant histology, and then obviously some that have a variant histology are those patients that have mixed or variant histology getting different chemotherapy? It becomes harder to compare a pure urothelial patient to maybe a variant histology patient if they're getting different chemotherapy regimens.

    Martin Swinton: Yeah, it's a really good question. So I suppose the problem is, so you are already talking about for bladder cancer, which is a reasonably less common cancer. We've got patients with clinical and positive nonmetastatic disease, which is five to 10% of those patients, I guess once you start getting into, it's difficult to tease out the variant histology in this. So we've combined it and not separated it. I suppose that the main differences, so the patients that received different chemotherapy were those who had small cell or neuroendocrine histology, and there was about, I think there was four patients in that. So there was a small number of patients that got a different chemotherapy, so they would get a carboplatin etoposide, but the vast majority of patients receive the same chemotherapy. I suppose it is more difficult if you have those patients with variant histology, how applicable the overall results are of this, but it's going to be difficult to ever get large numbers in those sorts of patients to have good data.

    Leslie Ballas: Do your clinicians there have equipoise in terms of treating variant histologies with chemo chemoradiation versus mastectomy, or are variant histologies more funneled toward one treatment or the other?

    Martin Swinton: So I think definitely small cell of the bladder doesn't tend to get surgery, tends to be treated with chemotherapy primarily. And then if they are going to get a locally directed treatment, it would be radiotherapy. But I think otherwise, as far as I'm aware, I don't think there would be with other histologies, I don't think there's a particular lean towards one treatment or the other.

    Leslie Ballas: Did you happen to notice any difference in outcomes based on the number of lymph nodes that were involved? There's some data in the surgical literature, certainly. One of the papers that you cited in your background, the large series from USC, the Stein data showing that five lymph nodes or more patients would do worse following cystectomy. I'm wondering if you had any of that same determination in your group?

    Martin Swinton: So the comparison that we made, we did a multivariate analysis of the patients who received a radical type treatment and there we compared those patients who had clinically N2 or N3 disease against those patients who had clinical N1 disease, so have a single lymph node and the overall survival was worse in those patients who had N2/N3 disease. We didn't separate out number of lymph nodes. And I think again, you'd run into this trouble of how many patients you'd get for each number. It's just difficult to get anything meaningful or get anything significant from that.

    Leslie Ballas: Fair enough. Yeah, I mean the Stein paper had a thousand patients, so it's a different magnitude obviously. Do you have any data, and maybe I missed it in the paper, on patterns of failure? Patients, were they failing distantly? Did patients fail in the bladder in those who got radiotherapy? What did you find?

    Martin Swinton: Yes, so we have collected some of that data, but we haven't analyzed it yet. So that is something that we are looking to analyze. That would be a really interesting question of, where are these failures happening? I suppose our suspicion given that it didn't seem to matter whether you got radiotherapy or radical cystectomy is that maybe a lot of these failures are actually distant failures, so maybe your local therapy of choice doesn't matter as much.But yeah, so we have some of that data collected, but again, we've not analyzed it yet.

    Leslie Ballas: There have been a couple of publications for node-positive patients. The IMPART data trial, as well as DUART data. And those are both small studies that include node-positive patients. But both of them sort of indicated that there wasn't really much difference in terms of outcomes in terms of the clinical N0 and clinical node-positive patients, which was sort of surprising to me because I mean we think of those patients as doing worse. And obviously based on your five-year overall survival rate of 34, 33%, which is very similar to surgical data in the same population, when we look at those who got radical therapy, that's not obviously what we would think of as a good or appropriate outcome in patients who have node-negative disease. And so what do you think? Do you think that patients who have node-negative disease, and node-positive disease, that maybe that's a function of small sample size on those trials or difference in therapy? What are your thoughts there?

    Martin Swinton: Yeah, So I suppose with our data, we didn't collect any data on patients with node-negative disease. So I guess we can't directly compare in the same patients, but as you say, it's what from our practice, it seems that these patients do worse in this state of these patients. Their overall survival is very poor and even though they've got radical treatment don't do as well as those patients in other series who had either surgery or radiotherapy. So they do seem to do much worse than that. Yeah, because I think where the IMPART data is, it's sort of 38... So to say small numbers, it's 30, 40 patients.

    Leslie Ballas: Yeah, and IMPART and the DUART is similarly small. Yeah. Okay. I think we certainly are very excited to see this data that you have published. Mostly because like I said, what to do with these node-positive patients is something that we discuss a lot at our tumor boards. And so this really helps us figure out different options for radical treatment and that they appear to be equivalent in this population is exciting to see. So thank you to you and your team for publishing this. Is there anything else you want to tell us? You've given us a great recap of the data.

    Martin Swinton: Yeah, I suppose the only other things I didn't talk about in terms of time, I suppose we also looked a bit about outcomes in terms of the questions of adding a radio-sensitizer and what field you treat. So we had a slightly unexpected... Well I suppose the patients who received a radio-sensitizer didn't have an improved overall survival in this cohort. And I suppose we feel that given that there's sort of level one evidence in the node-negative setting that from randomized trials that there is a survival benefit or there's a benefit. We think that probably this is not... We would still recommend giving a radio-sensitizer when treating these patients.

    The other question we were interested because some variation in UK centers of what field you treat when you treat these patients. So some centers would give bladder only radiotherapy as in console the bladder and give a 1.5 centimeter expansion and treat that with say 55 grade and 20 fractions. Whereas some centers would also would do that plus given elective dose to the pelvic lymph nodes. So we looked then at survival outcomes between those that received pelvic lymph, just bladder alone and nodes as well. And actually there was no benefit that we saw in this for giving a dose to the pelvic nodes.

    Leslie Ballas: Yeah, I think though it will be important when you get your recurrence data to see if those patients are failing in the nodes. It might not be enough to drive overall survival, but my first thought was we don't know where they're failing.

    Martin Swinton: Yeah, that's fair. And I suppose one of the things that we... With what we call bladder only radiotherapy, actually with that expansion we are giving quite a lot of dose to adjacent lymph nodes as well. So it might be that that's the difference. Even though with that data, the other things we're not sure if there might be some difference in the patient. So it may be that someone who has say a residual small node, a clinician might be more likely to add in pelvic lymph nodes. So it might be that there's some bias between those two groups.

    Leslie Ballas: Certainly something to think about because we do also struggle with the question of whether or not to do bladder only, which is a much more commonly done in the UK versus the classic RTOG teaching, which was to do a small pelvis along with the bladder. So I think that's something that we're all still trying to figure out. So thank you for that data as well. Thank you so much for joining us today. I really appreciate it.

    Martin Swinton: Thank you very much.


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