Five issued patents, 12 patents and provisionals filed both nationally and internationally

 Outcomes of Non-Surgical Treatment for Peyronie’s Disease: Retrospective, single clinic, observational cohort study
 
By:
Steven L. Morganstern, MD
Kenneth J. Carney, MD, PharmD, FACS
Angela Bates, APRN

 
Abstract

Objectives: The goal of this study is to evaluate the outcomes of a non-surgical treatment for Peyronie’s Disease.

Peyronie’s Disease (PD) is recognized as a difficult disease to treat within the medical community. The basis for difficulty may stem from the controversy in agreement on the etiology of PD (Nehra, et al., 2015). Most treatments to date are centered around treating the symptoms caused by the disease or for discouraging the initiation of fibrosis (Fallo & Sarnacchiaro, 2019) (Gonzalez-Cadavid & Rajfer, 2010). At this time there is only one treatment approved by the FDA (U.S. Food and Drug Administration) for non-surgical intervention of PD, clostridium collagenase histolyticum (CCH). This treatment can be effective however due to stringent qualifications for use, many patients suffering with PD are excluded from this treatment (Nehra, et al., 2015). Recommendations for treatment from the American Urological Association (AUA) include several options for medication usage with varying degrees of expected success, other than CCH. The evidence listed for these medications is rated as Grade C. This level of reliability in the research shows an expectation toward change in the confidence level with further research (Nehra, et al., 2015).
Materials and Methods: Of the 101 subjects reviewed, 31 patients were excluded due to a lack of continuity in record keeping leaving 70 patients who were actively in treatment between the dates of January 1, 2018 and March 6, 2020. Peyronie’s treatment using Exosurge follows current guidelines provided by the AUA for Peyronie’s Disease (Nehra, et al., 2015). No patients were excluded for past medical history, fibrotic condition of calcification, degree of initial curve or previous treatments.

Results:  Changes in presentation after treatment resulted in 84% of patients with improvement. Of these patients, there was a 58% average reduction in curvature. Fourteen percent showed no change and only one patient worsened after treatments began.
The average plaque reduction was found to be 79%. Patients who had an initial curve showed an average plaque reduction of 88%. An incidental finding revealed that only 24% of patients with a curve greater than or equal to 30 degrees measured an acceptable erection grade of 3.5 or 4.0 at baseline. After treatments, this number increased to 42%.

Conclusion:  Not only do these results show an impressive reduction in plaque size and consistency, but a notable difference was seen in the degree of curve and erectile function. This author feels there is enough evidence presented within this review to proceed to clinical trials for the use of ExoSurge as a foundational, non-surgical treatment for Peyronie’s Disease.

Key Points:
·      84% of patients showed improvement in their curve.
·      58% average reduction in curve.
·      79% overall reduction in plaque.
·      55% of patients with an initial curve greater than 30 degrees achieved an erection grade of at least 3.5 after treatment. This is an increase of 31%.
 
  

Outcome of Non-Surgical Treatment for Peyronie’s Disease: Retrospective, single clinic, observational cohort study

Introduction

Peyronie’s Disease (PD) has been defined as a disease of the tunica albuginea in which fibrosis and plaque formation alter the physiology of the corpus cavernosum. The presentation of this plaque may cause a singular or a combination of changes such as erectile dysfunction, pain, curvature, reduction in girth and length as well as a “wasting effect” of the penis (Hussein, Alwaal, & Lue, 2015). During a systematic review performed by the AUA (Nehra, et al., 2015), a definition of PD was constructed as an abnormality characterized by fibrosis. Further, it was reported that PD may include pain, erectile dysfunction, or a deformity. Although symptoms are included in the definition of PD, it should be recognized that the base definition of PD is fibrosis.

Treatment for PD is controversial as most treatment modalities have minimal success and few show a continued progress toward resolution. Many known treatments only address the symptoms that present with PD and do not look to the cause. The AUA recommends that clinicians should only offer treatment if the clinician is experienced to treat the condition (Nehra, et al., 2015). The purpose of this study was to review the outcomes of PD patients undergoing the non-surgical treatment, ExoSurge at a single clinic, Morganstern Urology Clinic (The Clinic) between the dates of January 1, 2018, and March 6, 2020. No patients were excluded based on past medical history or type of treatment received in the clinic.

2          Method
2.1       Eligibility criteria for participants

            A database search using The Clinic’s Electronic Health Records (EHR) system was completed extrapolating patient medical charts with the diagnosis of PD and undergoing treatment between the dates of January 1, 2018, and March 6, 2020. Patient charts were included when they were found to have identifiable and measurable plaque with no less than two duplex doppler ultrasound diagnostic tests within that timeframe providing a pre-treatment ultrasound and a post or intra-treatment ultrasound for comparison. Of these patients, 101 were found to be consistent in receiving treatments during this timeframe. Those excluded were patients who had not been seen in the clinic within three months or more prior to the post or intra-treatment ultrasound tests and considered inconsistent with treatment.

  Upon further review it was determined that within this patient sampling of 101, some pre-treatment recordings of the duplex doppler ultrasound diagnostic test was not complete and/or not comparable in recording to the post and/or intra-treatment ultrasound and therefor were not considered a good comparison. These patient charts were removed from the study leaving a total of 70 patient charts for comparison. All duplex doppler ultrasound diagnostic testing during the listed dates was completed by an independent, outside source on site at The Clinic.

2.2       Past Medical History

Past medical history (PMH) for each patient was recorded only. No participants were excluded based on PMH. Past medical history was broken down into these categories:  Cardiac, Diabetes Mellitus (DM), Cancer (CA), Cerebrovascular Accident (CVA) and Low Testosterone (Low T). The heading of cardiac included patients with diagnosis and having been medically treated for hypertension (HTN), hypercholesterolemia, arrhythmia, congestive heart failure (CHF) or had a history of myocardial infarction (MI). Patients were included in the diabetes category if they were found to have a history of being treated medically or were currently being treated for diabetes mellitus (DM).

2.3       Study Design

This was a single clinic, descriptive study conducted in review of clinical treatments by Morganstern Urology Clinic including patients undergoing treatment for Peyronie’s Disease between January 1, 2018, and March 6, 2020. Patient identification information was removed to maintain HIPAA Compliance.

Data retrieved from each duplex doppler ultrasound included degree of curve, identification of venous leak, identification of arterial insufficiency, erection grade, size of plaque, and consistency of plaque as either calcified or non-calcified.

2.4       Treatment Description

ExoSurge treatment includes a gas combined with an intralesional injection of no less than 1 mL of the calcium channel blocker verapamil. Other supportive treatments were used based on each patient’s individual presentation, but ExoSurge and Verapamil were administered to every patient in this study. Supportive treatments may have included straight stretching devices, vacuum devices, oral medications, intralesional medications and/or over the counter supplements.

2.5       Data Review & Analysis

A beginning baseline duplex doppler ultrasound analysis that included up to three measurable pieces of plaque was compared to a follow up duplex doppler ultrasound for measurable changes. Data retrieved from both the initial and final duplex doppler ultrasounds included findings of plaque. Plaque size was recorded in a 3-dimensional format in millimeters. Consistency of plaque was recorded as calcified or non-calcified. Penile curvature was identified in degree of curvature, which was then divided into two classes: curvature greater than or equal to 30 degrees and a curvature less than 30 degrees.
Vascular integrity was recorded by review of arterial flow and/or venous leak. A simple A to B Ratio was used to determine level of integrity. The average value of Peak Systolic Velocity (PSV) was recorded per sides left and right. The average value of End-Diastolic Velocity (EDV) was also recorded by sides left and right. These results were then divided into Healthy, Moderate or Severe and noted as left and right. An A/B ratio greater than 20 was labeled as healthy, between 7 and 19 as moderate and less than 7 as severe.  For final review only results shown to have Moderate or Healthy in both the left and right side were recorded as “unhealthy”.

Erection grade was recorded on a scale of 1 to 4 with increments of 0.5 based on the Erection Hardness Score (EHS).

Figure 1 EHS (Goldstein, et al., 2008)

2.6       Statistical Analysis

Of the total 70 patients reviewed, 50 were found to have a curve not considered as natural and developing later in life. All 50 patients were evaluated with color duplex doppler ultrasound for the following variables: penile plaque volume, calcified vs. non-calcified plaque, degree of penile curvature, and aspects of erectile function. Existing health conditions were noted but have not been used to score or further rate any changes in the level of disease for this review.

Plaque volume was measured, in mm3. To calculate the volume of the penile plaque, we measured three dimensions of each piece to determine the volume; V = length ×width × depth. Up to three separate pieces of plaque were recorded when present.
Degree of penile curvature was recorded during the initial and follow up duplex doppler ultrasound by use of a protractor. In many cases, but not all, pictures were provided with protractor showing measurement of current curve. Value of curve was accepted with or without confirmation picture.

Each duplex doppler ultrasound included an intra-cavernosal injection of 10 mcg alprostadil (Nehra, et al., 2015) administered prior to any measurements (Cavallini, Scroppo, & Zucchi, 2016). PSV was recorded every five minutes for a total of thirty minutes on both the left and right sides. For purposes of evaluation, PSV readings less than 30 were considered deficient (Gomez Varela, Mateos Yeguas, Rodriguez, & Duran Vila, 2020) and recorded as “arterial insufficiency”. EDV was also recorded in the same increments. It is commonly recognized that the EDV must be low to offer an effective veno-occlusive mechanism (Cavallini, Scroppo, & Zucchi, 2016). For evaluation, we considered readings >4 cm/sec as insufficient and this is labeled as “venous leak”. A simple ratio calculation of PSV / EDV provided the ratio between the two ratings.

3          Results

3.1       ExoSurge treatment changes in Plaque size

3.1A Plaque Area One Condition:

For the baseline duplex Doppler ultrasonography, the total number of pieces counted were 66. Of these, 52 were non-calcified and 14 were calcified. On the follow up duplex Doppler ultrasonography, the total number was 58. Of these, 48 were non-calcified and 10 were calcified. The reduction in the number of calcified plaque pieces was 28.6%.

3.1B Plaque Area One Measurement:

The total plaque size measured with the baseline duplex Doppler ultrasonography in Area One was 302.9 mm3 and the follow up duplex Doppler tally in Area One was 55.7 mm3, representing an 81.5% reduction in penile plaque for the 70 patients.

3.1C Plaque Area Two Condition:

For the baseline duplex Doppler ultrasonography, the total number of pieces counted in plaque area Number Two were 42 with the follow up study showing a total of 40. Of the original 42 pieces, 28 were non-calcified and 14 were calcified. On the follow up duplex Doppler ultrasonography analysis for plaque in Area Two, 32 were non-calcified and 8 were calcified, a 43% decrease in calcified plaque.

3.1D Plaque Area Two Measurement:

The average total size as measured from the baseline duplex Doppler for area two was 209.9 mm3 and the follow up results measured 63.4 mm3, representing a 70% reduction in penile plaque.

3.1E Plaque Area Three Condition:

For the baseline duplex Doppler ultrasonography, the total number of pieces counted in plaque Area Three were 22. The follow up duplex Doppler ultrasonography showed a total of 23 plaque pieces. Of the original 22 pieces, 15 were non-calcified and 7 were calcified. Data derived from the follow up duplex Doppler ultrasonography indicated 18 plaque fragments were non-calcified and 5 were calcified, representing a 28.6% improvement in the reduction of calcified plaque.

3.1F Plaque Area Three Measurement:

The total size as measured with the baseline duplex Doppler ultrasonography study for plaque in area three was 198.45 mm3 and the follow up duplex Doppler ultrasonography was 30.59 mm3, representing an improvement in the reduction of penile plaque of 84.6%.
Figure 2 Plaque Size Reduction

 
3.1G Combined Areas Condition:

The initial baseline number of calcified plaque pieces derived from duplex Doppler ultrasonography among all 70 patients in this study was 35. The follow up duplex doppler study showed the total number of calcified plaque pieces after treatment was 23. This shows a 34.3% reduction in calcified plaque pieces.

The non-calcified numbers increased from an initial count of 95 to the follow up count of 98. This is an expected finding as the calcified plaque will change to non-calcified before it is no longer measurable.

3.1 H Combined Areas Measurement:

The initial baseline plaque size total derived from duplex Doppler ultrasonography among all 70 patients in this study was 711.2 mm3. The follow up duplex Doppler ultrasonography was 149.7 mm3. The combined measurable penile plaque reduction for all areas was 79.0%.

Peyronie's Disease Study - Plaque Size Reduction

Figure 2 Penile Plaque Size Reduction

 
3.2       ExoSurge treatment change in curve

A comparison was made between initial duplex doppler ultrasound and final/intra-treatment ultrasound as some patients were still undergoing treatments. Of the initial 50 patients with a curve, 36 of those patients also had a venous leak. Of the 50 patients with a curve, 17 of them had a curve less than 30 degrees with 12 of those with a venous leak. Thirty-three of the 50 had a curve greater than 30 degrees, of which 24 had a venous leak. The final study review of the 50 pts who were initially found to have a curve, 8 of those patients had no curve at all. Of the original 33 with a curve greater than 30 degrees, this number decreased to only 20 patients. On the initial study only 17 patients had a curve less than 30 degrees and this increased to 22. Therefore, 8 patients completely corrected to no longer have a curve and 5 had reduced significantly, one patient's curve increased by 8 degrees. A 58% reduction in curve was noted for the entire group who showed a decrease in the degree of curve. Fourteen percent of patients showed no improvements with the curve.

During the time reviewed, we found only 24 patients still receiving therapy at the final date for review. The individual average improvement for these patients at the end date was 60%. Of the 26 patients no longer participating in treatment, there was an individual average

Peyronie's Disease Study - Average Improvement

Figure 3 Improvements Average Per Patient

 
 
improvement of 55% to their curvature. This change is congruent with our observations showing the largest change in curvature realized toward the end of therapy.

3.3       ExoSurge treatment changes in erectile dysfunction

Erection Hardness Score Improvement

Figure 4 EHS Patient Improvement

 
This study was a Peyronie's disease/plaque study and shows reduction in volume of plaque however, the results may be easier to see when reviewing the changes recognized in the degree of curve. Of the total 70 patients reviewed, 16 were initially found to show an erection grade of 3.5 or higher. The data reviewed is the measured erections grade found on the first and last vascular study to allow for comparison. Initially, of the total 70 patients, 13 patients were evaluated at an erection grade of 4, after treatments there was a total of 16 patients. Initially only 3 pts were graded at a 3.5 but there was a total of 20 patients on the re-evaluation. It could be that those 3 patients who were graded at a 3.5 moved up to a 4 and the 20 came from patients who initially were found with erections grades at a 3 or lower. Therefore, to begin with only 16 patients had erection grades of 3.5 or 4 out of the original 70 participants but afterward 36 patients showed a grade of 3.5 or 4.

4          Discussion

Although this study was to review the success or failure of a new, non-surgical technique for correction of Peyronie’s Disease the data obtained has value in treatments for erectile dysfunction related to venous leak and arterial insufficiency. Further review is necessary to identify the variables and obtain a more in-depth presentation toward future treatment recommendations for ED. Within the cohort information collected for this review, there is sufficient data for other conclusions related to abnormalities of the penile shaft.

Many of the tools used during the initial and subsequent duplex doppler ultrasound studies were standardized to the industry however the A/B ratio used for review of PSV to EDV was not. It appears to be sufficient to identify venous leak levels in conjunction with arterial flow for this data review, however the Resistive Index (RI) is more common practice and should be evaluated for future use. Although the A/B ratio is used in The Clinic for determining different treatment options, it does not seem to directly correlate with erection grade.

Surprisingly, there appeared to be a connection with patients who initially showed a venous leak alone or in combination with arterial insufficiency and their original erection score. This data should be reviewed for analysis of vaso-occlusive erectile dysfunction.

Based on our findings, it would be of interest to review and compare each patients PMH along with their level of treatment to see to what degree these disease processes affect the treatment of Peyronie’s Disease (Herrera, Henke, & Bitterman, 2018) (Ming, Ma, Xhang, Guo, & Yuan, 2020) and not just the disease itself.
 
5          Conclusion

The review of data has shown significant improvements with patients undergoing ExoSurge treatments and Verapamil. This data proves this to be a successful foundational treatment for Peyronie’s Disease in patients of all conditions and medical histories. Not only did these results show an impressive reduction in plaque size and consistency, but a notable difference was also seen in degree of curve as well as erectile function. Current guidelines from the AUA for the treatment of Peyronie’s Disease include several options for treatment and a category named “Other Treatments”. Also included are recommendations for surgical intervention if a patient presents with erectile dysfunction along with PD (Nehra, et al., 2015). The results indicate that not only is there is enough evidence presented to proceed to clinical trials for the use of ExoSurge as a, non-surgical treatment for Peyronie’s Disease but also shows that improvements can be made in PD patients who experience ED as well. We should not be going directly to surgical intervention for patients with ED. This treatment continues to follow current guidelines provided by the AUA while avoiding recommended irreversible surgical interventions such as penile prosthesis or grafting.

5          Authors Notes/Conflicts of Interest

Authors are current members of the care team at Morganstern Urology and active during treatment administration, data assimilation and extrapolation.
 
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Table of Figures
 
Figure 1 EHS (Goldstein, et al., 2008)
Figure 2 Plaque Size Reduction
Figure 3 Improvements Average Per Patient
Figure 4 EHS Patient Improvement
 

ExoSurge® is the world's first clinically-proven treatment to conservatively and permanently remove plaques and fibrosis associated with a Peyronie's diagnosis.