Patient Reported Health Related Quality of Life Outcomes After Viable Cryopreserved Umbilical Tissue Placement Directly Over Spared Neurovascular Bundles After Robotic Assisted Radical Prostatectomy

doi:10.21203/rs.3.rs-4875630/v1

Introduction

Incontinence and sexual dysfunction remain common side effects from robotic-assisted radical prostatectomy (RARP) despite nerve sparing (NS) and bladder neck reconstruction techniques. Placing growth factors and anti-inflammatory substances over neurovascular bundles is an emerging technique to enhance recovery of continence and potency. Viable cryopreserved umbilical tissue (vCUT) is FDA-approved for surgery. The objective is to determine if vCUT use in NS-RARP accelerates return of continence and sexual function.

Methods

A retrospective cohort of 176 patients undergoing NS-RARPs with and without vCUT from 2015-2020 was identified through the Michigan Urological Surgery Improvement Collaborative (MUSIC). Return to social urinary continence at 3, 6, and 12 months postoperatively was evaluated using MUSIC patient-reported outcomes (PRO), a validated questionnaire assessing urinary and sexual quality of life at baseline and post-treatment. A distinct cohort of 65 patients undergoing NS-RARP with and without vCUT was assessed for erections firm enough for intercourse at 12 and 24 months post-operatively using MUSIC-PRO. The association between vCUT use and social continence at 3 months was assessed via multivariable logistic regression. A descriptive analysis among patients with quality erections prior to surgery assessed the association between vCUT use and erection quality.

Results

Continence was achieved by 3 months post-op in 86% (99/115) of vCUT patients versus 74% (45/61) in non-vCUT patients (p=0.044). In a multivariable analysis, although not reaching conventional statistical significance, vCUT patients were more likely to achieve continence than non-vCUT patients (OR=2.21, p=0.073). At 24 months post-op, 32% of vCUT patients reported good sexual function versus 33% in non-vCUT patients (p=0.9).

Conclusions

vCUT use during NS-RARP is associated with quicker return to social urinary continence. However, no differences were seen in return of potency. Further studies with longer follow-up and larger sample sizes may further evaluate effectiveness of vCUT in accelerating return of postoperative continence and potency.

Trial registration: N/a

Radical Prostatectomy

Incontinence

Erectile Dysfunction

Nerve Sparing

Stem Cells

Cryopreserved Umbilical Tissue

Chorionic Membrane

Patient Reported Outcomes

The use of viable cryopreserved umbilical tissue over neurovascular bundles during nerve-sparing radical prostatectomy was associated with a higher likelihood of achieving social continence.
The rate of social continence by 3 months post-op was 86% in the viable cryopreserved umbilical tissue group versus only 74% in standard nerve-sparing prostatectomy.
The rate of good sexual function at 24 months post-op was 32% in the viable cryopreserved umbilical tissue group versus 33% in standard nerve-sparing prostatectomy.
The use of viable cryopreserved umbilical tissue may promote a quicker return to social urinary continence after nerve-sparing prostatectomy.
Further more extensive studies with longer follow up are required to further evaluate the effectiveness of this technique in accelerating the return of post-op continence and potency.

Prostate cancer (PCa) is the most commonly diagnosed malignancy in men in the United States, according to the Centers for Disease Control and Prevention.¹ While new therapies in the treatment of localized prostate cancer are emerging, robotic-assisted radical prostatectomy (RARP) remains a common first-line treatment modality for localized prostate cancer. Two undesired clinical outcomes in the post-operative management of patients undergoing RARP are erectile dysfunction (ED) and urinary incontinence (UI).

Potency and continence after surgery are dependent on many factors including age, pre-operative erectile function and continence, comorbidities, and surgical technique.^2,3 The use of the robot (da Vinci Surgical System by Intuitive Surgical) has led to enhanced surgical techniques, including nerve sparing (NS) and bladder reconstruction, that have improved functional outcomes postoperatively over the last two decades.⁴ Current techniques to minimize the risk of trauma to the neurovascular bundles (NVB) include athermal dissection, minimal countertraction, and pelvic cooling,^2,3,5, yet functional consequences remain an issue postoperatively. Even when direct injury to the NVB is avoided during surgery, it is suspected that localized post-operative inflammation leads to neuropraxia of the NVB and, consequently, a delayed return to continence and potency.⁶

The use of growth factors and anti-inflammatory substances over neurovascular bundles has emerged as a technique to enhance recovery of functional outcomes. For example, the utility of viable cryopreserved placental membrane (vCPM) was demonstrated in orthopedic surgery among patients with peroneal nerve injury with previously failed surgical repair and found all patients regained motor function with resolution of foot drop after placement of vCPM over the peroneal nerve at the time of surgical re-exploration and nerve decompression.⁷ Specific to the urologic setting, the use of dehydrated human amnion/chorion membrane (dHACM) placement over NVB’s at time of RARP has been studied to improve the recovery of erectile function and social continence. More recently, literature has shown that cryopreservation is a gentler preservation method for human placental membranes than dehydration.⁸ Cryopreserved placental tissue retains viable cells, which has improved repair functionality in vitro and in vivo wound models.⁸

Cryopreserved umbilical tissue (vCUT) composed of umbilical amnion and Wharton’s Jelly. It retains the extracellular matrix, growth factors, and endogenous neonatal mesenchymal stem cells found in placental tissue, which can provide better post-recovery parameters in comparison to standard care and potentially dHACM. vCUT provides an anti-adhesion and anti-inflammatory barrier that may also aid in wound healing. ⁹

vCUT is FDA -approved for use in surgery and is now being used over neurovascular bundles during prostatectomy. There is a paucity of evidence substantiating the role of cryopreserved umbilical tissue in improving functional outcomes after RARP. In this study we sought to determine if vCUT has a role in accelerating return to continence and preserving sexual function in the post-operative setting.

MUSIC

Michigan Urological Surgery Improvement Collaborative (MUSIC) is a quality improvement collaborative composed of multiple urologic practices across the state of Michigan and was established in 2011 with support from Blue Cross Blue Shield of Michigan. The primary goal of MUSIC is to improve the quality of care for patients with prostate cancer, kidney stones, and kidney masses in the state of Michigan. In each participating practice, trained abstractors prospectively enter standardized demographic and clinicopathologic data into an electronic registry for every newly diagnosed prostate cancer patient. Abstractors also enter data related to treatment and follow-up at fixed intervals in a patient’s course, along with validated patient-reported outcomes (PRO). Each participating MUSIC practice obtained an exemption or approval from their local institutional review board for participation in the collaborative. PRO data is collected using either the Prostate Quality of Life Survey developed and validated at Memorial Sloan Kettering Cancer Center, or the 26-item Expanded Prostate Cancer Index Composite Short Form questionnaire (EPIC-26). The EPIC-26 survey assesses urinary and sexual function on a scale from 0 to 100 points with good function for either parameter defined as a score of 74 or higher. For each survey period, an acceptable window for completion was defined as within 30 days for the three-month and six-month surveys and within 60 days for the 12-month and 24-month surveys, and surveys completed outside of the specified window were excluded from the analysis. Each participant was asked to complete a questionnaire to assess the above outcomes at baseline and at 3, 6, 12, and 24 months after surgery. Surveys were distributed via email and completed online through a web-based platform independent of the surgeons. For patients without email access, a paper version was sent via mail with a sealed return envelope to the MUSIC coordinating center.

Study Design

Our study was a retrospective cohort study among patients who underwent NS-RARP performed by three surgeons from 1 MUSIC practice utilizing vCUT over neurovascular bundles at the time of RARP between October 2015 and October 2020. The exposure cohort consisted of patients who received vCUT placement over their neurovascular bundles during NS-RARP; the non-exposed cohort consisted of patients who did not receive vCUT during NS-RARP. We used a standardized patient-reported outcomes survey to evaluate functional outcomes at 3, 6, 12, and 24 months after surgery to compare self-reported outcomes among patients receiving vCUT during surgery versus those that did not.

Data Sources

Patients of the three participating surgeons were identified through the MUSIC database. Via internal electronic medical record chart review, patients were selected and analyzed from a pool of NS-RARPs performed by surgeons also utilizing vCUT. Each participant was asked to complete the EPIC-26 questionnaire to assess their baseline functional status and bother as well as follow-up outcomes at 3, 6, 12, and 24 months after surgery.

Study Population

Full institutional review board (IRB) approval was granted for this study. We retrospectively reviewed data from 340 men diagnosed with localized prostate cancer who underwent NS-RARPs by surgeons utilizing vCUT at a single institution from October 2015 through October 2020. Patients were excluded if they had undergone androgen deprivation, radiation therapy, or brachytherapy before first survey response, reducing the eligible study population to 326 men. Additionally, patients were excluded from contributing to further surveys after undergoing any of these treatments post-operatively. The urinary continence study population required a baseline and 3-month survey responses for inclusion in the social urinary continence population. Baseline urinary continence was reported by 223 respondents, of which 176 also responded at 3 months. Out of the 176 patients included in the final urinary continence cohort, 115 had vCUT placed over NVBs at the time of prostatectomy, and 61 did not.

Similarly, the study population for sexual function required a baseline response with good sexual function, defined as erection quality firm enough for intercourse, and a response to the erection quality question at 12 months. Among the 216 baseline respondents, 125 had good sexual function. Further, 65 also responded at 12 months. Demographics, including age, body mass index (BMI), and history of diabetes, were available for each patient. Out of the 65 patients included in the final sexual function cohort, 51 had vCUT placed at the time of prostatectomy, and 14 did not.

Surgical Technique

Neurovascular bundle dissection was completed bilaterally using an athermal no-touch technique. A 3x6cm piece of vCUT was saturated in 0.9% saline solution. The piece was subsequently cut into 2 even vertical strips. Next, each neurovascular bundle was sprayed with Tisseel fibrin glue (Baxter Deerfield, IL). The vCUT was placed on the medial aspect of each NVB (see Fig. 1 below).

Study Variables

The primary endpoints were social urinary continence (0–1 pads per day) at 3, 6, and 12 months postoperatively and erection quality firm enough for intercourse at 12 and 24 months post-operatively.

Statistical Analyses

Pearson’s Chi-squared test, the Wilcoxon rank sum test, and Fisher’s exact test were used to examine bivariate relationships. Multivariable logistic regression was used to assess the association between the use of vCUT and 3-month social continence adjusting for continuous variables, BMI, age, and baseline urinary incontinence score, and a categorical variable, diabetes (yes or no). Statistical analysis was done with SAS 9.4 and R version 4.3.1. P-values below 0.05 were considered statistically significant.

Patient Characteristics

The urinary continence study population included a total of 176 patients between 3 surgeons (115 of these patients had vCUT utilized and 61 did not). Overall baseline continence and BMI was similar between the groups (Table 1). Both groups had good baseline continence (median score 100 for each) and sexual function (median score 94 for non-VCUT and 88 for VCUT group) per the EPIC-26 inventory. The vCUT group was younger than the non-vCUT group (median age 60 versus 63, p = 0.005) and had a lower prevalence of diabetes 5.2% vs 13% (p = 0.081). Continence data was available for 65% (113/174) of the original patient cohort at the final 12-month interval.

The sexual function study cohort included a total of 65 patients (51 of these patients had vCUT utilized, and 14 did not). Baseline urinary continence score, baseline sexual function score, age, BMI, and history of diabetes showed no statistically significant differences between the groups. Erection quality/sexual function data was available for 50 (77%) of the cohort at the final 24 month interval.

Univariate Analysis

The overall rate of social continence in vCUT group vs the non-VCUT group was 86% vs 74% (p = 0.44), 94% vs 92% (p = 0.7), and 98% vs 100% (p = 0.3) at the 3, 6 and 12 month intervals, respectively (Fig. 2). A descriptive analysis of potency data demonstrated erections firm enough for intercourse following NS-RARP in the vCUT group vs the non-VCUT group at a rate of 28% vs 29% (p = 0.9) and 32% vs 33% (p = 0.9) at the 12- and 24-month intervals respectively (Fig. 3).

Multivariable Analysis

A multivariable analysis was performed on the 3-month continence data. Use of vCUT, baseline urinary function, BMI, age, and history of diabetes were included in the analysis. The use of vCUT did not have a statistically significant difference in odds of return to continence (OR = 2.21, 95% CI: 0.92–5.34, p = 0.073). Increase in BMI was negatively associated with return to continence (OR = 0.84, 95% CI: 0.75–0.94, p = 0.002). Age, baseline urinary function, and history of diabetes did not demonstrate statistically significant associations with return to social continence in the multivariable analysis (see Table 2).

Despite advances in surgical techniques, delays in regaining sexual function and continence continue to be problematic for patients. Neuropraxia due to post-operative inflammation could explain the delayed return to functional status. In response to this need, allograft treatment over NVBs at the time of RARP has been proposed as a technique to reduce local inflammatory cytokines and promote faster wound and nerve healing.

For example, Patel et al. demonstrated that dHACM placement over NVBs at the time of NS-RARP could achieve an earlier return of continence.⁶ At a 2 -month follow-up, patients treated with an allograft in this study had returned to continence at a rate of 81% compared to 74.1% in the control group. This study was underpowered and failed to demonstrate a statistical difference in overall continence rates at 2 months but did show earlier return to continence by an average of about 2 weeks among those treated with allograft in a separate analysis. Subsequently, Ogaya-Pinies et al demonstrated that dHACM placement over NVB at NS-RARP achieved earlier return to potency at all follow-up periods (1, 3, 6, and 9 months) except at 12 months.¹¹ This data demonstrates a quicker return of potency in the early postoperative period with placental allograft, but the analysis did not include continence data. Given the limitations of the above data and newer studies demonstrating improved placental membrane preservation with cryopreservation as opposed to dehydration⁸, we sought to study the functional outcomes with viable placental tissues (vCUT) and dehydrated membrane (dHACM).

Our continence rate in the non-vCUT group (74%) appears to align with the literature demonstrating three-month social continence between 70–80%^6,12. At the three-month follow-up, our cohort demonstrated a 12 percentage point higher rate of social continence in the vCUT group (p = 0.044). At the 6 and 12-month follow-ups, there was no statistically significant difference in rates of social continence between the vCUT and non-VCUT groups (93.6% vs 91.7%, p = 0.7 and 97.5% vs 100%, p = 0.3, respectively). Our data supports the current literature demonstrating an earlier return to social continence in groups where a placental allograft is utilized over NVBs. Though the multivariate analysis failed to achieve conventional statistical significance, the use of vCUT appeared to be associated with an increased likelihood of achieving social continence at three months, with a large effect size of a 2.21 OR. Of note, lower BMI was associated with social continence at the three-month follow-up, while age, history of diabetes, and baseline urinary continence were not significantly related to subsequent rates of continence. Given the cohort predominantly consisted of patients with good baseline continence (median EPIC 26 urinary incontinence score = 100), the role of baseline continence in the multivariable analysis was not demonstrable. We suspect this relationship would be more apparent in a cohort with more diverse pre-operative urinary function.

Our potency data was limited by a small sample size, with sexual health inventory only answered by 65 patients at 12 months, 50 of which also answered at 24 months. We were able to perform a descriptive analysis of the potency data, and this demonstrated no statistically or clinically significant difference in preserving erectile function among vCUT patients at both the 12 and 24-month intervals. These results support the previous literature, which failed to demonstrate an absolute improvement in potency instead of simply an earlier return to potency.

Our data was not without limitations. To provide an adequate control group for our retrospective data, our analysis was conducted on RARPs performed at a single institution and only included three surgeons. As a byproduct, we were limited by a small overall sample size. We suspect our data was underpowered to demonstrate a statistically significant association between the use of vCUT and social continence on multivariable analysis despite a large effect size for improved continence in the vCUT group. Our data was similarly underpowered in being able to conduct a multivariable analysis for potency. If we extrapolate from studies using dHACM and our preliminary results, it would be judicious to achieve a larger enrollment of patients to adequately assess the association between vCUT use and erectile function. Our data must be interpreted cautiously as we did not use age-matched cohorts for our analysis, given the limited sample size. In addition, the use of vCUT was not randomized and was up to the surgeon's discretion. This non-randomized use of vCUT could introduce bias regarding baseline patient characteristics. There was also no standardization for the situational use of vCUT among the three surgeons, and the individual demographics of each surgeon's cohort could impact the functional outcomes reported. Finally, we were unable to directly compare various formulations of allograft (i.e., viable versus dehydrated placental membrane) in vivo use during NS-RARP. Thus the subset of available literature exists in isolation and makes it difficult to extrapolate the current data to other types of allografts. Despite these limitations, this study contributes to the current literature by providing insight into the use of viable membranes as opposed to dehydrated variants and evaluating both continence and potency in a single study at a single institution.

Our data supports the notion that the use of vCUT during NS-RARP was associated with higher social continence at three months compared to those without vCUT. However, no significant difference was appreciated in regard to erectile function. This study adds to the literature supporting the study of allograft use over NVBs to improve post-operative quality of life for RARP patients. Further large-scale studies with longer follow up are required to further evaluate the effectiveness of vCUT to enhance the return of continence and potency. In addition, a head-to-head comparison of various allograft technologies in the NS-RARP setting will help guide the standard of care in the future.

Funding

Support for MUSIC is provided by Blue Cross Blue Shield of Michigan as part of the BCBSM Value Partnerships program. Although Blue Cross Blue Shield of Michigan and MUSIC work collaboratively, the opinions, beliefs, and viewpoints expressed by the authors do not necessarily reflect the opinions, beliefs, and viewpoints of BCBSM or any of its employees.

Other Assistance

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Prior Presentation

AUA North Central Section Meeting – Poster Presentation – Chicago, IL – October 2021

AUA National Meeting – Podium Presentation – New Orleans, LA – May 2022

Disclosures

None

Conflicts of Interest

The authors have no conflicts of interest to disclose.

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Table 1. Urinary continence cohort patient characteristics between the vCUT and non-vCUT groups
	*With* vCUT (N=115)	*Without* vCUT (N=61)	p
Baseline Urinary Continence (out of 100)	100 (92-100)	100 (84-100)	0.11
Age (years)	60 (56-65)	63 (59-69)	0.007
BMI (kg/m²)	28 (26-31)	28 (26-31)	0.6
History of Diabetes	6 (5.2%)	8 (13%)	0.081
Answered Urinary Continence Question at 6mo	94 (82%)	48 (79%)	0.6
Answered Urinary Continence Question at 12mo	79 (69%)	34 (56%)	0.088

Legend: Comparison of baseline patient characteristics between the vCUT versus standard nerve-sparing patients with vCUT. Median values for baseline continence, age, and BMI are outlined above, with IQR provided in parentheses. Diabetic history and responses to urinary continence questions at 6 and 12 months are provided as a total number in cohort and percentage of cohort in parenthesis.

Table 2. Sexual Function cohort patient characteristics between the vCUT and non-vCUT groups
	*With* vCUT (N=51)	*Without* vCUT (N=14)	p
Baseline Urinary Continence (out of 100)	100 (86-100)	100 (100-100)	0.2
Age (years)	60 (57-66)	66 (57-70)	0.2
BMI (kg/m²)	28 (26-30)	28 (27-30)	0.9
History of Diabetes	3 (5.9%)	1 (7.1%)	>0.9
Answered Sexual Function Question at 24mo	38 (75%)	12 (86%)	0.5

Legend: Comparison of baseline patient characteristics between the vCUT versus standard nerve-sparing patients with vCUT. Median values for baseline continence, age, and BMI are outlined above, with IQR provided in parentheses. Diabetic history and responses to urinary continence questions at 6 and 12 months are provided as a total number in cohort and percentage of cohort in parenthesis.

Table 3. Multivariable analysis of social continence at 3 months
Modulating Variables	OR	95% Confidence Interval	p
Use of vCUT	2.21	0.92 - 5.34	0.073
Baseline Urinary Continence	1.00	0.97 - 1.03	0.8
Age	0.96	0.89 - 1.03	0.3
BMI	0.84	0.75 - 0.94	0.002
History of Diabetes	1.18	0.31 - 5.87	>0.9

Legend: Multivariable analysis of social continence (use of 0-1 pad per day) at 3 month follow-up interval controlling for other baseline patient characteristics.

No competing interests reported.

Patient Reported Health Related Quality of Life Outcomes After Viable Cryopreserved Umbilical Tissue Placement Directly Over Spared Neurovascular Bundles After Robotic Assisted Radical Prostatectomy

Status:

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Abstract

Figures

KEY SUMMARY POINTS

INTRODUCTION

METHODS