Intravesical nadofaragene firadenovec (recombinant adenovirus interferon alfa with Syn3 [rAD-IFNα/Syn3], FerGene) is a promising therapeutic option for patients who have bacillus Calmette-Guérin (BCG)-unresponsive high-grade non–muscle invasive bladder cancer (NMIBC), said Stephen A. Boorjian, MD, at the 2020 American Urological Association Virtual Experience.

He reported results from a subgroup analysis of a multicenter, phase 3, open-label trial, demonstrating that the novel intravesical gene-mediated therapy was well tolerated, safe, and efficacious, specifically highlighting the findings from the cohort of patients with papillary disease.

“The optimal management for patients with BCG-unresponsive NMIBC continues to be investigated because many of these patients are either medically unfit for or unwilling to undergo radical cystectomy,” said Boorjian, Carl Rosen Professor of Urology at the Mayo Clinic in Rochester, Minnesota.

“In this phase 3 study, nadofaregene firadenovec demonstrated a clinically meaningful benefit in a patient population for whom nonsurgical treatment options have been limited.”

Nadofaragene firadenovec combines a recombinant adenovirus vector encoding the human IFNα2b gene with the excipient Syn3, which enhances transduction of the adenovirus vector into bladder cells. A phase 2 study completed several years ago investigated 2 doses of nadofaragene firadenovec (1.1 or 3 x 1011 vp/mL) in 40 patients with BCG-unresponsive high-grade NMIBC. Its results showed that at 12 months after the first instillation, 14 patients (35%) were free fromhigh-grade recurrence.

“Of particular interest in the phase 2 study, the 12-month, high-grade, recurrence-free survival rate among patients with papillary-only tumors was 50%,” Boorjian said.

The phase 3 study investigated nadofaragene firadenovec 3 x 1011 vp/mL in patients with high-grade NMIBC who met the FDA definition for BCG-unresponsive disease. A total of 157 patients were enrolled, received at least 1 treatment, and were included in the safety population. Six patients who did not met the definition of BCG unresponsiveness were excluded from the efficacy population, leaving an evaluable cohort of 103 patients with carcinoma in situ (CIS) and 48 patients with papillary disease.

The investigational gene-mediated therapy was instilled into the bladder with a targeted dwell time of 1 hour. Efficacy was evaluated based on findings from cystoscopy and urine cytology performed every 3 months, with biopsy if indicated, and a mandatory biopsy performed at 12 months after first instillation. Repeat treatments could be given every 3 months to patients who remained free from high-grade recurrence.

“The quarterly delivery schedule for this agent was favorable to both patients and providers,” Boorjian said.

The primary end point analysis showed that a complete response was achieved by 55 of 103 patients with CIS (53.4%), which occurred by 3 months after the first instillation. Among the 48 patients with papillary disease, 35 patients (72.9%) achieved high-grade recurrence-free survival at 3 months after their initial treatment.

Analyses of data collected at 12 months showed that, among patients who achieved a complete response, 21 (60%) of those with papillary disease and 25 (45.5%) of those with CIS remained free from high-grade recurrence.

Only 3 patients (6.3%) from the papillary disease cohort experienced progression to muscle invasive disease during the available follow-up. Within the CIS cohort, 5 patients (4.9%) progressed to muscle invasive disease.

The safety analysis for the phase 3 trial included all 157 enrolled patients who received at least 1 dose of nadofaragene firadenovec. It showed that the most common study drug–related adverse events (AEs) were irritative lower urinary tract symptoms, which were transient.

Three patients (1.9%) experienced a serious study drug– or procedure-related AE. Those AEs included single episodes each of sepsis, syncope, and hematuria. In addition, 3 patients (1.9%) discontinued the study drug because of a treatment-emergent AE. There were no deaths in the study.

Disclosure: Dr Boorjian is a consultant for Ferring, Sanofi, ArTara Therapeutics, and FerGene.

1. Boorjian S, Dinney C, The Society of Urologic Oncology Clinical Trials Consortium. A phase 3 study to evaluate the safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive non-muscleinvasive bladder cancer: papillary disease cohort results. Presented at: 2020 AUA Virtual Experience. Abstract PD12-07.

Articles

72.9% of patients with papillary disease achieved high-grade recurrence-free survival at 3 months after initial treatment.

Gene-mediated therapy for high-grade NMIBC delivers positive results in trial

The year 2020 has been challenging for everyone. The Centers for Medicare & Medicaid 

Services (CMS) has made several unprecedented changes to adapt to the coronavirus disease 2019 (COVID-19) public health emergency (PHE), with other payors following suit. 

However, as stay-at-home orders are lifted, we are seeing several payors roll back or partially roll back some of the implementations regarding the use of telehealth. The health care system changes are only a fraction of the challenges each urology office is facing. We have been impressed with the innovation and outside-the-box thinking that many have taken on and shared with others to meet the challenges facing us. We encourage you to keep thinking and trying new things.

For this article, we are going to focus on a “burning” question that we have been asked repeatedly: With all that is happening, is CMS going to move forward with the adoption of new guidelines for E/M office coding?

Briefly, we can answer with a qualified “Yes.”

We are writing this article just prior to the release of the proposed rules for the Physician Fee Schedule. For a refresher on Medicare rule making, CMS releases a proposed rule for physician payment each year toward the end of the second quarter (late June or early July). This rule allows CMS to receive and react to suggested changes in the way physicians will be paid during the following year. Societies and individuals can provide direct feedback to CMS with arguments for or against these changes. Medicare reviews this feedback and incorporates its response in the final rule, which is typically released in October or early November. The final rule sets the policy for the forthcoming year. CMS is also required to accept and review comments on this rule, but it is unusual for the agency to make major changes at this stage.

Recall that the final rule for 2020, released in November 2019, included a commitment to adopt the upcoming changes in evaluation and management (E/M) codes, revise the relative value units (RVUs) for office and other outpatient E/M codes, and add or adopt codes to address additional time and impacts on certain specialties.

CMS also partially adopted the proposed documentation changes for 2021 E/M codes to allow for services provided via telehealth during the PHE. In short, our qualified “yes” regarding whether or not CMS will adopt the E/M changes for 2021 is based on what CMS has published. In addition, the American Medical Association (AMA) has indicated they will proceed with an updated publication of the office and other outpatient Evaluation and Management Services Guide, required for use under HIPAA. Our answer is qualified because CMS has not yet issued the final rule and, as we have seen, the agency could make alterations at the last minute.

We will focus on a few highlights of the upcoming changes and the preparations we recommend for the remainder of this year.

Second, and more importantly, history (H) and physical (P) examination will no longer follow the requirements currently included in the guidelines for 1995 or 1997. Instead, the new guidelines require only that the documentation include a medically necessary and appropriate H and P.

Hopefully, all of you have been using this new approach to H and P for your telehealth visits provided for Medicare and your Medicare advantage plans during the PHE. CMS adopted this change to the documentation guidelines for telehealth in its March 30 rule. Adapting to the change allows you to charge more appropriately regarding the medical decision making required for remote office visits. It should also give you a partial road map to the changes you may need to make to your EMR templates and patient intake forms, which can be fully implemented on January 1, 2021.

We encourage you to contact your electronic medical record (EMR) vendor to find out whether they are planning to update the current E/M calculator. Regardless of whether your vendor is able to keep up with the changes, we encourage you to learn the new rules in preparation for the changes so you can report the correct code for the services you provide now and in the future.

The other change adopted for the PHE was the amended definition of time. Although the 2021 updates in current procedural terminology will take things a step further by including revised time ranges for each E/M new and established office visit, the concept has already been implemented during the PHE for telehealth visits. Currently, time can be used as the overriding factor if you spend over 50% of the E/M face-to-face visit time in counseling and/or coordination of care, and document it. Under the new definition (again, currently allowed for telehealth visits), you can use time to select the appropriate level of service reported regardless of how much time you spent in counseling and/or coordination of care. In addition, the new definition of time allows you to count the total time spent during the date of service in support of the E/M encounter. For documentation, you will need to record total time. This includes time spent directly with the patient, reviewing records, discussing with other providers, coordinating care, and so on.

We do not yet know the extent of detail you may need to document. As is the case today, you are not required to document time unless it is to be used to determine the level of service charged. Further, although time is appropriate for some encounters, most urology encounters would be more accurately and efficiently reported by reviewing the medical decision making required.

The new guidelines rely primarily on the medical decision making documented. These proposed changes were not adopted for the PHE but will be adopted on January 1, 2021, for all new (99202-99205) and established (99211-99215) office visit codes. The new guidelines for medical decision making will require some education as the changes published by the AMA have been revised. The changes to this portion of the E/M office new and established patient guidelines include the same main categories of Number of Problems, Amount of Data, and Amount of Risk. What has changed is the way in which these categories will be divided by level.

Number of Problems is now based on severity of problem, with little accommodation for the number of problems addressed. Amount of Data is grouped by category, and the number of categories and amount of data for each category are used to determine the appropriate level of service. Amount of Risk is similar to the existing risk table, but has been simplified by grouping the former three columns of risk into one table representing the risk of morbidity from additional diagnostic testing or treatment.

We urge you to take time this fall to educate yourself on these changes. The American Urological Association and Physician Reimbursement Services will be offering courses on the new system over the remaining months of 2020, as well as providing support in 2021. Further, follow up with your EMR vendor to ascertain what changes if any are being made to your system to accommodate these updates. Although change is always difficult, we feel that these changes will be of great benefit to urologists once they are implemented. Get ready and embrace this challenge.

The information in this column is designed to be authoritative, and every effort has been made to ensure its accuracy at the time it was written. However, readers are encouraged to check with their individual carrier or private payers for updates and to confirm that this information conforms to their specific rules.

The deletion of code 99201 is among the evaluation/management coding changes for 2021.

It’s time to prepare for upcoming E/M coding changes

Urology Times® reached to three urologists (selected randomly) and asked them each: What has been your experience with telemedicine?

“Before COVID-19, we called patients back, but we never did video or phone consults. Now we do both. Telemedicine will have an important place now in urologic care of patients.

Initially, it was intimidating. How would timing come off? How would the back-and-forth work conveying information? But we quickly felt comfortable, especially with video. With face-to-face interaction, especially in pediatric urology, you can have them point to the affected area. I’ve even done it on postop. ‘Point the camera at the area. Oh, it looks great.’

It saves people traveling for quick follow-ups. It helps [with] managing patient flow and educational aspects of care.

With pediatrics, often it’s not just one kid families have to wrap up when they need to see us. They’ve got several children to bring. If we can handle things over the phone, they’re elated.

Sometimes you can look at lab results and prescribe preliminary medication. Then you can see how it works before patients come in. That can streamline the management of disease.

You can provide educational links to patients before we talk about a particular procedure. That can save time.

Facial recognition and communication are important when you’re going to do a procedure. You need the video-conferencing.

Most of our patients, even the elderly, seem to access their charts online. On the site, there’s an easy link to connect to a video consult. ‘My Chart’ has a prompt that allows them an easy video consult link.”

“We didn’t do telemedicine before the pandemic. My experience now is fairly positive. It’s for reviewing labs, discussing people’s prognoses and potential outcomes, as well as the direction of therapy.

In urology, if patients need certain examinations, the initial consult can be telemedicine. Eventually, they’ll need an in-person visit because nothing replaces that physical examination.

Cognitive appointments, especially if you know the people, work well because these people don’t necessarily need a physical exam if their symptoms are stable.

It’s also good because older patients are at higher risk for coronavirus and many are anxious about possible exposure coming in. If physical exams are not critical for decision making, for example, if you’re following a patient’s PSA, you can check laboratory data by telemedicine. Eventually, they’ll probably need a physical examination but maybe that can be delayed until the environment is safer.

Telemedicine works best on video. With audio only, you miss face-to-face communication. Body language is important, otherwise you don’t know whether they’re grasping concepts. It’s also more personal. Without that connection, they’re probably less likely to follow those things they should.

I expect we’ll continue telemedicine when coronavirus is no longer an issue, but probably not to the same extent. I have patients who travel who may request video appointments, which I would do sometimes. Other patients are less mobile and can’t always get here. It’s better to do a video conference than just keep rescheduling them and eventually have them drop out.”

“We didn’t do telemedicine before the coronavirus. We considered it a couple years ago, but technology wasn’t great, and, frankly, the payer system didn’t facilitate it. Not that we didn’t want the work, but you have to be fairly compensated.

With coronavirus, the government basically said, ‘We’ll waive onerous requirements. If you visit patients through telecommunication devices, we’ll cover them as in-person visits.’

Telemedicine is a mixed bag. I definitely see where it’s useful, particularly for elderly patients, or patients with difficulty getting into the office without help. Some of our patients are octogenarians. As long as it doesn’t require a physical exam, it’s a great way to go.

I have seen it take time when there’s a lot of data to go through, and you have to go to a different terminal to look at x-rays , but there’s definitely a role for it.

I’m concerned the government may revert to rules from before COVID…making it difficult to code for visits the way they require.

Certain things still require face-to-face visits, such as feeling a mass. But I have patients living 60 to 70 miles away. Having to come back for a quick post-op check costs time and gas money. Telemedicine works well in those cases. So I definitely think there’s a place for this after the virus, especially in less populated areas, like the Dakotas, Idaho, Arizona. Patients need care, but there’s a big onus on them to travel in areas where it’s hard to get doctors to locate.”

3 urologists discuss their experience with telemedicine during the COVID-19 pandemic.

What has been the telemedicine experience in urology during the COVID-19 pandemic?

From 1999 to 2016, testosterone levels have declined in adolescent and young adult men (AYA), according to results presented at the 2020 American Urological Association Virtual Experience

“Overall male testosterone decline can be attributed to multiple etiologies. The United States has an aging population with older males exhibiting lower testosterone levels. Furthermore, overall population has an increase in comorbidities, including diabetes, which may have cause this testosterone decrease nationally,” Soum Lokeshwar, MD, MBA, incoming urology resident at Yale School of Medicine, New Haven, Connecticut, said during a press briefing.

“However, most of these explanations for testosterone deficiency may be attributed to age. This time-dependent decline in testosterone has not been investigated in adolescent and young adult males,” added Lokeshwar, who was at the University Of Miami Miller School of Medicine, Miami, Florida, at the time of the study.

Testosterone deficiency has a prevalence of 10%-40% among adult males, and 20% among AYA men aged 15-39 years, he added. Therefore, Lokeshwar and colleagues hypothesized that serum total testosterone levels will decline in AYA men.

The investigators used data from the National Health and Nutrition Examination Surveys (NHANES) from 1999 to 2016 to analyze serum testosterone level changes over time in 4045 AYA males. During the study periods, 3 different assays (Biotin-Streptavidin from 1999-2004, IS-Liquid Chromatography from 2011-2012, and High-Performance-Liquid-Chromatography Tandem Mass Spectrometry from 2013 onwards) were used. However, of note, they demonstrate comparable testosterone values with only some additional accuracy in the latest modality, Lokeshwar said.

After controlling for confounders—including year of study, age, race, BMI, comorbidity status, alcohol and smoking use, and level of physical activity—total testosterone was lower among men in the later (2011-2016) versus earlier (1999-2000) cycles (

 < 0.001). Mean total testosterone decreased from 1999-2000 (605.39 ng/dL), 2003-2004 (567.44 ng/dL), 2011-2012 (424.96 ng/dL), 2013-2014 (431.76 ng/dL), and 2015-2016 (451.22 ng/dL; all 

Elevated BMI was associated with reduced total testosterone levels (P < .0001), with the mean BMI increasing from 25.83 in 1999-2000, to 27.96 in 2015-2016 (

 = 0.0006). Lokeshwar noted that even men with a normal BMI (18.5-24.9) had declining total testosterone levels (

Potential causes include increased obesity/BMI, assay variations

According to Lokeshwar, potential causes for these declines could be increased obesity/BMI, assay variations, diet/phytoestrogens, declined exercise and physical activity, fat percentage, marijuana use, and environmental toxins.

“We’ve seen that lower values of testosterone have been associated with increased comorbidities and an increase risk for all-cause mortality. This decline specifically, in these young adult men, with increased obesity may lead to an increase in precocious cancer,” Lokeshwar said, adding such decreases can also result in a lower libido and an increased risk for erectile dysfunction.

“This is especially worrisome in this young adult age group, as many men feel stigma and are less likely to seek care for these low libido and erectile dysfunction.” Lokeshwar added. “Testosterone levels in AYA men are used as the benchmark normal levels for testosterone. This is very scary, because generally, when we think of normal values of testosterone, we treat based upon this age group. This may ultimately lead to the undertreatment of testosterone deficiency, which can have large ramifications and severe consequences.”

1. Patel P, Fantus R, Lokeshwar S, et al. Trends in Serum Testosteron Levels Among Adolescent and Young Adults Men in the United State. Presented at: 2020 AUA Virtual Experience; May 15, 2020. Abstract MP78-01.

The decline in total testosterone was observed even among men with normal body mass index.

Testosterone levels show steady decrease among young US men

Results from an initial pilot trial show that an investigational, minimally invasive system for transurethral anterior commissurotomy of the prostate (TUAP) with localized transfer of paclitaxel (Optilume BPH Catheter System) is safe. Further, it provides significant objective and subjective improvements in benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms that remain durable for at least 1 year, reported Steven A. Kaplan, MD, at the 2020 American Urological Association Virtual Experience.

“The Optilume system is the first ever, minimally invasive treatment that can provide TURP [transurethral resection of the prostate]-like results without cutting, burning, steaming, lasering, or leaving a permanent implant behind, and it is designed to minimize or eliminate the common [adverse] effects associated with other surgical BPH procedures,” said Kaplan, professor of urology at the Icahn School of Medicine at Mount Sinai in New York, New York.

“Follow-up of men enrolled in the pilot study is still ongoing. Based on its results, a prospective, randomized, double-blind, sham-controlled pivotal trial known as PINNACLE is now underway at 20 sites in the United States. We look forward to presenting data from longer follow-up in the pilot trial and from the larger controlled clinical trial.”

Kaplan noted that a balloon catheter dilation system was investigated as a potential treatment for BPH approximately 25 years earlier. However, although its use was associated with initial symptomatic improvement, the benefit was not sustained.

“With the Optilume system, a predilation balloon catheter is passed to perform TUAP that opens and increases the size of anterior portion of the prostatic urethra to alleviate obstruction. Then, a drug-coated balloon catheter is introduced for circumferential delivery of paclitaxel, an antiproliferative drug that is believed to maintain the opening of the newly divided tissue,” Kaplan said.

The data he presented were from the EVEREST-1 trial (NCT03423979) that enrolled 80 men with BPH across 6 investigational sites in Latin America. The study investigated 3 sizes of the balloon, described as small, medium, and large.

“Multiple sizes allow for customized treatment based on ultrasound measurement of prostate length, height, and total volume,” Kaplan said.

At the cut-off date for data analysis, 73 men had completed 1 year of follow-up. The primary end points for the study were improvement of 40% or greater on the International Prostate Symptom Score (IPSS) from baseline to 3 months and major device- or procedure-related adverse events at 3 months. Among the 79 patients evaluated at 3 months, 82.3% met the efficacy end point; 1 subject who developed stress urinary incontinence, which resolved at the 30-day follow-up, met the primary safety end point, Kaplan reported.

Mean IPSS score was 22.3 at baseline and had improved to 8.3, 8.0, and 7.9 at 3, 6, and 12 months, respectively. Mean peak flow rate was 10.9 mL/sec at baseline and 19.6 mL/sec at 1 year. Improvements in both IPSS and Qmax were statistically significant.

Kaplan contrasted the efficacy results achieved in the pilot trial with those reported for other minimally invasive procedural treatments for BPH from studies investigating those modalities at a similar stage in their pathway toward regulatory approval.

“Compared with UroLift or Rezum, the benefits of the Optilume system for improving symptoms and peak flow rate occur earlier and are more pronounced, and its benefits also occur earlier than TURP,” he said.

Analyses performed with men stratified by balloon size showed that the level of symptom improvement and its durability were similar regardless of balloon size. However, maximum symptom relief was achieved by day 30 using the small balloon whereas it took 6 months to achieve maximum symptom relief with the large balloon.

Analyses of improvements in peak flow rate showed that the large balloon was associated with significant improvement within the first 30 days, but there was a slight deterioration in benefit at 1 year. Peak flow rate improvements were relatively smaller using the small and medium balloons, but peak flow still increased to about 17 mL/sec and remained stable throughout the 1-year follow-up.

“Based on these observations, only the small and medium balloons are being used in the PINNACLE trial,” Kaplan said.

Safety was favorable, and there were no changes in sexual function.

Kaplan is the principal investigator for EVEREST-1.

Disclosure: Urotronic provided funding for the study.

1. Kaplan S, Pichardo M, Rijo E et al. EVEREST-1: One-year Optilume BPH catheter system efficacy and safety experience. Presented at: AUA 2020 Virtual Experience. Abstract PD61-03.

Significant improvements in BPH-related lower urinary tract symptoms were observed with the system.

BPH catheter system shows encouraging outcomes in pilot trial

Results from 1 year of follow-up of patients enrolled in a pivotal clinical trial show that sacral neuromodulation (SNM) with a miniaturized, implanted rechargeable device (Axonics System) provides highly safe and durably effective treatment for urinary urgency incontinence (UUI), said Howard B. Goldman, MD, at the 2020 American Urological Association Virtual Experience.

Goldman, a professor of urology at Cleveland Clinic Lerner College of Medicine in Cleveland, Ohio, presented the research on behalf of the study investigators. He reported that reduction in UUI episodes observed at the study’s primary end point at 6 months were sustained through 1 year, and the safety profile of SNM with the rechargeable device was consistent with SNM experience reported in the literature.

“Patients also benefited with clinically significant improvements in quality of life, had a high level of satisfaction, and found the charging task user friendly,” Goldman said.

The rechargeable SNM system received FDA approval for treating UUI, urinary urge frequency, and urinary retention in November 2019. The pivotal trial supporting the decision had a single-arm design and enrolled 129 patients at 19 centers in the United States and western Europe. Subjects were eligible for inclusion if they had 4 or more UUI episodes in a 3-day diary, including 1 or more episode per day. Individuals with more than a minimal level of stress incontinence, anatomic urinary tract obstruction, or an underlying neurological condition were excluded.

The trial’s participants ranged in age from 21 to 86 years (mean 59) and were almost entirely women (98%). Mean UUI episodes per day at baseline was 5.6.

The primary end point for the study assessed the rate of therapy responders at 6 months. Ninety percent of women, defined as participants achieving a 50% or greater reduction in UUI episodes per 3 days, achieved the end point. The therapy responder rate was 89% at 1 year.

“The reduction in UUI episodes was quite significant in the study cohort,” Goldman said.

“At 6 months it had decreased to 1.3 episodes per day and it was 1.4 at 1 year. Furthermore, more than three-fourths of patients had at least a 75% reduction in daily UUI episodes at 1 year, and the remaining participants achieved at least a 50% reduction.”

Quality of life was evaluated using a validated questionnaire (International Consultation on Incontinence Questionnaire Overactive Bladder Quality of Life Module). At 1 year, changes from baseline in the total score and in scores for individual domains (concern, coping, sleep, and social) ranged from 22 to 34.

Quality of life improvements statistically significant

“All of the improvements were statistically significant and far exceeded the minimum 10-point change that is considered clinically significant,” Goldman said.

At 1 year, 93% of patients said they were satisfied with the therapy, and 92% said they would undergo the therapy again with the same expected results. Questions pertaining to the charging of the device showed that it was considered easy by 89% of participants, and 96% rated the frequency and duration of charging as acceptable. Ninety-five percent of participants reported recharging the device no more than once a week, and 86% reported that the total charge time was 60 minutes or less.

There were few adverse events (AEs) in the series and no serious device-related AEs. The most common AE was uncomfortable change in sensation or magnitude of stimulation (5%).

No patient underwent surgical intervention for pain, but 3 patients underwent a revision and the device was explanted in 1 patient due to infection.

“Interestingly, 6 patients had magnetic resonance imaging during the year after implantation, which was full body in 4 participants, without any evidence of adverse events,” Goldman said.

The rechargeable SNM device is also approved for the treatment of fecal incontinence, and changes in fecal incontinence were evaluated prospectively in the pivotal trial. Data collected in the subgroup of patients who had fecal incontinence at baseline showed they experienced a statistically significant improvement at 6 months and even greater benefit at 1 year.

“Overall, 91% of patients who had bowel symptoms at study entry were satisfied with how that problem was helped as well,” Goldman said.

Disclosures: Dr Goldman is a study investigator and a consultant to Axonics Modulation Technologies. Axonics Modulation Technologies provided funding for the study.

Long Term Clinical Results on Treatment of Urinary Urgency Incontinence with the Axonics Rechargeable Sacral Neuromodulation System. Presented at: 2020 AUA Virtual Experience. Abstract PD27-12.

The reduction in urinary urgency incontinence episodes observed was “quite significant,” an investigator said.

Rechargeable neuromodulation system safe and efficacious through 1 year

 Editorial Consultant, is executive director of the American Board of Urology, Charlottesville, Virginia.

Androgen deprivation therapy (ADT) has been a mainstay of treatment for advanced prostate cancer for decades and has been shown to provide long-term disease control and improve symptoms. However, there is evidence that ADT increases cardiovascular (CV) risk, especially in men with preexisting CV disease.

 Additional concerns for gonadotropin-releasing hormone (GnRH) agonists are delayed castrate levels of testosterone and the need for intermittent injections, among many others.

The recent results of a phase 3 randomized controlled trial investigating relugolix, an oral GnRH antagonist, vs leuprolide may change the landscape in the treatment of advanced prostate cancer (see article, page 8). HERO (NCT03085095) was a multinational, open-label trial that randomized 934 men 2:1 to treatment with relugolix (360 mg on day 1, then 120 mg po qd) or subcutaneous leuprolide injection 22.5 mg (11.25 mg in Japan and Taiwan) every 3 months. Eligible men had confirmed advanced prostate cancer defined as biochemical or clinical relapse, metastatic disease, or advanced localized disease. Additionally, the men had to have serum testosterone levels of 150 ng/dL or greater, serum prostate-specific antigen above 2 ng/mL, and require at least 1 year of ADT. Men with a history of ADT for more than 18 months, active liver disease, or significant CV risk were excluded. The primary end point for the study was sustained castrate levels of testosterone
(< 50 ng/dL) through the 48-week study.

The 2 groups were well balanced in their clinical characteristics. In addition, both arms met the primary end point with 96.7% of relugolix patients and 88.8% of leuprolide patients achieving sustained suppression of testosterone.

Key differences in secondary end points were a much quicker suppression to castrate levels (56% vs 0%, at day 4) and a quicker return to normal by day 90 (54% vs 3%) in the relugolix vs leuprolide arms, respectively. As expected, it took approximately 1 month for the leuprolide-treated patients to reach castrate levels. Known adverse events (AEs) such as hot flushes and fatigue were very similar in both groups, with more grade 1 or 2 diarrhea in the relugolix arm, but this did not result in study discontinuation. Major adverse cardiovascular events (MACE) were 2.9% in the relugolix-treated patients and 6.2% in the leuprolide-treated patients. The authors performed a Kaplan-Meier analysis of cumulative MACE incidence over the study period and found a 54% risk reduction in the relugolix group.

If further studies confirm the efficacy and lower CV adverse effects with this new oral GnRH antagonist, this could make a substantial impact on most urologists’ practices. Patients could avoid an injection, initial testosterone surge would be alleviated, and a significant reduction in CV events would be realized. However, several questions remain to be answered, among them the following: 1. What will be the cost of this new oral therapy? 2. Will third-party payers reimburse for the therapy with currently available injectables already on the market? 3. Will the quicker testosterone recovery make this a more appealing option for intermittent therapy? 4. Might we see more gastrointestinal AEs in a larger trial? 5. What will the AE profile look like when this drug is given in conjunction with nonsteroidal antiandrogens such as bicalutamide?

Although there remain several unanswered questions about this new drug, the initial report is very promising. This new therapy could change the landscape for the treatment of advanced prostate cancer.

1. Van Hemelrijck M, Garmo H, Holmberg L, et al. Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the population-based PCBaSe Sweden. J Clin Oncol. 2010;28(21):3448-3456. doi:10.1200/JCO.2010.29.1567

"This new therapy could change the landscape for the treatment of advanced prostate cancer," Thrasher writes.

Are phase 3 HERO results a game-changer for urologists?

Analyses of data from prospective follow-up of more than 3800 men show that photoselective vaporization of the prostate (PVP) with a proprietary laser system (GreenLight XPS) is a safe and durably effective procedure for treating lower urinary tract symptoms related to benign prostatic hyperplasia (BPH), said Kevin Zorn, MD.

At the 2020 American Urological Association Virtual Experience, Zorn presented findings on behalf of coinvestigators in the global GreenLight Group, which is comprised of 8 expert surgeons practicing at 7 international referral centers1. He reported that the procedure was completed using just a single fiber in 92.5% of men; resulted in a prostate-specific antigen (PSA) reduction of 53.5% at 24 months, which was comparable to that achieved with other treatments for BPH; and was associated with few major complications. Furthermore, during follow-up of up to 5 years, only 1.5% of men underwent repeat surgical intervention for BPH recurrence.

“There has been accumulating evidence in the literature demonstrating the long-term durability of GreenLight PVP. To our knowledge, our multi-institution, multi-user study is the largest collective experience with this treatment modality,” said Zorn, a professor of urology at theUniversity of Montreal (CHUM) in Quebec, Canada.

The men included in the study were treated with the XPS 180W system between 2011 and 2019. They had a median age of 70 years and a median prostate volume of 65 mL as measured by transrectal ultrasound. Median lobe presence was observed in 36.5% of men, 35% had a Foley catheter preoperatively for urinary retention, and 34% were on anticoagulant therapy other than aspirin.

Median operative time was 62 minutes and median energy used totaled 250 kJ, corresponding to an energy density of 3.9 kJ/mL prostate volume.

“The operative characteristics in this population were typical of what we would expect with this procedure. Operating time tends to average 1 min per mL of prostate volume, and energy use typically ranges from 3 to 4 kJ per mL,” Zorn said.

The perioperative transfusion rate was only 0.8% and the median hospital stay was 2 days.

“It is important to recognize that several of the participating centers were in Europe, where surgeons are obliged to keep patients in the hospital for at least 2 or 3 days because of criteria for reimbursement,” Zorn said.

Median duration of Foley catheterization was 1 day or less in approximately two-thirds of men, and 5.9% of men required recatheterization, which is consistent with other large BPH series, according to Zorn.

Incidental prostate cancer was observed in final surgical pathology in less than 2% of men. Thirteen percent of men were readmitted to the hospital within 30 days, and most of them were on anticoagulant therapy.

Postoperative adverse events (AEs) occurring within 30 days after the procedure were categorized using the Clavien-Dindo classification system. Most were minor (grades 1-2), with the most common being lower urinary tract symptoms (22.3%), incontinence (10.4%), hematuria (9.9%), and retention (7.4%). The most common major AEs (grades 3-5) were retrograde ejaculation (4.4%) and postoperative transfusion (1.3%). All other major AEs occurred at a rate of 0.8% or lower.

“The lower urinary tract symptoms were mainly managed with anticholinergics; retention occurred mostly in men who were in retention preoperatively, and most cases of hematuria were managed with hydration without need for hospitalization or a return to the OR,” Zorn stated.

Functional outcomes analyses showed that median PSA was decreased by about 50% throughout follow-up to 5 years. Median International Prostate Symptom Score was 22 at baseline and remained at 4 or 5 between 6 months and 5 years. Median peak flow rate decreased from 6.3 mL/s at baseline to 17 mL/s at last follow-up, and median postvoid residual volume decreased from 122 mL at baseline to 23.5 mL at 5 years.

Discussing limitations of the global retrospective study, Zorn mentioned that because of its global nature and retrospective design, it is difficult to account for variations between surgeons in preoperative medical therapy and skill. In addition, many of the patients returned to their referring urologist after their procedure, so follow-up data needed to be obtained via phone contact.

Disclosures: Dr Zorn is a paid consultant and proctor surgical trainer for Greenlight PVP and Rezum by BSCI (Boston Scientific), an investigator and paid consultant for Procept BioRobotics for Aquablation, and investigator for Zenflow and Urotronic BPH treatments.

1. Law K, Tholomier C, Couture F et al. Global GreenLight Group: Largest International GreenLight Experience for Benign Prostatic Hyperplasia. Presented at: AUA 2020 Virtual Experience. Abstract PD61-07.

Only 1.5% of patients undergo repeat surgical intervention for BPH recurrence.

Photoselective vaporization of the prostate found safe, durably effective

HERO, the phase 3 clinical trial investigating relugolix for the treatment of advanced prostate cancer, met its primary end point showing that the oral gonadotropin-releasing hormone (GnRH) antagonist provided sustained testosterone suppression to castrate levels through 48 weeks of follow-up.

The FDA recently granted a priority review designation to a new drug application for relugolix for the treatment of patients with advanced prostate cancer, according to Myovant Sciences, the manufacturer of the oral GnRH receptor antagonist.

Additional findings from the randomized, controlled study (NCT04352946) showed that men treated with relugolix achieved faster and more sustained testosterone suppression than the control group treated with subcutaneous leuprolide and had a markedly lower risk of having a major adverse cardiovascular event (MACE), said Neal D. Shore, MD.

Shore presented data from HERO as a late-breaking abstract for the 2020 American Urological Association virtual meeting. He is the lead author of an article reporting the study’s findings that was published online in the 

“Prostate cancer is the most common cancer diagnosis in the United States, and cardiovascular mortality is the leading cause of death among patients with prostate cancer. Luteinizing hormone-releasing hormone receptor agonists, such as leuprolide, that are used for androgen deprivation therapy [ADT] in advanced prostate cancer have several drawbacks. They are associated with an early testosterone surge, do not fully suppress follicle-stimulating hormone [FSH], which may be a mitogen for cancer cells, and since 2011 have carried an FDA mandated label warning about an increased risk of myocardial infarction, sudden cardiac death, and stroke,” said Shore, the medical director at Carolina Urologic Research Center in Myrtle Beach, South Carolina.

“Through a direct inhibitory effect on pituitary GnRH receptors, relugolix more completely suppresses both luteinizing hormone and FSH compared with leuprolide, and relugolix avoids an early testosterone surge. Based on the results of HERO, relugolix has the potential to become a new standard for ADT in men with advanced prostate cancer.”

HERO is a multinational, open-label trial that randomized 934 men 2:1 to treatment with relugolix (360 mg on day 1, then 120 mg once daily) or subcutaneous leuprolide 22.5 mg (11.25 mg in Japan and Taiwan) every 3 months. Eligible men had confirmed advanced prostate cancer with a biochemical or clinical relapse, newly diagnosed metastatic disease, or advanced localized disease and were deemed as candidates for at least 1 year of ADT. Men with a history of MACE within the prior 6 months were excluded.

The relugolix and leuprolide patient groups were well-balanced at entry in their demographic and clinical characteristics. Approximately 90% of men in both arms completed the 48-week
trial, and the treatment compliance rate was 99% in both groups.

More than 90% of men in each treatment arm had at least 1 cardiovascular risk factor, and approximately 14% had a history of MACE.

“Approximately 30% of men with advanced prostate cancer would be expected to have a history of a MACE. The lower rate in HERO reflects the study’s exclusion criteria,” Shore noted.

Relugolix demonstrates noninferiority, superiority to leuprolide

The primary end point analysis showed that 96.7% of men treated with relugolix and 88.8% of the control group achieved sustained suppression of testosterone to castrate levels (< 50 ng/dL) from day 29 through week 48. In statistical analyses, relugolix demonstrated both noninferiority and superiority to leuprolide.

Relugolix also demonstrated statistically significant superiority compared with leuprolide in all key secondary end points, which included measures of onset of prostate specific antigen response and testosterone suppression, FSH reduction, and sustained castration rates (

“By day 4, 56% of men treated with relugolix achieved testosterone suppression to castrate levels. In the leuprolide arm, the testosterone level showed the expected initial surge, reaching a mean of 625 ng/mdL, and the mean did not fall to castrate levels until day 29,” he reported.

A substudy investigating testosterone recovery showed that by day 90 after treatment was stopped, serum testosterone returned to the normal range in the relugolix group (mean, 288 ng/dL), but the mean testosterone level was just 58.6 ng/dL in the leuprolide group. At day 90, 54% of relugolix-treated patients versus just 3% of leuprolide-treated ones achieved testosterone recovery, Shore reported.

In both study groups, > 90% of men experienced at least 1 adverse event (AE). The rate of a grade 3 or higher AE was 18% in the relugolix group and 20.5% in the leuprolide group. The fatal AE rate in the relugolix and leuprolide groups was 1.1% and 2.9%, respectively.

“The known consequences of ADT, including hot flashes, were the most common adverse events in both groups. The rate of diarrhea was higher in the relugolix group, but these events were mild or moderate and did not lead to treatment discontinuation,” Shore said.

The HERO protocol included a prespecified analysis of MACE, which included nonfatal myocardial infarction, nonfatal stroke, and death from any cause. At 48 weeks, MACE rates were 2.9% in the relugolix group and 6.2% in the leuprolide group. A Kaplan-Meier analysis of cumulative MACE incidence over the 48-week treatment period showed a 54% risk reduction in the relugolix group relative to the leuprolide group.

“The MACE event rate was almost 6-fold higher in the leuprolide group compared with the relugolix group among men with a history of MACE (17.8% vs 3.6%) and was 50% higher in the leuprolide group compared with the relugolix group in men without a history of MACE (4.2% vs 2.8%),” Shore said.

Disclosure: Myovant Sciences provided funding for the study. Dr Shore does research for and is a consultant to AbbVie, Ferring Pharmaceuticals, Myovant Sciences, and Tolmar.

1. Shore N, Saad F, Cookson M et al. Oral Relugolix for androgen-deprivation therapy in advanced prostate cancer. N Eng J Med 2020; 382(23):2187-2196. doi:10.1056/NEJMoa2004325

Oral GnRH receptor antagonist has “potential to become a new standard for ADT,” a study investigator says.

Oral gonadotropin-releasing hormone receptor antagonist shows benefits

 began noticing a new group of patients in his practice: men following up after being treated abroad with high-intensity focused ultrasound (HIFU). This prompted Peretsman to investigate and ultimately incorporate HIFU into his own practice. In this interview, Peretsman discusses which prostate cancers can be treated and which prostate glands can be treated with HIFU, contraindications to the treatment, and what expectations patients need to have postoperatively. Peretsman is with Urology Specialists of the Carolinas in Charlotte, North Carolina. He was interviewed by 

 executive director of the American Board of Urology.

Please describe your experience with HIFU.

In the late 1990s, a number of the academic centers here in the southeast were considering joining an Ablatherm trial, which was the only HIFU trial available at the time. We were referring patients to Washington, DC if they were interested. That trial never expanded, so none of the men in my part of the country were able to participate locally.

Within a few years I began seeing patients who would make appointments for their HIFU follow-up. They weren’t patients I was treating primarily; they were returning to the area. Their urologists were not comfortable taking care of them after they were treated in Europe. In 2004, when I encountered the first of these men, I decided that if people from my part of the country were going to Europe to get treated, I needed to understand HIFU so I could care for them. Secondly, I should consider the technology’s advantages because men were opting out of robotic prostatectomies, brachytherapies, cryotherapies, and IMRT. What weren’t we offering our patients that they would get on a jet and fly to another country to pursue an alternative treatment?

What actually is prostate HIFU energy, and how is it delivered?

The “U” in HIFU stands for ultrasound, meaning therapeutic sound waves, which are basically higher-power diagnostic sound waves. The energy wave must pass through a medium, which is the human tissue. Most of the HIFU machines use a piezoelectric crystal to create amplified sound waves that are then targeted at a focal point. The focused sound energy creates thermal coagulation—coagulative necrosis. Our target tissue temperature runs in the low 90s centigrade. There are also secondary effects including mechanical disruption and immunologic responses. Similar to cryotherapy, the actual response is multimodal, but primarily thermal-created coagulative necrosis.

Are your patients asleep during the procedure?

Yes, they need to be asleep and motionless. We did do the procedures under continuous spinal anesthesia about 15 years ago. Most importantly, you need to target well so patients can’t be moving. With cryotherapy and brachytherapy, the prostate shifting is lessened somewhat by the needles. With HIFU, patient movement is an issue.

How many different HIFU devices are currently available? Is one more commonly used?

In the United States, there are currently four ultrasound based devices. Over 90% of cases are done with the Sonablate 500. That’s the device that came along in the 1980s in this country and was also sold in Asia and Europe. EDAP TMS, a French company, markets the Ablatherm and, more recently, the Focal One. There’s the INSIGHTEC ExAblate, which the FDA approved in the past for conditions such as bone metastasis and fibroids. The most recent addition is the Profound Medical TULSA-PRO, which is an in-gantry MRI-guided device that delivers thermal ultrasound from a device within the urethra. It is radially directed from a urethral transducer, so not technically focused.

What are your treatment criteria in terms of size of prostate or a certain cancer type? Give me an idea of how you choose your patients for HIFU.

There are technical limitations, safety limitations, prostate limitations, and cancer limitations. In terms of technical limitations, you have to be able to get the sound to target. For example, the Ablatherm and Sonablate devices, have AP height limitations due to focal length. For the commonly used Sonablate, you’re able to treat about 3.4 to 4 cm away.

There can’t be interference such as rectal wall calcification, large prostate calculi, or many closely approximated brachytherapy seeds. Things that impede diagnostic sound are going to impede therapeutic sound. These factors are part of the evaluation. The issue is not the total prostate size; it’s whether you are able to reach the target from the plane of the transducer. In most cases with the Sonablate 500, we’re looking for 34 mm or less to give us some wiggle room above the lesion such as an anterior lesion.

From a cancer perspective, whether you’re referring to cryotherapy or HIFU, nobody has ever shown that there’s a grade-dependent response to thermal ablation. The important question is, is all the cancer you want to treat reachable? By default, you’re not going to treat much beyond 4 cm away, so that’s the prostate and the base of the seminal vesicles. You’re certainly not going to treat lymph nodes. At the University of Southern California (USC), they’ve done robotic outpatient lymphadenectomy before they’ve taken on prostate HIFU for high-grade disease.

The first contraindication is a target that’s too far away. If, on MRI, your patient has a 15-mm lesion in a 70-gram prostate and the lesion is up by the anterior capsule, you’re not going to reach it. Now you can do things to bring it toward the energy source such as transurethral resection of the prostate or any type of hormonal downsizing. Another contraindication would be a sound path issue. If the cancer on MRI is on the anterior side of a cluster of brachytherapy seeds along the rectal wall, you can’t effectively pass sound through all that metal.

There could be rectal wall calcification, and if you heat the rectal wall, you could create a fistula. The next would be a large, distal apical lesion where you don’t want to heat the backside of the pubis and create osteitis pubis. Those are the therapeutic, geometric, and safety issues.

Would you say HIFU is contraindicated in patients who have had rectal surgeries or a previous ulcer?

Not absolutely, but it is on the manufacturers’ list of relative contraindications. What I do is assess the rectal wall by ultrasound. If it’s not overly thickened from radiation and there is not calcium or a very low anterior resection compromising vascularity, then HIFU is not necessarily contraindicated.

Talk to me about the expectations of the patients. What do you tell them to expect postoperatively?

The procedure is done on an outpatient basis, it’s painless, and patients are not prescribed pain medicine. Patients have some urgency from the heat for a couple of hours after the procedure. The postoperative management depends on whether you are performing whole-gland or targeted HIFU. I recently had a HIFU patient whose Foley catheter was removed in just a few days, but that was a hemiablation in a young man. His prostate was only 23 cc, and we treated one side. If you take on a 40-gram prostate, you can see swelling in the course of the procedure. In some men, I might leave a suprapubic tube and not even have a voiding trial for 10 to 12 days. It takes time for that edema to go away.

I try to give modest expectations. I really want patients to understand that they’re choosing HIFU in lieu of something else: including radical prostatectomy, brachytherapy, or cryotherapy—approaches with which I have decades of experience. They need to understand what they’re gaining and what they’re giving up.

There are two things about HIFU unequivocally demonstrated in the literature for over 20 years. When you choose HIFU, you are going to have some obstructive symptoms potentially, and you can experience an infield recurrence (as you could with radiation or cryotherapy). You can’t have an infield recurrence with a robotic prostatectomy. So you need to understand that’s what you’re inheriting.

What you’re gaining is the lack of morbidity. Our group, along with the USC group, had an abstract presented at the 2020 International Symposium on Focal Therapy and Imaging in Prostate and Kidney Cancer, reporting on our first hundred hemiablations1. The rate of incontinence—measured as anything greater than zero pads—was zero in 100 consecutive patients. International Index of Erectile Function (IIEF-5) scores dropped 1 point. Patients are seeking diminished morbidity. I personally don’t view obstructive problems as a complication to the therapy; I build it into the expectation.

If a patient seeks to reduce the need for an inflatable penile prosthesis, artificial sphincter, or postoperative sling following surgery/radiation, he’s got to get through the short-term recovery of HIFU. I think I’m known in the community as an aggressive HIFU surgeon as far as how much tissue I treat and how much swelling I’m willing to create, because I just consider it a short-term nuisance. That’s how I counsel the patients. Other HIFU surgeons will choose to treat less surrounding tissue.

Do you generally prescribe patients alpha-blockers and anticholinergics postoperatively?

They all get alpha-blockers. They only get an anticholinergic or mirabegron (Myrbetriq) if they have prolonged irritative symptoms, which is uncommon. If there are 10 problems postoperatively, 9 are going to be mechanical weakening of the stream.

What do you tell patients about the risk to the bladder or bowel when you compare it to nonsurgical treatments?

Unlike any type of ionizing radiation, there are no delayed bladder, rectal, or urethral issues. Patients will not develop a secondary malignancy or gross hematuria years after ultrasound energy ablation. The fistula rate is about 0.7%, although most of that occurs in post-radiation patients; I’ve never had one.

Compared to surgery—let’s use robot-assisted radical prostatectomy because it’s the most common in this country—there are no intraabdominal issues. There’s no ileus, and there’s never a bowel obstruction. A rectal injury without prior radiation is exceedingly rare in the literature. The main issue is prolonged obstructive symptoms based on how much tissue you ablate.

Samuel J. Peretsman, MD, discusses which patients with prostate cancer can be treated  with HIFU, contraindications to the treatment, and what expectations patients need to have postoperatively. 

Vol 48 No 7

Gene-mediated therapy for high-grade NMIBC delivers positive results in trial

It’s time to prepare for upcoming E/M coding changes

What has been the telemedicine experience in urology during the COVID-19 pandemic?

Testosterone levels show steady decrease among young US men

BPH catheter system shows encouraging outcomes in pilot trial

Rechargeable neuromodulation system safe and efficacious through 1 year

Are phase 3 HERO results a game-changer for urologists?

Photoselective vaporization of the prostate found safe, durably effective

Oral gonadotropin-releasing hormone receptor antagonist shows benefits

HIFU in focus: An expert's take on high-intensity focused ultrasound

Is low-intensity surveillance feasible for patients with high-risk NMIBC?

How to fill the gap between retirement, Social Security

Relugolix emerges as "exciting" new treatment in prostate cancer