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Rashid Sayyid: Hello everyone, and thank you for joining us in this UroToday recording. I'm Rashid Sayyid, a Urologic Oncology fellow at the University of Toronto. And along with Zach Klaassen, Associate Professor and Program Director at Wellstar MCG Health, we'll be discussing the recently updated AUA guidelines looking at the management of lower urinary tract symptoms attributed to BPH. In this four-part series, we've discussed different aspects of these guidelines, including the epidemiologic background, the evaluation, the medical therapy. And now we'll be discussing the surgical therapy and future directions of this guideline. Starting with the surgical therapy, there's a lot to cover here, and we'll start with statement 26, which states that surgery is recommended for patients who have renal insufficiency secondary to BPH, refractory urinary retention secondary to BPH, recurrent urinary tract infections, recurrent bladder stones, or gross hematuria due to BPH, and/or with lower urinary tract symptoms, BPH refractory to, or unwilling to use other therapies as a clinical principle.

It's really interesting how the advent of medical therapies in the 1980s, with the emergence of alpha blockers, and in the 1990s with 5-ARIs, has led to a decreased utilization of transurethral resection of the prostate, or TURPs, over the last three decades. In the 1980s, this was commonly the most common or second most commonly performed surgery in the US. Between 1999 and 2005, we saw a 5% per year decrease in the TURPs performed. As illustrated in the graph below, we saw a 20% decrease between 2005 and 2008 for TURPs specifically.

Statement 27 tells us that clinicians should not perform surgery solely for the presence of an asymptomatic bladder diverticulum. However, evaluation for the presence of bladder outlet obstruction should be considered, and this is a clinical principle. Now specifically pertaining to TURP or transurethral resection of the prostate, statement number 28 tells us that TURPs should be offered as a treatment option for patients with LUTS/BPH, and this is a moderate recommendation with a grade B level of evidence. That's because TURP is still considered a historical standard and a gold reference standard to which all new treatment approaches are compared to. Statement 29 tells us more specifically that clinicians may use a monopolar or bipolar approach TURP as a treatment option depending on their expertise with these techniques as an expert opinion.

Let's talk about the nuances and the differences between monopolar and bipolar approaches. With the energy source monopolar, the energy travels through the body to reach the skin pad, and that's why we typically see a Bovie pad placed on these patients. Whereas with bipolar, the energy travels between the active pole, which is the loop that we see, and the passive pole, which is located on the resectoscope tip. None of the energy directly transfers through the body. There's another important difference, which is the irrigant solution. With monopolar, we use iso-osmolar solutions, be it sorbitol, mannitol, or glycine, whereas with bipolar we use iso-osmolar sodium chloride at 0.9%, and this eliminated the risk of TUR syndrome, which is commonly referred to as acute dilutional hyponatremia. We'll talk about this in the further slides.

What about monopolar versus bipolar TURP? Is there any difference? There's been a lot of studies and these have been culminated in five systematic reviews and meta-analyses. If we look at the efficacy, essentially there's no difference. They both are equally effective in reducing the IPSS score and improving the peak urinary flow rates at 12 months. But one important difference, the TUR syndrome, and this is significantly lower with the bipolar approach, and that's because we don't use the iso-osmolar solution, be it glycine, sorbitol, or mannitol. This allows for longer resection time and thus you can tackle bigger, larger glands with a bipolar approach compared to monopolar. And what's the cutoff that's recommended? Typically, 60 to 90 minutes is the cutoff for monopolar, so it allows us more time to tackle these larger glands.

There's some weak, inconsistent evidence that the bipolar approach may be associated with improvements in time to catheter removal, or catheterization time being slightly shorter with a bipolar approach. The hospital length of stay may be a little shorter with bipolar, and there may be a lower risk of clot retention, bleeding, hemoglobin drop, or a need for a transfusion in bipolar TURP. But these really are very weak, show minimal to no differences, and are yet to be really substantiated in high-quality evidence.

What about a simple prostatectomy? So, statement 30 tells us that open-lap or robotic-assisted prostatectomy should be considered as treatment options by clinicians depending on their expertise with these techniques and only in patients with large to very large prostates. This is a moderate recommendation with a grade C level of evidence. The simple prostatectomy was particularly effective and useful for large and very large glands in the pre-bipolar TURP era. When your resection time is limited to 60 to 90 minutes, you're really limited by how much you can resect. For those larger glands, a simple prostatectomy was particularly effective in this scenario. It's important to note that the guideline does not recommend a gland size limit to favor a simple prostatectomy versus a TURP approach. This is really from a practical standpoint going to depend on the surgeon's experience, skill, and obviously, patient preference, with a staged approach being perfectly reasonable in this scenario.

There have been numerous RCTs that have compared an open simple prostatectomy to TURP, and essentially these have favored the open simple prostatectomy approach with an improved maximum flow rate at 12 months, favoring this approach. Similar need for blood transfusions, relative risk is 1.2 higher in the prostatectomy. And importantly, there's a significantly lower risk of re-operation in the open simple prostatectomy, about tenfold lower. As we have seen with the radical prostatectomy and other different surgeries, we've seen the adoption of minimally invasive approaches, initially with laparoscopy and now predominantly with robotics. These have shown the classic benefits of shorter catheterization time, shorter hospital length of stay, lower transfusion rate, and lower complication rates favoring the MIS approaches.

Statement number 31 regarding the TUIP or transurethral incision of the prostate tells us that a TUIP should be offered as an option for patients with prostates 30 grams or smaller for the surgical treatment of LUTS or BPH. This is a moderate recommendation with a grade B level of evidence. You may ask, what are the key advantages of a TUIP? Based on results from a systematic re-meta-analysis, there's a significantly lower rate of retrograde ejaculation, 18% versus 65% for TURP. We'll see that this is a common theme that comes up with newer MIS or the minimally invasive surgical techniques. There's also a decreased need for a blood transfusion, 0.4% versus 8.6%, which makes sense given that you have less resection with this procedure.

More recently, an Egyptian RCT of 86 patients who underwent a TURP versus TUIP with small prostates and a mean IPSS of 19 demonstrated really no differences in IPSS improvements. Efficacy is pretty much the same in well-selected patients. There's no difference in the need for re-operation, blood transfusion. There's a significantly lower risk of ED with TUIP, 8% versus 20% with TURP. And a lower risk of retrograde ejaculation, 23% versus 53%. Taken together, TUIP really appears to have a role in the smaller prostates, maybe a high bladder neck, with the benefits of maybe a lower blood transfusion rate, but definitely a lower risk of retrograde ejaculation.

What about TUVP or transurethral vaporization of the prostate? Statement 32 tells us that bipolar TUVP may be offered as an option for patients for the treatment of LUTS or BPH, a conditional recommendation with a grade B level of evidence. This transurethral vaporization can be accomplished by a multitude of different technological advancements, which include the rollerball that we see up here up top, which is a spherical rolling electrode; we have the vaportrode next, which is a grooved roller electrode; we have the loop electrode, it's the same as what we would use for bipolar TURP; then there's the button, which is a hemispherical oval mushroom electrode that is popular in numerous hospitals. Data from 14 RCTs with a mean IPSS about 23 and a prostate volume about 50 cc's. Essentially, there's really no difference in terms of safety or efficacy outcomes. So really, these advances have not translated to a benefit in terms of efficacy or safety compared to TURP.

Next, statement 33 discusses the PVP or the photovaporization of the prostate, which essentially reflects the green light laser technology and states that PVP should be offered as an option using 120 watts or 180 watt platforms for the treatment of LUTS and BPH. This is a moderate recommendation with a grade B level of evidence. This green light laser or PVP utilizes a 600 micron side firing lithium triborate laser fiber in a non-contact mode. Importantly, the laser wavelength is 532 nanometers. Why is this important? At this wavelength, the energy source is preferentially absorbed by hemoglobin, resulting in tissue ablation or vaporization that results in a thin layer of underlying coagulation that provides the desired hemostasis in these patients. Also importantly, it's performed with 0.9% sodium chloride, and so there's no risk of TUR syndrome. It may allow for the ablation of larger glands.

And as previously discussed by Zach in the prior recordings, the GOLIATH study of photovaporization of the prostate versus TURP in prostate volumes less than 80 grams showed that there's really no major differences with respect to IPSS change and the max flow rate at twenty-four months post-op. And recently there's been a trial of this modality in larger prostates, 80 to 150 grams, that showed that PVP may not be as effective in this setting in the greater than 80 gram prostates. There was a 27% retreatment rate at three years, so about a quarter of patients had retreatment within three years. But there was a lower need for transfusion compared to TURP, so this really highlights the utility of this modality preferentially for medically complicated patients on anticoagulation. We'll really discuss this complicated high-risk population in later statements.

Next, statement 34 addresses prostatic urethral lifts, commonly known as UroLift, and says that this modality should be considered as a treatment option for patients with LUTS and BPH, provided that the prostate volume is 30 to 80 grams and there is a verified absence of an obstructive middle lobe. This is a moderate recommendation with a grade C level of evidence. Essentially, what UroLift is, is a transprostatic suture implant that pulls the lumen of the prostatic urethra towards the capsule, leading to the widening of the prostatic urethral lumen. And then the urethral side of the implant epithelializes within 12 months. This implant induces a benign inflammatory response in the prostate with histologic analysis showing that, at least in the short to medium term, it does not increase the risk of prostate cancer.

A lot of the data in favor of the UroLift comes from the LIFT study, which included 206 patients and compared UroLift to sham in patients with prostates of 30 to 80 grams and no obstructive middle lobe, hence the recommendations for this specific patient population. The UroLift was shown to be superior to sham for the mean IPSS change. UroLift was better by about 5 points. There was an IPSS quality of life improvement in favor of UroLift by about 1.2 points, and an improvement in the mean Qmax by about 2 mL per second. Clearly, UroLift is efficacious in this setting.

Next came the BPH6 study, which is a non-inferiority trial of 80 patients of UroLift versus TURP, the gold standard. When they looked at the primary objective of a 12-month IPSS reduction by at least 30%, essentially, they're asking for a clinically meaningful IPSS reduction at 12 months. This favored TURP 91% versus 73%. And again, at 24 months, the IPSS scores favored TURP by an average of about 6 points. Although the quality of life, which some may argue is the most important metric, was similar across all groups at all follow-up intervals, and the max flow was significantly lower in the UroLift patients. There has been recently emerging data looking at UroLift in patients with prostate ranging between 81 to 100 cc's or with median lobes potentially. But at the current time, there's really insufficient high-quality evidence to make recommendations in these patient populations.

And so, statement 35 tells us that the prostatic urethral lifts may be offered as a treatment option to eligible patients who desire preservation of erectile and ejaculatory function. This is a conditional recommendation with grade C level evidence. You may ask then why we are considering this treatment option if efficacy is clearly lower. One attractive feature of this modality is the decreased risk of erectile dysfunction and ejaculatory dysfunction. Woo and all have demonstrated that sexual function in men with normal or moderate ED at baseline was unaffected in patients receiving these implants. Interestingly, those with severe ED reported modest improvement. There was no evidence of de novo ejaculatory dysfunction or ED over the course of the study. This was also corroborated by the BPH6 study that showed that none of the UroLift patients had novel ED or retrograde ejaculation. Conversely, this was about 9% and 20% respectively with TURP, and ejaculatory function was better in the UroLift group. Similarly, the LIFT study of the prostatic urethral lift versus the sham showed a non-significant difference in sexual function. Again, this really speaks to the benefits of this treatment approach with regards to these two domains.

Next, we have statement 36, which discusses water vapor thermal therapy, commonly referred to as Rezum in practice, and says that Rezum should be considered as a treatment option for patients with LUTS/BPH provided the prostate volume is 30 to 80 grams, and this is a moderate recommendation with a grade C level of evidence. This technology utilizes convective radiofrequency to create stored thermal energy in the form of steam, which is delivered transurethrally via a specialized device into the transition zone. Then the steam travels through this transition zone, denaturing the tissue and ablating the adenoma to create the opening. This technology has been evaluated in a double-blind RCT of Rezum versus sham in patients with prostate volumes of 30 to 80 grams.

But, contrary to the LIFT study of the UroLift, patients with obstructing median lobes were included in this trial, whereas they were excluded in the LIFT study. So, we saw that the three-month IPSS improvement of at least 30% or at least 8 points, again clinically meaningful benefits, favored the Rezum group by 74% versus 31%. The mean IPSS improvement from baseline to three months also favored Rezum, with a mean difference of about 7 points. The three-year data, recently published in 2018, showed that the IPSS improvement was about 11 points. The mean IPSS quality of life improvement was about 50%, and the max flow had improved by about 40%.

Statement 37, again about the water vapor thermal therapy, tells us that this technology may be offered as a treatment option to eligible patients who desire preservation of erectile and ejaculatory functions, similar to UroLift, and that is a conditional recommendation with a grade C level of evidence. We saw in the trial that we previously discussed that there was no de novo ED in the Rezum group by 36 months. The function scores associated with ejaculation improved over time, 36 and 48 months following treatment. And the bother scores associated with ejaculation also significantly improved over time following treatment. Again, this speaks to the benefits of this technology in this setting. At this point, I'll turn it over to Zach to go over statement 38 and the remainder of-

Zach Klaassen: Thanks so much, Rashid. So, we're going to discuss statement 38, which is about laser enucleation. So, we see here that the holmium laser enucleation of the prostate, or HoLEP, or the thulium laser enucleation of the prostate, or ThuLEP. So basically, these are similar types of procedures just based on what laser is being used. And this should be considered as a treatment option depending on the clinician's experience with these techniques, as well as prostate size independent options for treating LUTS and BPH. We know that holmium and thulium both have minimal depth penetration and, combined with the chromophore of water, lead to rapid vaporization and tissue coagulation, which is superior to monopolar or bipolar TURP.

Looking further at HoLEP and ThuLEP versus TURP, there were seven studies with long-term follow-up of 12 to 92 months. This showed a mean change in IPSS of 19 points, 1.3 points in favor of HoLEP. There was no difference in quality of life score changes between these groups. The Qmax was higher in the HoLEP arm for three studies and similar in the remaining studies. The outcomes for HoLEP versus TURP were consistent when analysis was restricted to prostates greater than 75 grams. Importantly, there was no difference in erectile function outcomes or scores. Furthermore, similar outcomes were observed for the comparison of ThuLEP and TURP in randomized trials.

Statement 39 looks at robotic water jet treatment, or aquablation, and says that this may be offered as a treatment option to patients with LUTS and BPH, provided their prostate volume is 30 to 80 grams, and this is based on grade C level of evidence. This is not a minimally invasive approach because it does require general anesthesia. It utilizes a robotic handpiece, a console, and a conformal planning unit to perform prostate resection using a water jet from a transurethrally placed robotic handpiece. Pre-treatment TRUS ultrasound is performed to map out the area of the prostate while minimizing the resection of the verumontanum. The TRUS is then used to monitor tissue resection in real-time. And once the procedure is completed, hemostasis can be obtained with post-op electrocautery either using a cystoscope or resectoscope, or using a three-way catheter with balloon retraction.

When looking at aquablation versus TURP, there has been one randomized control trial comparing these two in prostate sizes 30 to 80 grams with five-year follow-up data. The treatment response was similar between both groups. And similar improvements also in IPSS and quality of life scores, as well as similar changes in Qmax, which improved by about 10 mL per second. There were lower rates of three-month grade greater than or equal to two adverse events with aquablation, 26% versus 42%. And there was less reduction in prostate volume at three months with aquablation, 31% versus 44%. Importantly, from a quality of life and symptom standpoint, there were lower rates of retrograde ejaculation with aquablation, 6% versus 23%. And the need for additional therapy at five years follow-up was 6% for aquablation and 12% for TURP. This is quite similar in terms of the need for re-procedure.

Statement 40 looks at prostate artery embolization and says that this may be offered to patients with LUTS and BPH if the patient and the proceduralist are comfortable with this approach. It's important that this is really a multidisciplinary approach with our interventional radiology colleagues. So, basically having the patient see the radiologist in a consultation may be reasonable, based on grade C recommendations. This involves embolization of the prostate artery, which is also known as the inferior vesical artery. This table here shows that there's some significant variation in the anatomy to the prostate, particularly with the inferior vesical artery. So, it's important for the patient, as well as the interventional radiologist, to be aware of this.

With regards to the data, there has been one single-blind RCT of prostate artery embolization versus sham in 80 patients. This was published in 2020 in European Urology. After six months, patients in the sham arm were crossed over to receive PAE. There were patients with an IPSS of greater than 20, a quality of life score of greater than 3, and a Qmax of less than 12, with a prostate volume greater than 40 cc's, that were included in this trial. The average procedure time was only 71 minutes with a radiation dose of 48 gray per centimeter squared. And at six months, the PAE improved IPSS by 13 points, quality of life by 2 points, and Qmax by 7 mL per second. The mean prostate volume reduction was 17.6 grams. Common adverse events included hematuria, urethral pain, and dysuria.

There have been 5 RCTs over the course of the last decade or so that have compared PAE to TURP. Overall, TURP appears to have better IPSS improvements within 3 to 12 months, as well as quality of life improvements, showing no to mild benefit in favor of TURP. Ejaculatory dysfunction was less frequent with PAE at 12 weeks, 56% versus 84%. Of note, post-op acute urinary retention was higher with PAE, 26% versus 6%. The panel concludes that they were unable to find substantial evidence to recommend PAE over more widely available minimally invasive therapies for the routine treatment of LUTS. But there is evidence showing a short-term benefit of PAE compared to observation in a very select patient population.

Looking at statement 41, this is about temporary implanted prostatic devices. These may be offered as a treatment option for patients with LUTS and BPH, provided the prostate volume is between 25 and 75 grams as well as no median lobe, and this is based on expert opinion. There has been one RCT of what's called iTind versus sham in 185 patients with this size of prostates, as highlighted here, 25 to 75 grams. A 3-point IPSS improvement at 3 months favored the iTind at 79% versus 60%. The mean IPSS improvement at 3 months was 9 versus 6.6 points. There was a slight quality of life improvement, no difference in sexual function at 3 months, and overall adverse events were slightly more common in the iTind procedure at 38% versus 18%, but these were overall low-grade adverse events. The need for additional surgery or initiation of BPH medication within the first 3 months was similar between these two groups.

This is the AUA treatment algorithm for surgical management of lower urinary tract symptoms attributed to BPH. Starting at the top left, it's important that we assess the prostate size because this is really the main feature as to what we can offer these patients. So if we start here in the bottom left, for small prostates, we have several options as listed here. Notably TURP, HoLEP, PVP, and ThuLEP. If we have average-sized prostates, 30 to 80 cc's, there are about nine options here that we can offer the patients, as you can see on the screen. For very large prostates and large prostates, this is really greater than 80 cc's. Probably the best options are a simple prostatectomy with whatever approach the surgeon is most comfortable with, open, laparoscopic, or robotic, as well as the other options of HoLEP or ThuLEP.

With regards to hematuria, this is statement 42. Based on expert opinion, after exclusion of other causes of hematuria, 5-ARIs may be an appropriate and effective treatment alternative in men with refractory hematuria presumably due to prostatic bleeding. Surgical intervention may be considered depending on the ability to hold anticoagulation and/or the patient's frailty. We know that finasteride suppresses intraprostatic VEGF, which decreases prostate-related bleeding, and this has been shown in long-term prospective studies to reduce bleeding. This may also be considered in prostate artery embolization in this setting if the bleeding is significant and refractory to 5-ARIs.

Let's talk a little bit about medically complicated patients. Statement 43, based on expert opinion, suggests HoLEP, PVP, and ThuLEP may be considered as treatment options in patients who are at high risk of bleeding. Procedures likely associated with lower blood loss and need for transfusion compared to TURP, we see a relative risk of 0.2 in this setting. The decreased penetration depth of holmium and thulium as compared to monopolar energy leads to a more superficial area of ischemia and can reduce the risk of delayed bleeding with an eschar sloughing at approximately 7 to 14 days post-procedure.

In a retrospective review of 125 patients undergoing HoLEP, of which 52 were on antithrombotic therapy, 8% in the antithrombotic group required transfusion compared to none in the control group. A meta-analysis in 2017 demonstrated that anticoagulated patients undergoing HoLEP are at a slightly greater risk for prolonged bladder irrigation, secondary to bleeding, but surgical outcomes are otherwise similar. So, these are options for patients that may or may not be able to come off their anticoagulation.

With regards to bridging with low molecular weight heparin versus maintaining patients on anticoagulant or antiplatelet therapy, in 2013 there was a study of 76 patients that demonstrated no difference in hemoglobin drops between these two groups. In 2017, there was a study of 103 patients that demonstrated that the hemoglobin drop was worse in the low molecular weight heparin bridge group. So, we have some conflicting data here, but the panel recommends abandoning low molecular weight heparin bridging in favor of continuing anticoagulant or antiplatelet therapy during thulium laser surgery. Additionally, prostate vaporization may be safe and effective for these patients who continue their anticoagulant or antiplatelet therapy. Longer catheterization and irrigation are increased with the risk of delayed bleeding. So, PVP is a reasonable option for these patients that cannot come off or should not come off their anticoagulation.

Finally, we're going to conclude with several future directions, and so there are several important points here. First, furthering our understanding of BPH etiology, pathogenesis, and progression. Like most things in medicine these days, computational biology, genomic factors will continue to be assessed and should be aimed towards understanding the drivers of BPH and prostate growth as well as therapeutic targets. Secondly, it's always important to evaluate and address healthcare disparities in BPH, particularly for the care of Black men and Latinx men. Third, management of nocturia is a huge issue in our clinic, and this is often multifactorial. This may be related to BPH, underrated is sleep apnea, as well as additional lifestyle habits. The most bothersome symptom of LUTS affecting quality of life is related to nocturia, and nocturia is associated with increased overall mortality. This is certainly an area of future evaluation and direction.

Furthermore, the development of patient-centered approaches to improving adherence and compliance. We need to overcome current issues such as variability in prescribing patterns among physicians, such as those receiving monotherapy versus combination therapy. We need to address insurance coverage issues, type of medication, side effects, availability of information and technology, as well as managing patient expectations as these typically are quality of life procedures. As we've mentioned, there are many new therapeutic options, emerging novel minimally invasive surgical approaches such as prostatic stents, temporary implantable prostatic devices, drug-eluting catheters, balloon dilation devices, transurethral prostatic split techniques. There's going to be additional data coming over the next several years and decades, but this has to be evaluated rigorously and will need to be done in order to be incorporated into the guidelines.

For a MIST to have successful uptake and practice, what are the hallmarks from the patient and urologist perspective? For the patient, this needs to be tolerable; there needs to be rapid and significant relief of symptoms, a short recovery time with a rapid return to life activities, low risk of serious complications; ideally, preservation of sexual function and continence, and it has to be affordable. From the urologist's perspective, the capacity for performance in an ambulatory setting under reduced anesthesia is needed; there needs to be a fast learning curve, generalizability, ease of performance and follow-up care; again, a low risk of complications, and it needs to be applicable to a wide variety of patients.

Finally, improved standardization of success, outcomes, and treatment failures across clinical research, allowing for a more transparent comparison of surgical modalities and medical therapy. Future research may utilize population-based registries and electronic medical records, with the major limitation being that patients whose symptoms improve may be lost to follow-up. They may be less inclined to continue to see their urologist if they're doing well.

And finally, the panel strongly suggests that a proposed evidence-based classification system for guiding patient care, reimbursement practices, and research outcome assessment that is applicable across a variety of surgical treatments is of critical importance in the future. We thank you very much for your attention. We hope you enjoyed this AUA guideline discussion of BPH, specifically highlighting the surgical treatment option.