Device-Assisted Therapies for Bladder Cancer: History, Mechanisms, and Clinical Trials - Wei Shen Tan

August 3, 2023

Ashish Kamat and Wei Shen Tan delve into a discussion on the advances in device-assisted therapies for non-muscle-invasive bladder cancer. Dr. Tan details the history, mechanisms, and clinical trials of various therapies including chemohyperthermia and electromotive drug-administrated chemotherapy (EMDA). He also highlights newer treatments such as the TAR-200 system and Jelmyto. Despite promising early-phase data and their general tolerance, Dr. Tan underlines that more research is needed to confirm the efficacy of these treatments, especially considering differing results according to specific patient populations. He emphasizes the potential of these therapies to enhance treatment for patients with intermediate-high risk disease and those unresponsive to Bacillus Calmette-Guérin (BCG) therapy. Both physicians anticipate further advancements in this field, suggesting a promising future for device-assisted bladder cancer therapies.


Wei Shen Tan, MD, PhD, FRCS (Urol), Urologic Oncology Fellow, Department of Urology, MD Anderson Cancer Center, University of Texas, Houston, TX

Ashish Kamat, MD, MBBS, Professor, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, President, International Bladder Cancer Group (IBCG), Houston, Texas

Read the Full Video Transcript

Ashish Kamat: Hello and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of urologic oncology at MD Anderson Cancer Center. Joining us again today on the forum is Dr. Wei Shen Tan, who is currently a fellow here with me at MD Anderson, but who has independently established himself as somewhat of an expert in device-assisted therapies for non-muscle-invasive bladder cancer.

Shen, you've done a lot of work in this arena and you've developed a lot of expertise, so thanks again for taking the time and spending it with us today and sharing your insights into this topic with our audience.

Wei Shen Tan: Great. Thank you very much, Dr. Kamat, as well as UroToday, for the opportunity to talk about device-assisted therapies for non-muscle-invasive bladder cancer. This is something that I've done some work on back in London at UCL together with John Kelly.

Some conflict of interest. I've worked with these companies in terms of designing clinical trials, as well as been a consultant for them as well.

Treatments for non-muscle-invasive bladder cancer typically involves interval cycle treatments in the form of BCG or chemotherapy. Device-assisted therapies came about because of options that clinicians want to augment the efficacy of treatment for these interval cycle treatments, particularly in intermediate high-risk disease where we can improve efficacy of treatment, as well as also in the BCG-unresponsive setting where some of these patients, who might not be candidate for cystectomy or might not be keen for a cystectomy might have alternative treatments in the form of bladder-sparing approaches.

There's several device-assisted therapies out there in the market. The most well-established one, particularly in Europe, is chemohyperthermia. There are typically two forms of treatment. The radiofrequency chemohyperthermia where there is a catheter with radiofrequency antenna that delivers heat and heats the urothelial lining and chemotherapy is circulated within the system. You also have the conductive chemohyperthermia system which essentially pumps hot, heated chemotherapy from the outside into the bladder itself.

The other treatment is EMDA, which stands for electromotive drug-administrated chemotherapy. EMDA uses a special catheter that has an electrode and also a cutaneous electrode. This increases the permeability by increasing the penetration of mitomycin drug into the bladder lining.

More recently, there have been two other device-assisted treatments. The TAR-200 system, which essentially is gemcitabine slow-release system in the form of a pretzel and, over the course of seven days, this releases gemcitabine within the bladder itself. Also, Jelmyto which, essentially, it's a gel that solidifies at body temperature when heated and is liquid at room temperature. Both TAR-200, as well as Jelmyto, works on the concept that it increases the contact time between the tumor and with chemotherapy.

In terms of chemohyperthermia, chemohyperthermia, there's good evidence to suggest that it works in vitro, as well as in vivo. The concept of chemohyperthermia is not new to bladder cancer and there's good level one evidence for colorectal cancer as part of surgical treatment as well.

Chemohyperthermia works by increasing cell necrosis, as well as apoptosis. It works in the immune system by activating T-cells, as well as heat shock proteins. It causes denaturing of proteins and also increases the permeability of cell membranes so that drugs can act better and it's been used for over 15, 20 years now in bladder cancer.

There's been quite a lot of data out there for chemohyperthermia and in the next coming slides, I'll be summarizing some of the data. In this slide here, there is RITE, which is the radiofrequency hyperthermic, conductive hyperthermia, as well as EMDA.

For radiofrequency hyperthermia, there have been several randomized trials out there, one comparing mitomycin against radiofrequency hyperthermia, another one comparing BCG and radiofrequency hyperthermia. These are patients who are intermediate risk, as well as high-risk patients. There's also a trial looking at BCG failures. This was done in the pre-BCG unresponsive definition era so where radiofrequency was compared to standard of care, which typically comprised of BCG.
In terms of the conductive hyperthermia, there have been three randomized trials as well, two of them HIVEC I and II, evaluated intermediate risk, so heated chemotherapy versus room temperature chemotherapy for intermediate risk. And there's HIVEC-HR that looked at high-risk papillary disease.

In terms of EMDA, there have been three randomized trials. However, one of them was sort of immediately post-op treatment and will focus on the two adjuvant treatments where EMDA was compared against BCG, as well as mitomycin. Another alternative approach was alternating EMDA treatment with BCG versus BCG itself and we'll go through some of the data out there that's been published.

This represents one of the early studies looking at radiofrequency hyperthermia and this paper here, they looked at long-term outcomes. For a median follow-up of 91 months, patients with intermediate and high-risk non-muscle-invasive bladder cancer treated with radiofrequency hyperthermia had actually a much better disease-free survival here. At 10 years you can see 53% versus 15% for just passive room temperature mitomycin. However, as one expects, there is no difference in terms of overall survival and this is pretty common in non-muscle-invasive bladder cancer because the event rate for death actually is quite low.

Moving on, subsequently, Fred Witjes, as well as Tom Arends, looked at patients with intermediate and high-risk non-muscle-invasive bladder cancer. This was predominantly in a BCG-naive treatment cohort. They compared BCG versus radiofrequency hyperthermia and with a median follow-up between six months, they found actually there was no difference in intention-to-treat analysis. However, looking at per-protocol analysis, there was actually a significant difference where patients treated with chemohyperthermia had a lower risk of recurrence, 18% versus 35% at the median follow-up, suggesting that there is potentially a benefit for chemohyperthermia in intermediate and high-risk patients.

It's important to point out that this data, that it was reported only included papillary-only patients. So although the trial included CIS patients, CIS patients were never really reported in this publication here.

We've also published, and this is the HYMN study, and the HYMN study was looking at patients who had recurrence following BCG treatment so this is all come as a BCG treatment. This includes some patients with unresponsive BCG-intolerant and essentially BCG failures. This trial interestingly closed early because of patients with CIS +/- papillary so it was unexpected that we recruited more patients with CIS disease. In the patients actually with CIS +/- papillary, chemohyperthermia-treated patients actually did significantly worse compared to the control arm. In the control arm here, this typically comprised of 60% of BCG and the remaining patients were treated with either mitomycin or EMDA.

Overall, there was no difference in treatment between the two treatment arms, but interestingly, in papillary treated-only patients, we found the reverse actually. That although there was no difference because of very small subgroup balances and because the trial closed early, we found that patients with papillary-only disease actually did better when treated with radiofrequency hyperthermia compared to control itself. That's 54 versus 25% at 24 months, suggesting that they might be a signal in papillary-only-treated patients. However, in the data for CIS was actually the inverse.

Synergo recently has been evaluated by NICE. This is the National Institute of Health and Care Research in the UK. NICE has actually allowed for the use of Synergo, which is the radiofrequency hyperthermia system in patients with high-risk non-muscle-invasive disease after they've had recurrence following BCG treatment, as long as they are part of a prospective data collection audit. So now in the UK, NICE has sort of allowed the use of Synergo in this patient population.

Moving on to conductive hyperthermia, as mentioned earlier, there have been two large randomized controlled trials, HIVEC I and HIVEC II. Both evaluated patients with intermediate risk, non-muscle-invasive bladder cancer. HIVE I had three arms, passive, room temperature, mitomycin versus 30 minutes of heated mitomycin, versus 60 minutes of heated mitomycin. This was a multicenter study that recruited patients throughout Spain. HIVEC II was a multicenter study throughout the UK and randomized patients to essentially room temperature mitomycin versus heated mitomycin for 60 minutes and both trials actually recently reported outcomes.

First, HIVEC II, and I was privileged to be part of this study together with John Kelly, and HIVEC II, we reported that there was no difference essentially in disease-free survival comparing the two treatment arms. We also evaluated various subgroup analysis looking at patients with recurrent disease with grade I versus grade II multifocality, as well as tumor size, and we found that there was no difference, essentially, regardless of the subgroup that we looked at. There was, however, a significant difference in progression-free survival favoring actually room temperature mitomycin. This is likely due to small numbers itself because the number of progression rates in this patient cohort was actually quite low. So, overall, we do not find that chemohyperthermia was beneficial from an efficacy point of view in intermediate risk non-muscle-invasive disease.

HIVEC I actually mirrored the results of HIVEC II and the authors found that there's no difference in patients treated with 30 minutes of chemohyperthermia versus 60 minutes of chemohyperthermia in terms of recurrence-free survival. So there is good data now to suggest that two randomized trials, both an intermediate risk, both recruiting each of them 300 to 200 patients, suggesting that an intermediate risk disease conductive chemohyperthermia but no benefit in terms of efficacy.

HIVEC-HR looked at high-risk patients and at this study they recruited just 50 patients randomized one-to-one ratio looking at papillary-only high-risk, 50% of these patients had T1 disease. They found no difference in recurrence-free survival between the two treatment arms and in progression-free survival they showed like a benefit for chemohyperthermia with a P value of 0.043. It's important to point out that this study only had 50 patients and in terms of sample size and power calculations, it will be difficult for it to provide definite conclusive results.

Moving on to some of the data in terms of electromotive EMDA treatment, most of the studies that we'll go through and from EMDA actually has been published by Di Stasi. In this study they looked and compared outcomes between EMDA versus BCG, as well as mitomycin. They found that EMDA and BCG had similar efficacy in terms of recurrence rate and room temperature mitomycin had a significantly lower recurrence rate. However, in terms of time to progression there was no difference between the three treatment arms.

Di Stasi also looked at sequential treatment where BCG was given an alternation with EMDA and this was compared against BCG. In this study here, quite interestingly, they reported that in terms of disease-free survival, progression-free survival, as well as disease-specific survival, there was a benefit for alternating treatments of BCG and EMDA compared to BCG alone. Of course, this represents one randomized study and results of this would require further validation, but these report quite promising outcomes for EMDA.

In terms of safety and efficacy, these treatments are relatively quite well-tolerated. Most patients, in terms of adverse events, they tend to occur around the time where treatment is delivered. More common adverse events include hematuria, UTI, suprapubic pain and discomfort. They also can get allergic reaction, very similar to passive mitomycin itself. So generally, they are pretty well tolerated. High-grade major complication rates are quite low actually in terms of the treatments of these device-assisted treatments.

Moving on, there have been more newer device-assisted treatments and in this study here, they look at Jelmyto. Jelmyto is the gel that solidifies at body temperature. So Jelmyto has already been approved by the FDA to treat upper tract disease in terms of ablation for upper tract low-grade tumors and this study they evaluated the role of Jelmyto in chemoablation of intermediate risk non-muscle-invasive bladder cancer patients. These patients were treated with six -weekly treatments itself and they reported a quite impressive response rate of 65% at three months, suggesting that Jelmyto is quite effective in terms of chemoablation for bladder tumors.

This is pretty impressive when compared to other treatments where chemoablation has been administered, which typically could range from somewhere between 28% to about 60+% percent as well. Interestingly, the patients who had chemo had complete response following chemoablation, 73% of them continued to remain recurrence-free at 12 months. Jelmyto has been evaluated in the phase three single-arm study looking at chemoablation. This study, ENVISION, has completed recruitment and data would be equally awaited.

The other treatment would be the TAR-200 system. This represents a phase one study in muscle-invasive bladder cancer, actually, where patients were treated with the gemcitabine slow-release pretzel for seven days. In this study of muscle-invasive bladder cancer, they report a pathological response rate of between 40 to 60%. In Arm 1 here, as you can see, that was patient treated with radical cystectomy and in Arm 2 are patient treated with TURBT itself. The response rate seems to be pretty good for patients and this represents early phase, phase one data.

This gemcitabine has been released so it's currently being evaluated in multiple studies. These are the SunRISe studies 1 to 4, SunRISe 1 and SunRISe 3 evaluating patients with non-muscle-invasive bladder cancer. Here, as you can see, BCG unresponsive, CIS +/- papillary. In SunRISe 3, they're evaluating the gemcitabine pretzel in high-risk non-muscle-invasive bladder cancer. In SunRISe 2 and 4, patients with muscle-invasive bladder cancer is being evaluated and these data would be quite interesting and equally awaited.

In conclusions, there are multiple agents out there at this point. Chemohyperthermia, it's probably been around for the longest with the most amount of data. However, sometimes these data, it's a little bit mixed and might pose more questions than answers.
I feel that for radiofrequency treatment there is some reasonable data to support its use in papillary disease. The data for CIS is to be decided. In our study and the HYMN study, we didn't find that it was beneficial. However, there's some limitations in terms of dose and so on. In terms of chemoablation that remains untested in chemohyperthermia whether it would increase the CR rate compared to just room temperature treatment.

EMDA has reported pretty impressive results, particularly in BCG and EMDA treatment. However, this requires further validation. Jelmyto, as well as TAR-200, early stage data is actually pretty impressive and late phase trials would be equally awaited.
Thank you very much.

Ashish Kamat: Thank you, Shen. I mean, that was a nice summary of the current status of essentially device-assisted therapies. Let me ask you, based on your extensive work in this area and your insight into the field, to clarify a few points.

First off, you said there's reasonable data to support papillary disease, but that's based on sort of small number, single-center studies or subgroup analyses. In your own study where you actually looked at the intermediate risk patients, you did not show a benefit. So could you sort of help our audience understand whichpatients you might say that the chemohyperthermia is potentially beneficial for, even if they have papillary disease?

Wei Shen Tan: Oh, thank you very much for that. I think it's very important to clarify that they are different treatments for chemohyperthermia. You've got the radiofrequency treatment, as well as the conductive hyperthermia.

In terms of the radiofrequency treatment, there is randomized data to support its use where it's superior in terms of comparing chemotherapy versus radiofrequency with chemotherapy in intermediate high-risk disease. That was from the initial Colombo study.
The Witjes study looks at this and they showed a signal in the per-protocol analysis. This was compared to BCG, so chemohyperthermia, radiofrequency chemohyperthermia versus BCG and it shows that there was a benefit for the papillary-only patients.

In our study that looked at patients who are essentially BCG failure, we showed that while there was not a significant difference based on small numbers, we did show, we report that the patients treated with papillary-only disease actually had a lower rate of recurrence. This is data for radio radiofrequency hyperthermia.

In our other study looking at HIVEC 2 and similarly data from HIVEC 1 as well, in the intermediate risk disease, I feel that the case is closed for conductive chemohyperthermia. There are two big studies now, randomized studies reporting data and I think it's pretty definite that there's no increase in efficacy when using conductive chemohyperthermia.

So it is still debatable in terms of outcomes for high-risk disease itself for conductive chemohyperthermia. In theory, we don't have data out there at the moment, but it doesn't work in intermediate risk disease and I'm not too sure in terms of efficacy and how well it would work in high-risk disease.

Ashish Kamat: Right. Again, just to clarify for the audience, in conductive chemohyperthermia, the chemotherapy is heated and then delivered. In radiofrequency hyperthermia, the chemotherapy is sort of heated in situ, in the patient's body itself because of the radiofrequency waves. Important distinction to be made.

Now, just to clarify again, in North America, Synergo is not available, even though many of us have been studying it and trying to get it in the US and until, of course, the FDA-approved studies are done, it will not be available. But in countries where it is available, that is certainly an option for our patients.

Now in someone that is considering chemotherapy, say with combination chemotherapy with gemcitabine and docetaxel, do you have any insight or any knowledge of studies with chemohyperthermia with combination chemo?

Wei Shen Tan: Currently, I don't think that there is any reported outcomes for combination chemotherapy and that'll be quite interesting to see whether it will potentiate the efficacy of combination chemotherapy.

Ashish Kamat: You talked about EMDA and again EMDA is something that, as you rightfully mentioned, Di Stasi had done work with decades ago. It's been somewhat puzzling to many of us and I've talked to Emilio in person many times as to what has happened with the company, how come things haven't moved forward.

So again, I think, like you said, until there's further validation, EMDA remains sort of a one-trick pony and we need to see what happens with that moving forward. I do hope that somebody picks it up again and moves forward because the results with EMDA appeared almost, in some ways, too good to be true and we really need something that's that extensively better than BCG for our patients.

Then you alluded to the UGN and the TAR-200 platforms. There is a TAR platform that uses erdafitinib as well, which might be appropriate for patients with FGFR alterations and, of course, as you mentioned and alluded to in the SunRISe studies, those are certainly exciting avenues.

In summary, Shen, if you would essentially highlight in brief what do you think the future holds for device-assisted therapies?

Wei Shen Tan: I think the data to-date, particularly in chemohyperthermia, there's a lot of data out there, but a lot of the data with the trials could have better designed in terms of reaching their efficacy, their endpoints. They have been around for some time and to-date, we don't have definite, solid, positive studies. I think we've got several positive studies for radiofrequency, like the HYMN study was sort of closed early. For conductive chemohyperthermia, currently, we've got some studies, but they were negative itself. So I think there's more work that needs to be done, even though chemohyperthermia has been used quite extensively over many years now. EMDA particularly also requires further validation.

I think in terms of Jelmyto, as well as TAR-200, they are systematically going about doing these trials that would report very interesting outcomes. I think these results are equally awaited to see whether they could be added onto other treatment options that we have for non-muscle-invasive bladder cancer.

Ashish Kamat: Great. Thank you again, Shen, for taking the time and for spending it with us.

Wei Shen Tan: Great. Thank you very much, Dr. Kamat.