Janelle Hart

More minimally invasive treatments are being developed to manage benign prostatic hyperplasia, including the new Zenflow Spring System. This is a novel investigational device implanted transurethrally into the prosthetic urethra with the unique capability to be removed safely.

In a recent study, presented at the 2021 American Urological Association Annual Meeting,

 and co-authors assessed the efficacy of this new technology in treating patients with BPH. Chin is an associate professor at the University of Wollongong, New South Wales, Australia.

Please provide an overview of the Zenflow Spring System and its use in men with BPH.

The Zenflow is essentially a spring system. It's made of nitinol, and it's designed to open up the prostate, or the prostatic urethra, to allow relief of obstruction secondary to BPH.

What are the advantages of Zenflow Spring System compared with other treatments for BPH?

Most other treatments associated with BPH management involve either ablating the prostatic tissue, resecting it, causing some kind of thermal damage, or pulling it aside, which requires you to pierce the prostate and pull the adenoma to one side. So, the main advantage with regard to the Zenflow is that there's no piercing, there's no trauma, and there's no heat involved with the treatment. And what it does is essentially open the prostate and allow relief of that obstruction. It can be done under local anesthetic, and it's done through a flexible cystoscope. It's not a rigid cystoscope, so it should be a bit more comfortable for patients during the implantation.

What are some of the notable findings from this study, and were any of them surprising to you and your co-authors?

I wasn't sure what to expect with regard to this. I was involved with the initial trials and the feasibility studies with other devices as well, so this seemed to me similar to a stent or a Memokath, but there's a lot less metal involved with it. One of the things that we did find was that the durability was pretty good. Up to 3 years, there was still good relief of symptoms. It seemed to last a good amount of time. It's hard to know when you go into a completely new device as to what to actually expect because you always think, "Is the prostate going to grow? Is it going to be durable? Can you actually remove it?" With this particular device, it seems that so far, it's durable out to 3 years, and in the cases that have been removed, they seem to be able to be removed quite easily. It also doesn't stop you from doing something else if it fails, or if it doesn't work.

What is the take-home message for the practicing urologist?

The take-home message is that this minimally invasive surgery for BPH is rapidly expanding. There are lots of different devices that are being developed and I think there's been a new focus on trying to treat men with minimally invasive surgery. The Zenflow device is certainly something that appears to be able to be placed quite easily, seems to be minimally invasive, and so far seems to be durable. But really, the pivotal trials are what's going to determine if this is going to be useful in the long term. The initial results seem to be promising. But like with everything else, the trials are really what's going to tell us whether this is going to be a keeper in the end.

Is further research on this topic planned? If so, what will the focus be?

The Zenflow company is looking to initiate a pivotal trial. It's called the BREEZE trial to pave the way for FDA clearance. It's going to be a randomized control trial, as most minimally invasive medical devices go through. And that'll probably be the trial that will determine if this is going to be useful in the long run.

Is there anything else you feel our audience should know about this research?

It's exciting to be part of any development of a new device. And I think that it's certainly a device to keep your eye on and, like I said, we can only go and test it in a trial basis to know definitely whether it's going to work. But so far, the initial results seem to be promising.

1. Chin P, Salvador L, Guerra G, et al. Evolution of the Zenflow Spring System: A novel nitinol implant for benign prostatic hyperplasia (BPH). Paper presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP09-03

Articles

In a recent study, presented at the 2021 AUA Annual Meeting, Peter Chin, MD, and co-authors assessed the efficacy of the investigational Zenflow Spring System in treating patients with BPH.

Zenflow Spring System shows promising results in early trials for patients with BPH

Erectile and ejaculatory dysfunction are prominent post-operative symptoms in men who are treated for benign prostatic hyperplasia (BPH) with traditional prostate surgeries, such as transurethral resection of the prostate (TURP). Newer treatment methods, like Rezum or Prostatic urethral Lift (PUL), aim to reduce those symptoms.

In a recent study presented at the 2021 American Urological Association Annual Meeting,¹ 

 and co-authors assessed the 5-year outcomes of Rezum water vapor thermal therapy in patients with BPH, specifically focusing on erectile and ejaculatory function. McVary is a professor of urology and director of the Center for Male Health at Loyola University Medical Center, Maywood, Illinois.

Please discuss the background for this study.

The basis of this study was to look at the sexual function aspect of the 5-year Rezum study, the pivotal study that looked at lower urinary tract symptom improvement in men with BPH who had convective water vapor therapy Rezum treatment. We published those pivotal results concerning LUTS improvement about 6 months ago.² It had a marked improvement in lower urinary tract symptoms that were durable for 5 years. Prospectively, in this trial we measured various aspects of sexual function. The purpose of this particular manuscript, which is under review and presented at this year's AUA, was specifically focused on aspects of sexual function over 5 years following a Rezum treatment. It's an ancillary study to the pivotal study of Rezum treatment, but with this investigation we're focused entirely on male sexual health.

What were some of the notable findings? Were any of them surprising to you and your co-authors?

I think there's a couple of very important aspects of this study that are worth mentioning. By way of review, men had a significant and durable improvement in lower urinary tract symptoms and flow rates over the 5-year period. And that is represented in our previous published paper this past year. There are several ways of addressing sexual function. A very common way is to track sexual function with the use of sexual function questionnaires. It's considered a quantitative, more objective evaluation of sexual function. One of those is called the SHIM, the Sexual Health Inventory for Men. It's a measurement of their assessment of erection quality over time. In this study, we focused on the men who are in the trial and sexually active, measuring their erectile function. In this you see a very stable response to erection measurement over the 5-year period of time. Rezum does not appear to affect erection, which again confirms what we saw at 3 months, at 1 year, at 2, 3, 4, and now at 5 years at the end of the report, so that's good.

Similarly, we measured ejaculatory function. If you look at the questionnaire data, it's basically a straight and stable line across time and with very narrow confidence intervals, meaning ejaculatory function doesn't change much either.

Additionally, if you look at men who reported a history of sexual dysfunction at the beginning of the study, compared to men that had good sexual function at the beginning of the study, both groups of men had an equal response to improvement in their lower urinary tract symptoms. So, there isn't an influence of sexual function on response to Rezum. That's 1 message that you can tell patients.

There are 2 other important things, and one of which was unexpected. First, the unexpected one. If, at the beginning of the trial, in addition to doing the standard questionnaires, we also asked men about their previous sexual history, questions like, "Have you ever had an alteration in sexual function prior to enrollment in the study?" a man could say, "Yes, I've had sexual dysfunction in the past, but I'm still sexually active," or, "No, I've had no problems in the past." When you follow those sexually active men with no sexual dysfunction in their past and men who reported sexual complaints in the past, you note they diverge. Men that had no history of sexual dysfunction had absolutely no change in their erectile function over time, but men who say in the past, "Yes, I've had episodes," actually have a slight decline over time, which is very consistent with what we saw in a previous trial, the MTOPS trial where we followed sexual function in a placebo group of men with BPH for 5 years.³

So, what does that mean? Well, that means it's still important to ask patients, face to face, "How is erection? How is ejaculation?" because they can give you a clue as to how their natural history of sexual function may be perform going forward. The fact that the questionnaires go straight across is 1 thing, but the fact that the history can help you differentiate who might have a slight decrease over time and who can be very beneficial for a physician to counsel patients. They can gauge expectations. No one's ever done that before. So, in my own view, this new finding should really make a difference in the way we do clinical trials in the future. You still have to stick to the NIH consensus conference of 1990, where it said questionnaire data is important, but you have to talk to men to fully gauge their sexual function. It turns out that same process occurs in men who say that they had an ejaculatory complaint. They also track a little bit different from men who say there was no history of ejaculatory problems. They're not substantial decreases, but they're different than men who say, "No, I've never had a problem in the past." So, that's 1 surprising finding, which I think is a contribution to the field.

The other is a reassurance point that I'm grateful doesn't surprise me. It's that if we rate men at baseline, no sexual dysfunction, mild ED, moderate ED, or severe ED, you'll see over the 5-year period that no one changes their level of sexual function category. If you start with no ED, no history of ED, good sexual function, you remain there over the 5 years of the trial. If you're in mild category, you remain there over the 5 years of the trial. Your score can alter a little bit, but you don't do a categorical shift. So, if a guy says, "Yeah, I have a little problem now and then," then you can say, "Well, that's not getting better. It's not getting categorically worse." So again, the ability to reassure the patients on that is another finding from this study.

How do these data build previous research of Rezum?

It tells us good impact on BPH outcomes, lower urinary tract symptom improvement, and urinary flow rates. It confirms that as well as the fact that sexual function doesn't seem like it influences that. That's one. Second is that you have stable sexual function over a 5-year period of time. You don't do a categorical shift; however, if you do have a history of ED, you actually track differently than men that say, "No, I've been perfect my whole life."

With so many options available, please describe your patient selection process for BPH procedures.

As co-chairman of the AUA BPH clinical guidelines, my comments dovetail identically with the BPH guidelines. So, the first approach is if a man has LUTS he needs to be informed of his options: medicine and surgery. If he is not responding to medications for LUTS/BPH or wishes to avoid medications altogether, you have to inform them of the option of medicine versus various interventional procedures and surgery. If at the start a man is not interested in medications, then it's totally legitimate to proceed directly into an intervention once he understands the range of options. The choice of intervention is based in part on prostate size; how severe and how big is the prostate. The other factor is his willingness to accept risk. That means if we have a man whose prostate size is, let's say 50 grams, and you say, "We have a minimally invasive option versus a more traditional surgical option, like bipolar TURP or PVP," you can discern choice by asking him about his proclivity for wanting to preserve sexual function.

If the man says, "Sexual function is very high on my particular “balance beam of motivation," then choosing a minimally invasive therapy might be a better choice for that guy because it is known that current minimally invasive surgeries do a better job at preserving sexual function. For a man like that, I would encourage him to proceed in that direction. If the man said, "Those days are passed. Sexual function is not really a motivation for me," then many times the discussion turns to durability of procedure. What we can say about MIST, minimally invasive surgical treatment, and in the current guidelines the real players are Rezum and UroLift, there is reliable data to 5 years, but not beyond. And we know about retreatment rates within 5 years. Surgical retreatment rates in terms of Rezum at 5 years is 4.4%, relatively low. In prostatic urethral lift, surgical retreatment rates are much higher. If you add medication retreatments as another way to fail, then both are a little bit worse. So, the discussion is a review of durability of response, and we can only say durability to 5 years because that's the farthest the data goes.

When we look at bipolar TURPs or PVPs, then the durability data is more extensive, because the procedures are more well-established. Some men will say, "I want the procedure with the best durability that you know of," and I’d say, "Well, there are some unknowns with the MIST, so perhaps it might be better for you to choose a laser procedure or a bipolar TURP."

The other aspect is level of invasiveness, regardless of sexual function. There's no question that the MISTs are much easier for men to undergo and recover from. There's no hospital stay, there's no general anesthesia, and that is attractive to men with or without sexual dysfunction. So, if that is a big deal, then the MIST is going to be a better approach for that particular patient. It has to be individualized to the motivations of the patient, and also what I call his "phenotype.” How big is his prostate? How bad is his problem? What is his tolerance for side effects?

Rezum is a durable therapy for lower urinary tract symptoms, secondary to BPH. The adverse event profile is quite favorable, the impact on sexual function is minimal, and retreatment rates are exceedingly low with this therapy.

Is there anything else you feel our audience should know?

I think that summarizes where we're going to be because the pivotal trial is over. Looking forward to comparisons of minimally invasive surgery versus medical therapy, that is, at this point, untapped. It's something which we think we have insight into, but we really don't have good data. We have done some modeling in that regard, where minimally invasive surgery compares favorably to medication as seen in the MTOPS cohort, but that is a modeling investigation.4-5 That is not the same as a randomized control trial.

Another area is utilities, quality of life. How do patients rate these types of therapies as impactful in the quality of their life? This is done quantitatively looking at risk tradeoffs. “I will accept this amount of side effect if I can have this amount of quality years in my lifetime,” called a utility or quality of life years. And that's not been done, other than some projects that we're doing right now to address that. It's very exciting.

The other is cost benefit. There's a health policy issue here. We're doing these procedures and there is an expense to our society and our health care system. What are we getting as a nation in return? Are we getting men with a sustained benefit? Are we spending a lot of money for procedures which may or may not be durable? So, cost effectiveness evaluation is also a thing that we need to look forward to. And then there is the question: has anyone really compared these MISTs to more traditional surgeries? The answer is, yes and no. Rezum has not done that. It's a newer therapy. UroLift has done that, not in the US. There was a European trial looking at TURP versus UroLift, and TURP seem to beat urolift in most important aspects, except the patient softer measures about time to recovery, sexual function and those types of things. Regardless, that's additional health policy questions which really need to be addressed.

1. McVary K, El-Arabi A, Roehrborn C. Preservation of sexual function 5-years after water vapor thermal therapy for benign prostatic hyperplasia. Paper presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD18-08.

2. McVary KT, Gittelman MC, Goldberg KA, et al. 

. 2021 Sep;206(3):715-724. doi: 10.1097/JU.0000000000001778. Epub 2021 Apr 19

3. McConnell JD, Roehrborn CG, Bautista OM, et al. Medical Therapy of Prostatic Symptoms (MTOPS) Research Group. 

. 2003 Dec 18;349(25):2387-98. doi: 10.1056/NEJMoa030656

4. Gupta N, Rogers T, Holland B, et al. Three Year Treatment Outcomes of Water Vapor Thermal Therapy Compared to Doxazosin, Finasteride and Combination Drug Therapy in Men with Benign Prostatic Hyperplasia: Cohort Data from the MTOPS Trial. 

. 2018 Aug;200(2):405-413. doi: 10.1016/j.juro.2018.02.3088

5. McVary KT, Rogers T, Mahon J, Gupta NK. Is Sexual Function Better Preserved After Water Vapor Thermal Therapy or Medical Therapy for Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia? 

 2018 Dec;15(12):1728-1738. doi: 10.1016/j.jsxm.2018.10.006

In a recent study presented at the 2021 AUA Annual Meeting, Kevin T. McVary, MD, FACS, and co-authors assessed the 5-year outcomes of Rezum water vapor thermal therapy in patients with BPH, specifically focusing on erectile and ejaculatory function.

5-year Rezum study results show low rates of erectile and ejaculatory dysfunction

Recurrent stress urinary incontinence (SUI) is a problem that many women face, especially following failed surgical intervention. This condition tends to impact their daily functioning and quality of life.

and co-authors conducted a study that assessed the efficacy of autologous muscle derived cells for urinary sphincter repair (AMDC-USR) in treating women with SUI. Chancellor is a professor and director of neurourology at Beaumont Health System and Oakland University Beaumont School of Medicine, Royal Oak, Michigan.

Could you discuss the background for this study?

There's increasing interest in regenerative medicine, and this is applied for the very first time in the urology field for the indication of stress urinary incontinence in women. It's neat looking back to see that this started off with an NIH R01 grant and now, over the years, has translated from academic to a medical device and regenerative medicine company, Cook MyoSite, that was able to run a global phase 3 trial. But the most important thing is that there's great unmet need for women with stress incontinence who have failed previous surgery. You've probably heard of all the mesh mess that's been going on over the years, so now there's a promise of regenerative medicine for women who've failed previous surgery.

I think there's 3 points, and the first is 75 women who have failed previous surgery entered this double-blind, placebo-controlled trial. I was surprised. They have failed up to 5 surgeries in the past, and the median duration is not a year later; rather, the median duration is 12.8 years after the surgery, so they've been suffering a long time. But even then, greater than 40% of women reported greater than 75% improvement in their stress incontinence episodes. And those that received placebo did not improve. But after a year, when they can get their own cells back, their improvement was similar to this other group. So, that was a very positive finding for me. And moreover, there's been [demonstrated]safety of the procedure with at least 2 years’ follow-up.

If approved by the FDA, how would AMDC-USR affect the treatment paradigm for stress urinary incontinence?

It will be an alternative. There's no drug treatment for stress incontinence, and it's such a big disease, so either you get a surgery, and everybody knows about the meshes, or you get a synthetic bulking agent. This would be the potential treatment—trying to use a person's own muscle cells to regenerate a deficient weakened sphincter muscle. This has received a breakthrough designation by the FDA. It's called RMAT, regenerative medicine advanced technology, through the 21st Century Cures Act, where they want initiatives for regenerative medicine to help with diseases that have such great unmet need.

This is a successfully completed phase 3 trial in regenerative medicine in our field, and there's demonstrated safety and efficacy for women who have failed previous surgery, a very difficult group of patients for all of us.

Is there anything else you feel our audience should know about the findings?

It's always bothered me that there's been no treatment. What is the right thing to do for women who have had prior failed surgery? Do you do another surgery or bulking agent? Now, finally, there's a potential treatment we've found where regenerative medicine with cell therapy can be safe and effective, and it brings the promise of regenerative medicines closer to reality, closer to the urology community.

Study was funded by Cook MyoSite, Inc.Michael B. Chancellor M.D. conflicts: One of the inventors of the autologous muscle-derived cell (AMDC) process and has received royalty payments for the stem cell process and payments for consulting from Cook MyoSite Inc.

1. Chancellor MB, Peters KM, Benson KD, et al. An evaluation of women with persistent or recurrent stress urinary incontinence (SUI) following surgery in a double-bling, randomized, controlled trial comparing safety and efficacy of autologous muscle derived cells for urinary sphincter repair (AMDC-USR) with placebo (PBO). Paper presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD06-02.

In a recent study presented at the 2021 AUA Annual Meeting, Michael B. Chancellor, MD, and co-authors conducted a study that assessed the efficacy of autologous muscle derived cells for urinary sphincter repair in treating women with SUI.

New regenerative medicine AMDC-USR treats women with recurrent SUI

Radical cystectomy (RC) outcomes in patients with cT1 micropapillary bladder cancer (MP) were similar or worse compared with patients with cT2 conventional urothelial carcinoma (UC), underscoring the aggressiveness of this rare bladder cancer variant.

The findings come from a study from Fox Chase Cancer Center shared during the 2021 AUA Annual meeting. Using data from the National Cancer Database, the investigators determined that the likelihood of having pathologically node positive disease (pN+) was higher in patients with cT1 MP (odds ratio [OR], 1.74; 

 = .009) and lower in patients with cT1 UC (OR 0.76; 

 <.001) at RC, compared to patients with cT2 UC. Overall, 39% of patients with cT1 MP had pN+ disease versus 11% of patients with cT1 UC and 19% of patients with cT2 UC.

Similarly, 31% of patients with cT1 MP experienced an advanced pathologic stage (pT3/4) at RC, whereas a significantly lower percentage of patients with cT1 and cT2 UC (18% and 27%, respectively) were upstaged.

“Micropapillary bladder cancer is a rare and often aggressive variant of bladder cancer, which poses a very difficult treatment dilemma when diagnosed in the non-muscle invasive stage because it often presents at an advanced stage. When it’s caught at an early stage, it’s very difficult to know what to do with it because it is such an aggressive variant,” lead author Kevin Ginsburg, MD, second-year fellow in the Urologic Oncology Fellowship Program at Fox Chase Cancer Center, Philadelphia, Pennsylvania, stated in a news release.²

To assess the association of clinical stage and histology with oncological outcomes, multivariable models and Cox proportional hazards models tested for upgrades to pT3/4 disease and pN+, and the Kaplan-Meier method estimated overall survival (OS) at RC. Models were adjusted for use of systemic therapy, radiation therapy, comorbidity score, age, year of diagnosis, race, urban/rurality index, education status, income, sex, transfer status, distance from treating facility, and facility type.

Patients from the National Cancer Database who underwent RC for cT1/cT2 UC or cT1 MP bladder cancer between 2004 and 2016 were examined in this study, excluding patients who previously received neoadjuvant RT, patients with missing information, and any clinical evidence or suspicion for nodal disease or metastasis. Overall 27,404 patients were identified: 112 (0.45%) with cT1 MP, 305 (1.1%) with cT2 MP, 6889 (25%) with cT1 UC, and 20,088 (73%) with cT2 UC.

“The point was to find out whether someone who’s being treated with a cystectomy with cT1 micropapillary cancer behaves like someone who has a cystectomy for cT1 urothelial carcinoma or whether they have outcomes more like someone who has cT2 urothelial cell carcinoma,” Ginsburg explained.

Results showed similar OS between patients with cT2 UC and cT1 MP (HR 0.74; 

 = .059), whereas patients with cT1 UC had improved OS versus patients with cT2 UC (HR. 0.70; 

“[This] suggests [cT1 MP disease] is a very aggressive variant despite the fact that it’s at an earlier stage,” said Ginsburg.

Other results found that after adjustment in the multivariable model, patients with cT1 MP and patients with cT2 UC experienced similar odds of upstaging to pT3/4 at RC (OR, 0.96; 

 = 0.830), while upstaging was less common in patients with cT1 UC versus patients with cT2 UC (OR, 0.60; 

Commenting on the primary outcomes of the study, Ginsburg concluded, “This is just another piece of information that physicians can use when discussing the aggressiveness of early stage micropapillary bladder cancer with their patients. Physicians can also use it to explain to patients that an aggressive treatment, such as bladder removal, may be necessary because cT1 micropapillary bladder cancer may behave like cT2 urothelial cell bladder cancer.”

1. Ginsburg K, Chandra A, Murray N, et al. Oncological Outcomes of cT1 Micropapillary Bladder Cancer Compared with cT2 Conventional Urothelial Carcinoma Treated with Radical Cystectomy. Paper presented at 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract PD63-11.

2. Researchers Find Early Stage Micropapillary Bladder Cancer Outcomes Similar to Late-Stage Conventional Urothelial Carcinoma. September 13, 2021. Accessed September 14, 2021. https://bit.ly/3kzaYgg.

An aggressive treatment, such as bladder removal, may be necessary in patients with early stage micropapillary bladder cancer because the disease may behave more like late-stage conventional urothelial carcinoma.

Janelle Hart

Articles

Zenflow Spring System shows promising results in early trials for patients with BPH

5-year Rezum study results show low rates of erectile and ejaculatory dysfunction

New regenerative medicine AMDC-USR treats women with recurrent SUI

Study results underscore alarming aggressiveness of early stage micropapillary bladder cancer