Ashish Kamat: Hello, and welcome to UroToday's Bladder Cancer Center of Excellence. I'm Ashish Kamat, professor of Urologic Oncology and Cancer Research at MD Anderson Cancer Center. And we have with us today Dr. Wei Shen Tan, who is currently a fellow with us here at MD Anderson, but has done a lot of this work that he's going to present today, when he was a lecturer at the University College of London in the UK.

And of course, Dr. Tan has done and reported on other randomized clinical studies, but this one here really generated a lot of buzz in the bladder cancer community, and the adjuvant chemotherapy community, and really excited to hear what you have to say Shen. So with that, the stage is yours.

Wei Shen Tan: Great. Thank you very much Dr. Kamat for that kind introduction, and UroToday for the opportunity to share some of the HIVEC-II results.

HIVEC-II is a randomized controlled trial done across the UK, where we compared patients treated with adjuvant chemohyperthermia with mitomycin ( chemotherapy) against passive mitomycin at room temperature in  intermediate-risk non-muscle invasive bladder cancer.

One conflict of interest to declare is that I was a  consultant to Combat Medical. Combat Medical is the company that supplied the  hyperthermia delivery system, and also funded the trial itself, but Combat had no say in the running of the trial, decision to publish, and also, the trial protocol and design. Whatever I say here today, represents my opinion, and has nothing to do with Combat.

Adjuvant intravesical chemotherapy is the recommended standard of care, and it's been proven to reduce the risk of recurrence in non-muscle invasive bladder cancer. As the audience well know, we use chemotherapy as well as intravesical BCG, to reduce the risk of recurrence in this patient cohort. There is significant evidence to suggest that in vitro and clinical studies support the role in chemohyperthermia. This is particularly important because of the constant ongoing issue with BCG supplies. Hence, alternatives to BCG are definitely required and needed in the clinic. Chemohyperthermia works in several ways. It works by denaturing protein in cancer cells, by activating heat shock protein, that then activates T-cells. It increases the permeability of the drug, so that increases absorption into the cancer cells, which leads to cellular necrosis, as well as apoptosis. In the field of bladder cancer, chemohyperthermia, typically in most cases, are delivered through a device assisted method, where the bladder can then be heated up, and chemotherapy be instilled intravesically, as seen in the diagram

There is a lot of data out there to support the role of chemohyperthermia. And if you look at Fred Witjes’ group publication in  2016, they showed that in the BCG naive group, patients with papillary only diease treated with the Synergo radiofrequency system had better outcomes compared to BCG in the per protocol analysis.. This was not significant using the intention to treat analysis.

However, we published our HYMN study. HYMN represents a randomized controlled trial comparing in patients with recurrence following BCG treatment, comparing radiofrequency hyperthermia compared to control institutional standard practice, which predominantly comprises of a second re-challenge of BCG. This trial was actually stopped early because in the CIS plus papillary cohort of patients,  the patients with chemohyperthermia actually did worse, compared to the control arm.

However, on intention to treat analysis of the whole patient cohort, there was no significant difference between treatment arms. But quite interestingly, when you look only at the papillary only disease, and you exclude the CIS patients, you do see this widening of the Kaplan-Meier curves favoring chemohyperthermia. Although in subgroup analysis, the limited number of patients suggest that this was not significant.  This signal was very similar to what Fred Witjes’ group published in European Urology in 2016.

Look back to the HIVEC-II study, the HIVEC-II study looked at intermediate-risk non-muscle invasive bladder cancer patients, stratified patients by hospital at randomization, and compared chemohyperthermia delivered by six weekly installations, at 40 milligrams of mitomycin, at 43 degrees Celsius for an hour. Again, the control arm, with six weekly mitomycin,  40 milligrams of mitomycin at room temperature for an hour. The primary endpoint was disease-free survival at 24 months, with various oncological secondary endpoints, as well as safety and tolerability as secondary endpoint. And this study was powered to identify a 12.2% difference in disease-free survival between the two treatment arms, leading to a sample size of 259 patients, who were recruited across 15 centers.

This diagram represents a summary of illustration of the HIVEC system. A HIVEC system essentially heats up the mitomycin using an aluminum heat exchange system. It has a bubble trap and a pump that pumps the chemotherapy through a 16 French catheter into the bladder, and this is recirculated back into the system. And this goes on for about 60 minutes.

Here  are some of the results. This represents the patient demographics for the control arm, as well as the chemohyperthermia arm. They were equally balanced, with roughly 50% new diagnosis, and the remaining 50% of patients with previous recurrences. This was a predominant pTa patient cohort, and most patients actually had grade two disease in this patient cohort. Most patients, again, had less than two tumors, and had tumors  less than three centimeters in tumor size.

These are some of the results. This represents an intention to treat and per protocol analysis Kaplan Meier curves for disease-free survival between the two cohorts. As you can see here, there is actually no difference in chemohyperthermia against the control arm in the intention to treat analysis, as well as in the per protocol analysis.

And moving on, if you look at the progression-free survival data for intention to treat, there was actually a significant difference favoring the control arm and the intention to treat. However, this was  not significant following per protocol analysis. This difference likely represents a very small number of event rates in the progression data. As you can see, the confidence intervals are really wide. In total, four chemo hyperthermia patients developed disease progression and none of them in the control arm. Eight patients in the chemohyperthermia arm died without disease progression, and another four in the control arm. So these are very small number of events and might explain a significant differences in the progression data.

We also did some exploratory subgroup analysis, looking at whether stratifying patients according to new diagnosis versus recurrent disease, grade one versus grade two, less than two tumors versus more than two tumors, and also size of tumors. And we did not find any differences when we compared  treatment between chemohyperthermia and the control arm.

Looking at the safety data, the safety data suggests that chemohyperthermia is pretty well tolerated. There is very few grade three or more adverse events. There was more frequency, as well as more hematuria, in the chemohyperthermia arm. However, for the other adverse events, they were well balanced between the treatment and control arm.

If we look at the number of patients who completed treatment per protocol, there was more patients in the control arm completed treatment, 89% versus 59%. Most patients who did not complete chemohyperthermia was because of drug reactions or bladder spasm. It's also important to point out, there was some equipment issues that accounted for about nearly 20 patients treated with chemohyperthermia. I believe that these would have been addressable, and this was probably part of the learning curve of the treating center when they started to use the equipment.

In conclusion, the HIVEC-II results would suggest that there is no oncological benefit for chemohyperthermia over passive room temperature chemotherapy in intermediate risk non-muscle invasive bladder cancer. Adverse events with chemohyperthermia was low grade, and generally short-lived around the time of the delivery of treatment although, there were more patients who were unlikely to complete treatment. Based on the HIVEC-II results, we cannot recommend chemohyperthermia for intermediate-risk non-muscle invasive bladder cancer over passive mitomycin.

The result of the trial has been published recently in European Urology, and I'm very grateful for all the PIs for recruiting the patients. As well, in particularly, to John Kelly, my  mentor.

Ashish Kamat: Thanks very much, Shen. And congratulations once again to you and the entire group on completing this, and actually publishing the results of this randomized study. Very important. Given your findings, let me ask you a provocative question, and that simply is, to cut to the chase, what do you think is the role of chemohyperthermia in bladder cancer?

Wei Shen Tan: In my view, regarding the role of  chemohyperthermia,  it's important to acknowledge that there are several systems out there. This represents the conductive chemohyperthermia system. It is the first randomized trial published using this system. They have been some positive results from the Synergo system, which is a different system that works using radiofrequency. They have randomized data to support radiofrequency chemohyperthermia in  the BCG naive patients to some degree, as well as the intermediate-risk patients. I feel that looking at the HIVEC-II results, I would say that the case is closed for intermediate-risk disease.

For high-risk disease, if you are a purist from a trial perspective, there is no trial data. The Combat system has some retrospective data to support this use.

Ashish Kamat: Yeah. That's a good summary and distillation at the data that we currently have. Let me ask you this question, and have you done work in vitro, or have access to any data that suggests that the Synergo system, which we all know, it's a different mechanism of heating the chemotherapy, but also, incorporates radiofrequency with the antenna that's put in the bladder. Is there any data to suggest that that mechanism of action might be helping the results, other than the actual heating of the chemotherapy? Do you have any knowledge about that?

Wei Shen Tan: There is a study, a preclinical study, published in Scientific Reports, that suggests that using radiofrequency,  promotes the formation of nanotubules leading to increased permeability of the drugs into the cancer cells. These is a preclinical study. I don't know of any other study unfortunately, In our group, as well as other  preclinical models, particularly cell line work, chemohyperthermia is essentially delivered by  heating up the incubator to about 43 Celsius.

Ashish Kamat: All right. Now coming back to your particular report in HIVEC-II, you mentioned intermediate-risk, non-muscle invasive bladder cancer, and of course, you outlined the type of patients that were included in the study. For the purposes of our listening audience, could you just clarify in simple terms, what is this intermediate-risk? Is it the intermediate-risk bladder cancer patients that you, for example, have led an effort, through the International Bladder Cancer Group, in defining, or is this the AUA, or the EAU, or what classification did you actually use, and what should the audience be considering intermediate-risk, when taking into account the results of the study?

Wei Shen Tan: The intermediate-risk cohort here was actually derived from a historic EAU classification. It's important to highlight that, this predominantly comprises of a recurrent G1 pTa, or a new diagnosis G2 pTa. We actually did sensitivity analysis in this study, and we excluded the pT1 low grades, and there was no difference, essentially. They were really small number in the total patient cohort. Only about 10 patients actually had T1 low grade disease. So this is a predominantly G1, G2 pTa cohort of patients.

Ashish Kamat: And that's an important distinction I want to make for our listeners, because if you look at certain classification systems, the American Urological Association for example, and the new EAU, high grade or grade three small TA tumors are considered intermediate-risk. And this trial did not actually evaluate chemo hypothermia in that group of patients. Of course, we don't know whether it would work or not, but just to clarify what you said, that this is the intermediate-risk group of patients that are predominantly low grade, grade 1/2, and that's the old EAU classification, or the current IBCG recommendation classification of intermediate-risk.

Another question I have for you, Shen, is that, with all the data that you have, and I know you can't make conclusions based on your study per se, but is there a group of patients, leaving aside the small numbers and the subgroup analysis, et cetera, in whom you think that you would recommend chemohyperthermia over chemotherapy without heating it?

Wei Shen Tan: From looking at the data out there, if we look at Fred Witjes’ BCG naive patient cohort,  the HYMN study, as well as this patient cohort, I believe  that if you were to treat patients with chemohyperthermia, the patients that would benefit the most would be the papillary only disease. For the CIS disease patients, there were some discussions on whether the dose of the HYMN patient cohort was lower, and now the  company would recommend a higher dose of 80 milligrams rather than the  40 milligrams which was previous recommended and used in HYMN. Again, that is based on retrospective data, but I would say that, if you were to treat patients with chemohyperthermia systems, go for the ideally smaller tumors, solitary and if you are treating high grade disease, go for the patients without CIS. That's probably the patient cohort that would benefit the most in hyperthermia.

Ashish Kamat: Yeah. And you raise an important point about the dose of the chemotherapy. Just to clarify for the audience, I mean dose is important, but it's concentration that's also very irrelevant when you consider intravesical installation. Because the diffusion gradient depends on the concentration, not the absolute dose. And there have been changes in mitomycin formulation across the globe over the last five, six years, where previously, you could get a 40 milligram in 20 ccs, or 80 in 40 dissolution, but the current mitomycin formulation doesn't really allow that high concentration. So if you increase the current dose, you have to also increase the volume, which means that the concentration is lower, and that that's something to keep in mind when you're considering these studies or moving forward. Anybody that's considering designing prospective studies.

Another question for you that, again, feel free to give me your postulation or hypothesis, because again, it's not based on this particular publication, but do you think that there might be a role for enhancing the benefit that we are seeing with combination chemotherapy, using one of the techniques to provide hyperthermic chemotherapy? For example, gem/doce. We are seeing excellent results in BCG naive, and of course, BCG unresponsive populations, I mean, better than many thought. But moving forward, would you consider using a heating modality for combination chemotherapy?

Wei Shen Tan: I think there is scope to suggest that chemohyperthermia would work, even in the combination treatment. If you look at the patients using HIPEC, it is now the standard of care in selected group of patients (advanced colorectal cancer). Although, I acknowledge that there is preclinical data, there is the safety data that is needed  also, pharmacokinetics data to ensure that the drug does not lose its efficacy when it's being heated. But I think, that there is a role in combination chemohyperthermia.

The one thing that I also would want to point out, in terms of the trial, we use 40 milligrams, that was recirculated, but it's important to understand that there was also some priming fluid that was in the tubing system. So the actual concentration of the drug, it would be lower concentration that would be delivered into the bladder itself, if you're looking at a concentration effect. The reason for us using the 40 milligrams was based on the  manufacturer's recommendation. Currently, I believe that everyone who uses the Combat system still uses the 40 milligrams. But one could postulate that maybe, if you increase the dose, you could deliver higher concentration, and possibly the effect might be possibly better.,But it remains unproven, of course.

Ashish Kamat: Right. And that's why I brought that up. And I'm glad you clarified that, because it's a constant moving target. And anytime we have results that look suboptimal, one of the points in the manuscript, or the discussion as well, let's increase the dose, or let's increase the concentration. But at some point, we have to realize, that just increasing the dose will not necessarily increase the concentration, because there's a limit to how much you can have dissolution. And actually, one of our pharmacy students here at MD Anderson, published on this a few years ago, that many clinics think they're getting a higher concentration of mitomycin, but it's actually not true, because they just can't get it dissolved. So they get a higher concentration on the label, but that's not what the patient is actually getting.

But anyway, coming back to you, Shen, thank you so much for taking the time, and clarifying the results of this very important study. In closing, let me hand the stage back to you, and have you maybe share with the audience two or three of your top level messages from this publication.

Wei Shen Tan: So to summarize the results of the HIVEC-II study,  there is good data now to suggest that, in the intermediate-risk non-muscle invasive bladder cancer patient cohort, chemohyperthermia, using a conductive system, does not improve efficacy. The hyperthermia, however, it is pretty well tolerated, although, more patients did not complete treatment. There are very, few significant adverse events and is during the time of treatment delivery.  It is important to acknowledge, that we do not have data for the higher risk group of patients. Although, in the intermediate-risk disease, I feel that the, based on the HIVEC-II data, there is convincing evidence that it does not work in this patient cohort. Thank you.

Ashish Kamat: Great. Once again, thank you, and stay safe.