Long-Term Outcomes of Using Hyaluronic Acid-Carboxymethylcellulose Adhesion Barrier Film on the Neurovascular Bundle

Abstract

Introduction/Objective:

We hypothesize that the use of hyaluronic acid-carboxymethylcellulose (HACM) adhesion barrier at the neurovascular bundle may hasten the return of erectile function after robot-assisted laparoscopic prostatectomy.

Materials and Methods:

A retrospective review identified 462 consecutive patients who underwent a nerve-sparing prostatectomy between 2009 and 2012. The first 246 patients were administered the barrier film, while the next 216 patients, the control group, did not receive HACM. Postoperative erectile function and oncologic outcomes were compared. Independent t-test and Kaplan–Meier analysis were conducted, p < 0.05 was considered significant.

Results:

The two groups were well matched, without significant differences in age, weight, operative time, prostate size, preoperative prostate-specific antigen, sexual health inventory for men (SHIM), or AUA symptom scores. The mean SHIM was significantly higher for the experimental group at 6 months (6.39 vs 4.75, p = 0.008), 9 months (7.32 vs 5.44, p = 0.006), 1 year (8.52 vs 6.90, p = 0.049), and 18 months (10.01 vs 7.60, p = 0.018). This effect was not noted beyond 18 months. A subgroup analysis of patients with initial SHIM scores 22 or greater demonstrated a higher rate of return to the preoperative SHIM score for the barrier film group, 23% vs 12% (p = 0.046). There was no significant difference in biochemical recurrence between groups, with a median follow-up duration of 18 months.

Conclusions:

HACM application at the neurovascular bundle during prostatectomy may decrease the time to return of erectile function, with improved SHIM at 6 to 18 months after surgery. This effect is more pronounced in patients with better baseline erectile function. There is no significant effect on biochemical recurrence.

Introduction

Prostate cancer (CaP) is the most common malignancy in men, with an approximate incidence of 27% of new cancer cases this year in the United States.¹ Radical prostatectomy (RP) is the gold standard for the treatment of localized CaP. However, it results in high rates of erectile dysfunction (ED). Current data show that 60% of men report ED 18 months after RP, and only 20% of men report erections strong enough for penetration after 1 year.² Improved surgical techniques such as nerve sparing, minimization of thermal energy along the apical and posterolateral borders of the prostate, intrafascial dissection, and high apical release of periprostatic fascia to minimize nerve traction injury allow for better preservation of erectile function.^3
–5 Furthermore, robot-assisted laparoscopic prostatectomy (RARP) is the most common RP technique used today and allows for better optics and finer motor control than open surgery, although improved erectile function has not been definitively shown.^6,7

However, intraoperative insult to the neurovascular bundle (NVB) is not the only potential mechanism of post-RP ED; inflammation and wound healing after RP may also contribute. Some research has suggested that limiting the effects of these processes may improve return of erectile function (ROEF).^8,9 Hyaluronic acid-carboxymethylcellulose (HACM) is a sterile, bioresorbable, translucent adhesion barrier composed of two anionic polysaccharides, sodium hyaluronate and carboxymethylcellulose. This adhesion barrier has been shown to effectively reduce adhesions postoperatively in abdominopelvic surgeries.¹⁰ It is indicated for use in patients undergoing abdominal or pelvic laparotomy as an adjunct intended to reduce the incidence, extent, and severity of postoperative adhesions between the abdominal wall and underlying viscera. HACM effectively sequesters inflammatory tissues and organs while normal healing takes place. The barrier starts to break down in 7 days and then is fully resorbed within 28 days, with a well-tolerated safety profile.¹¹ Initial experience using HACM in RARP has shown encouraging results.¹² In this follow-up study, we examine a larger population than the previous study, include a larger experimental group, and perform a more extensive follow-up to determine the long-term oncologic and functional outcomes in our cohort of patients who underwent RARP with HACM.

Materials and Methods

We performed an institutional review board-approved retrospective review of a prospectively maintained database of patients who underwent RARP from 2009 to 2012. A total of 462 consecutive patients underwent RARP with the bilateral nerve-sparing technique. A single fellowship-trained robotic surgeon, with a history of 390+ total RARP surgical cases, performed all surgeries at a single institution. The study population was stratified by HACM use: the HACM group included the first 246 patients who underwent a nerve-sparing RARP and received HACM delivery to the NVB. The next 216 patients, the control group, received a standard nerve-sparing RARP without HACM. All 462 patients were treated after the surgeon was well beyond his learning curve. The HACM group consisted of case no. 390 to 635, the control group then consisted of case no. 636 to 851.

RP was performed in all patients using a standard nerve-sparing technique, which has been described previously.⁴ After completion of the vesicourethral anastomosis, HACM slurry was delivered through the laparoscopic assistant port and placed in the anatomic area of the left and right NVB. The HACM slurry, delivered through a 35-cm cannulated laparoscopic injector through the assistant trocar, consisted of one standard (13 × 15 cm) sheet of HACM dissolved in 20 mL of sterile saline. Slurry was selected as the method of delivery because it can pass through a standard 5-mm laparoscopic irrigator without difficulty, will adhere well to tissues where it is placed, is viscous enough to remain in contact with the NVB, and can conform to contours better than a standard sheet. The area of delivery was bordered laterally by the levator ani muscles, medially by the bladder, cranially by the superior pubic ramus, and caudally by the urethral stump. Delivery was performed under visual guidance. At the end of the procedure, no surgical drains were used. In the immediate postoperative period, patients were generally discharged postoperative day 1 with a urethral catheter, which was subsequently removed postoperative day 7. All patients were placed on penile rehabilitation program with a phosphodiesterase type 5 inhibitor.

The following preoperative data were prospectively collected and retrospectively analyzed: patient age, estimated blood loss (EBL), preoperative prostate-specific antigen (PSA), Charlson comorbidity index (CCI), American Urological Association Symptom Score (AUASS), sexual health inventory for men (SHIM), and prostate size. Postoperative erectile function, utilizing SHIM scores, oncologic outcomes, and Clavien complications, was also analyzed. Return to erectile function was defined as postoperative SHIM score equivalent to or higher than the preoperative score. All patients underwent routine follow-up with physical examinations at the 3-, 6-, 12-, 36-, and 48-month intervals. The SHIM score and AUASS were also recorded at each visit.

The demographic and clinical characteristics were analyzed using the chi-square test for categorical variables and independent t-test for continuous variables. Fischer's exact test was conducted to compare mean SHIM values between the two groups, and Kaplan–Meier analysis was used to determine biochemical recurrence (BCR)-free survival. p < 0.05 was considered to be statistically significant.

Results

The two groups were generally well matched with respect to demographic and clinical characteristics (Table 1) and did not show any statistically significant differences in terms of age, AUASS, SHIM score, prostate weight, preoperative PSA, or CCI. Perioperative characteristics such as operating time and changes in hemoglobin were also similar between the two groups, although EBL was significantly higher in the HACM group. In addition, the HACM group had a significantly higher proportion of Gleason score (GS) <7 when compared with controls. However, as seen in Table 2, pathologic GS was similar between the groups. The rate of positive margins was significantly lower in the HACM group, 16.7% vs 28.8% (p = 0.0021).

Table 1.

Demographics

Characteristics	Control (n = 212)	HACM (n = 246)	p
Age	59.7	59.2	0.3860
SHIM score	16.91	16.34	0.4516
AUA symptom score	8.27	9.21	0.1485
PSA	6.808	6.071	0.3361
Biopsy Gleason score
2–6	79 (37.4%)	152 (62.0%)	<0.0001
7	104 (49.3%)	70 (28.6%)	<0.0001
8–10	28 (13.3%)	23 (9.4%)	0.1902
Operative time (minutes)	203.00	197.41	0.3317
EBL (mL)	232.13	274.69	0.0156

AUA = American Urological Association; EBL = estimated blood loss; HACM = hyaluronic acid-carboxymethylcellulose; PSA = prostate-specific antigen; SHIM = sexual health inventory for men.

Table 2.

Pathologic Data

Path stage	Control	HACM use	p
pT0, n (%)	2 (0.9%)	1 (0.4%)	0.4867
pT2a-pT2b, n (%)	32 (15.1%)	37 (15.1%)
pT2c, n (%)	121 (57.1%)	153 (62.4%)
pT3, n (%)	56 (26.4%)	54 (22.0%)
pT4, n (%)	1 (0.5%)	0
Positive surgical margin, n (%)	61 (28.8%)	41 (16.7%)	0.0021
Prostate mass (g)	47.85	51.31	0.0420

The total number of complications was 34 in the HACM group and 16 in the control group. A significantly higher rate of minor complications, Clavien grade I/II, was seen in the HACM group (13% vs 6.2%, p = 0.011). The vast majority of minor complications were episodes of urinary retention after catheter removal, requiring replacement of a drainage catheter. In contrast, a significantly lower rate of major complications, Clavien grade III/IV, was seen in the HACM group (0.8% vs 1.3%, p = 0.011) (data not shown).

The HACM group had a smaller average decrease in the SHIM score from baseline at the 6-month follow-up interval, −10.2 vs −12.5 (p = 0.007). The mean SHIM scores were also significantly higher in the experimental group at 6 months (6.39 vs 4.75, p = 0.008), at 9 months (7.32 vs 5.44, p = 0.006), at 1 year (8.52 vs 6.90, p = 0.049), and at 18 months (10.01 vs 7.60, p = 0.018) (Fig. 1). A further subgroup analysis of only patients with preoperative SHIM scores of 22 or greater was conducted (Fig. 2) and demonstrated a higher rate of return to baseline erectile function (EF) in the HACM group, 23% vs 12% (p = 0.046). When considering patients younger than 66 years only, the ROEF rates rose to 30% vs 19%. In addition, relaxing the definition of ROEF to postoperative SHIM ≥17 yielded similar rates (46% vs 44%) between the two groups (p = insignificant). However, a significant difference in this population was seen in the proportion of patients with postoperative SHIM scores ≥22 (23% vs 12.5%, p = 0.0019). No difference in continence rates was seen between the two groups.

FIG. 1.

Postoperative SHIM Score up to 18 months. Hyaluronic acid-carboxymethylcellulose (HACM) adhesion barrier film. HACM = hyaluronic acid-carboxymethylcellulose adhesion barrier film; SHIM = sexual health inventory for men.

FIG. 2.

ROEF in men with preoperative SHIM of 22 to 25. ROEF represents the number of patients with postoperative SHIM score equivalent to or higher than the preoperative score. The y-axis represents the total number of patients. ROEF = return of erectile function.

There was no significant difference in risk of BCR between the two groups (Fig. 3).

FIG. 3.

Kaplan–Meier curves of biochemical recurrence-free survival.

Discussion

Despite a focus on nerve-sparing techniques, improved instrumentation, and postoperative penile rehabilitation programs, early return of EF post-RARP has been limited.^5,13 Recent data show that many men report ED at 18 months postoperatively, and only 20% report return to preoperative EF at 1 year.² Independent predictors of potency have been identified: age, CCI, and preoperative International Index of Erectile Function-Erectile function (IIEF-EF) score.¹⁴ Baseline SHIM score has also been demonstrated as an independent predictor of potency and continence.¹⁵ These preoperative characteristics are generally inflexible, and therefore, the focus of the vast majority of research has been to limit intraoperative injury to the NVB.

Damage to cavernosal nerves results in transient or permanent loss of endothelial nitric oxide synthase and nitric oxide to the penis, resulting in decreased smooth muscle relaxation and inhibition of EF.¹⁷ Transection or thermal injury by electrocautery is widely considered to be the major contributor to nerve-based injury during RARP.³ Yet, even simple exposure of the cavernosal nerves during laparotomy, without any direct manipulation, has been shown to cause decreased intracavernosal pressures.¹⁸ The implication of these findings is that nerve sparing and other surgical techniques may not account for all factors related to functional impairment of cavernous nerves. The neuropraxia seen after RARP may be due to the body's normal wound healing response, resulting from an upregulation of fibrogenic cytokines (TGF-β), smooth muscle and endothelial apoptosis, and production of collagen excess.^19,20

With this pathogenesis in mind, our aim was to limit the potential effects of remodeling and wound response that occurs to the NVB. Recent studies in colorectal, obstetrics/gynecology have demonstrated the safety and efficacy of using the HACM barrier to reduce the incidence of postoperative adhesions in patients undergoing abdominal and pelvic surgery.^11,21,22 This is likely due to the fact that hyaluronic acid (HA) is a natural component of the extracellular matrix and plays an important role in wound healing. It is an endogenous stimulator of interleukin-1 (IL-1) production and affects fibroblast proliferation along with collagenase production.^23,24 HA also regulates leukocyte activity, thus, suppressing the scar formation process that occurs with the infiltration of inflammatory cells. In addition, carboxymethylcellulose is a polysaccharide and has also been shown to act as a physical barrier and reduce nerve adhesion and fibrosis after surgery.²⁵ Recent literature experimenting with HACM solution on peripheral nerve injuries has shown decreased scar formation, fibroblast, inflammatory cell counts, and improved neural organization at nerve repair sites that were treated with the HACM solution.²⁶

Our initial experience with HACM use to the NVB has also shown promising results. In the previous study, the HACM group had increased EF recovery at 6- and 12-month follow-ups and on multivariate analysis, HACM use was found to be an independent predictor for EF recovery at 6 months.¹² In the current study, HACM use had a statistically significant improvement in EF after surgery and displayed earlier recovery of EF after surgery, especially in the subgroup of patients with improved preoperative sexual function. Over the long-term follow-up, HACM use was associated with a quicker return to EF and with a larger proportion of patients who returned to their baseline EF. The perioperative complication rate was in favor of HACM use. While concerns have been voiced about use of HACM leading to anastomotic leaks secondary to reduced wound healing, recent studies have not shown any statistical difference in anastomotic leak rates.²⁷ Our study also did not result in any clinically apparent anastomotic leaks.

Given the small magnitude of differences in the SHIM scores between groups, it is possible that this represents a statistically, but not clinically, significant finding. This concern is compounded by the use of SHIM score as the only measure of erectile function in this retrospective database analysis. Additional metrics and patient-centered quality of life measures would make the case for HCAM use more compelling. Ideally, a prospective multicenter trial would need to be performed to definitively address the question of benefit from HCAM application. However, at this time, we are not currently planning such an undertaking.

With regard to oncologic outcomes, HACM use displayed a similar BCR-free survival rate to the control group over the course of 48 months. While there was a significant difference between margin status postoperatively, this difference did not translate into a variation in the BCR-free survival rate. One reason for this could be that inadequate time has passed to detect a difference in the recurrence rate. A recent study comparing recurrence rates with respect to margin status found a significant increase in the BCR-free survival rate in low- and intermediate-risk groups over the course of 5 years.¹⁶ A reason that the rate of positive margins was different between the two groups could be from routine changes over time in how specimens were evaluated for pathologic staining and grading, which might have affected the initial specimens. Another intraoperative variation included EBL. A potential reason for this difference could be due to an improved efficacy with increasing case number in using the athermal technique to control the vascular pedicles.

In addition to the relatively short follow-up, this study has some limitations, largely related to its retrospective nature that can lead to selection and information bias. In addition, as this was a single-surgeon experience study, a potential for bias due to a surgical learning curve can also exist. However, all RARP surgeries were performed by a surgeon with experience of 500+ cases, and 350+ using the same athermal intrafascial release technique. Given that the robotic learning curve is generally regarded as 200 to 300 cases, the impact of this potential bias is likely minimal.²⁸ Another potential for bias, selection bias, is limited in this study as the two cohorts were selected sequentially. Furthermore, the control group of patients was selected after the HACM cohort, thus, arguing against the learning curve benefitting the experimental group. While the individual surgical technique may vary, HACM use can be standardized in its dosage, delivery, and target area.

Conclusion

HACM application at the NVB during RARP may decrease the time to return of EF, with improved SHIM scores at 6 to 18 months after surgery. This effect appears to be more pronounced in patients with better baseline erectile function. In addition, HACM application has no significant effect on BCR and survival.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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