Floseal Reduces the Incidence of Lymphoceles After Lymphadenectomies in Laparoscopic and Robot-Assisted Extraperitoneal Radical Prostatectomy

Abstract

Purpose:

To evaluate the efficacy and cost-effectiveness of FloSeal^® hemostatic matrix in preventing lymphocele development after pelvic lymphadenectomy (PLA).

Materials and Methods:

This was a single-center, matched comparison of lymphadenectomies in laparoscopic and robot-assisted extraperitoneal radical prostatectomy (ERP) performed with and without FloSeal between January 2008 and October 2009. FloSeal was applied topically in the lymphadenectomy zone immediately after node resection. Cost analysis for lymphocele treatment was performed.

Results:

A total of 142 patients underwent PLA with ERP (32 with FloSeal, 110 without FloSeal). The mean number of lymph nodes removed was 6.5±4.5 (range 2–20). Median prostate-specific antigen concentration was 8.5 ng/mL (range 1.5–24 ng/mL). There was one (3.1%) symptomatic lymphocele in the FloSeal group compared with 16 (14.5%) in the non-FloSeal group. The median number of lymph nodes removed was 8 (range 5–20) in the FloSeal group and seven (range 3–25) in the non-FloSeal group. The only lymphocele in the FloSeal group was treated with percutaneous drainage alone. In the non-FloSeal group, six symptomatic lymphoceles were managed conservatively—four with percutaneous puncture and six with fenestration after percutaneous drainage. The mean cost per patient of treating symptomatic lymphoceles was €327 ($455) in the FloSeal group (total costs €10,481 [$14,559]) vs €553 ($769) (total costs €60,870 [$84,551]) in the non-FloSeal group.

Conclusions:

These preliminary data suggest that the use of FloSeal after lymphadenectomy can reduce the number of symptomatic lymphoceles and is cost-effective.

Introduction

P elvic lymphadenectomy (PLA) is still the gold standard for staging the patient's disease, because no imaging study reaches the sensitivity or specificity of PLA for the detection of lymph node metastasis.^1,2 The overall reported complication rate that is attributable to PLA is high, ranging from 4.1% to 17.4%.³ The most frequent postoperative complication is the development of symptomatic lymphoceles, which have been reported in 1.6% to 9.1% of patients.³ Lymphoceles are associated with secondary infection and may cause thromboembolic events because of compression of the pelvic venous blood vessels. In addition, patients with a postoperative lymphocele have a significantly higher chance of reintervention.³ Up to 50% of reinterventions performed in patients with extraperitoneal radical prostatectomy (ERP) are related to lymphocele management. Options include percutaneous drainage, sclerotherapy, and open or laparoscopic peritoneal fenestration.⁴

Intraoperative measures for lymphocele prevention are a primary transperitoneal approach, bipolar coagulation, and precise dissection and clipping of lymphatic vessels. A further measure to prevent lymphoceles is the use of a hemostatic agent. A prospective, randomized study in 60 patients that used TachoSil^® (Nycomed, Zürich, Switzerland) as an adjunct to standard therapy for lymphocele prevention during open ERP showed a reduction in lymphoceles in the TachoSil group (5 vs 19, P=0.001).⁵ But TachoSil is a surgical patch, which makes it difficult to apply in laparocopic surgery.

Another option is FloSeal^® hemostatic matrix (Baxter Healthcare, Deerfield, IL), a paste that facilitates application during laparoscopic procedures. FloSeal consists of two components—a bovine-derived gelatin matrix that is mixed before use with human-derived thrombin. The putative effectiveness in lymphocele prevention may come from the cross-linked gelatin granules that allow conformation to irregular wound geometries, thereby maintaining contiguous contact with the active site of lymphorrhea in the small pelvis. A second effect is swelling of the gelatin granules by up to 20% within 10 minutes after local application, which may offer a local tamponade effect. Moreover, as lymph is a transudate from the plasma and contains a limited amount of fibrinogen, a third effect may be the formation of a fibrin clot with the thrombin solution.

The current study was performed to evaluate the efficacy and cost-effectiveness of FloSeal in preventing lymphocele development after PLA.

Materials and Methods

Study

This was a matched-comparison analysis of patients who were undergoing laparoscopic PLA in laparoscopic ERP and robot-assisted ERP, with and without the use of FloSeal, at our institution between January 2008 and October 2009. All PLAs were standard obturatoric and external iliac procedures. In patients who were undergoing robot-assisted ERP, PLA was also performed by standard laparoscopy. All patients were operated on by one experienced surgeon (HCK). In all patients, the same PLA procedure was performed regardless of disease stage. PLA was always performed before the ERP. Indications and type of operation were only surgeon dependent. FloSeal was applied in 32 consecutive patients without any specific preoperative or intraoperative selection criteria.

Surgical procedure and postoperative management

PLA included the lymphatic tissue along the external iliac vein and tissue overlying the external iliac artery. The lymph-node–containing tissue in the obturator fossa was also removed, preserving the obturator artery and vein. The afferent and efferent lymphatic vessels were ligated using clips. Bipolar electrocoagulation was used for meticulous dissection. In patients who received FloSeal, the hemostatic matrix was applied locally in the lymphadenectomy zone immediately after lymphadenectomy. Preparation was performed according to the instructions and 2.5 cc were applied on the right and left resection areas respectively.

Two 21F silicone drains were placed bilaterally in the prevesical space once surgery was completed, and drains were usually removed after 2 to 3 days when the drainage volume was <50 mL/d. Administration of low-dose unfractionated heparin was started the day before surgery and continued until 14 days after surgery. Administration was by subcutaneous injection into the upper arm. Patients were also routinely prescribed compression stockings. The catheter was usually removed on day 7 or 8 after a cystogram showed no signs of leakage. Ultrasonography of the small pelvis was performed routinely after catheter removal and at 4 weeks follow-up or before if a symptomatic lymphocele was suspected.

Postoperative assessment

The size and location of postoperative lymphoceles were documented. A lymphocele was considered significant when it caused lower abdominal pain and/or local swelling, leg swelling, fever, a thromboembolic event, or obstruction of urination. Diagnostic measures encompassed pelvic CT and color duplex sonography of the deep veins. Primarily, a percutaneous puncture was performed in all cases to ensure the diagnosis by assessing serum creatinine and as first-line treatment. The indication for surgery was a prolonged leak or reformation of the lymphocele after percutaneous puncture.

Cost analysis

Cost analysis for lymphocele treatment was performed using the following values as given by the hospital management: FloSeal (per patient), €218 ($301); drainage, €200 ($276); standard CT scan, €305 ($421); one day of hospitalization, €1000 ($1382); laparoscopic fenestration, €1500 ($2073).

Statistical analysis

Continuous variables are presented as median or as mean plus or minus the standard deviation. For univariate analysis, the Student t test was performed. Categorical variables are compared using chi-square tests. A P<0.05 is considered statistically significant. Data are analyzed using R v.2.8.0 Software.

Results

A total of 142 ERPs with PLA were performed during the observation period; 32 patients received FloSeal and 110 patients did not receive FloSeal (Table 1). The median prostate-specific antigen (PSA) concentration at surgery was 8.5 ng/mL (range 1.5–24 ng/mL). The mean number of lymph nodes removed was 6.5±4.5 (range 2–20). Only one patient had positive lymph nodes at final histologic evaluation but had no lymphocele. Intraoperative complications that were attributable to PLA were not observed.

Table 1.

Patient Characteristics

	FloSeal group	Non-FloSeal group
	(n=32)	(n=110)	P value
Age (years), mean±SD	61.6±6.3	60.5±6.8	0.525
PSA (ng/mL), mean±SD	8.1±8.1	8.7±9.8	0.771
pT stage, n (%)
pT₂	24 (75%)	77 (70%)	0.583
pT_3a/b	8 (25%)	33 (30%)
pT₄	0	0
N+	0	1 (1%)	0.588
R+	7 (22%)	26 (24%)	0.857
Gleason score, n (%)			0.626
5	1 (3%)	6 (6%)
6	17 (53%)	45 (41%)
7	13 (41%)	48 (44%)
8	1 (3%)	10 (9%)
9	0	1 (1%)
No. of nodes removed, mean±SD	6.7±4.1	6.3±3.2	0.741
Symptomatic lymphoceles, n (%)	1 (3.1%)	16 (14.5%)	0.149

SD=standard deviation; PSA=prostate-specific antigen.

The median number of nodes removed in the FloSeal group was eight (range 5–20). One (3.1%) symptomatic lymphocele occurred in this group, which was managed with percutaneous drainage. The lymphocele was symptomatic with pelvic pain.

The median number of nodes removed in the non-FloSeal group was seven (range 3–25). Sixteen (14.5%) symptomatic lymphoceles were recorded, of which 12 were symptomatic with pelvic pain and swelling of the lower extremity; one was associated with thrombosis, one with fever, and one with urinary retention. Six patients were treated conservatively and needed no further intervention. Four patients had to be treated with percutaneous puncture, and six needed drainage and subsequent laparoscopic fenestration.

Treatment costs for the symptomatic lymphoceles are given in Table 2. The cost of using the hemostatic matrix in the FloSeal group was offset by an increased need for CT scans and laparoscopic fenestration, and an increased number of hospitalization days in the non-FloSeal group. The mean costs per patient were €327 ($455) in the FloSeal group (total costs €10,481) ($14,559) vs €553 ($769) (total costs €60,870) ($84,551) in the non-FloSeal group.

Table 2.

Economic Analysis

	No/cost
	FloSeal group	Non-FloSeal group
Cost element	(n=32)	(n=110)
FloSeal	32/€6976 ($9662)	0/€0
CT scan	1/€305 ($421)	16/€4880 ($6731)
Percutaneous puncture	1/€200 ($276)	10/€2000 ($2759)
Hospitalization days	3/€3000 ($4138)	45/€45,000 ($62,084)
Laparoscopic fenestration	0/€0	6/€9000 ($12,415)
Overall costs	€10,481 ($14,559)	€60,880 ($84,551)
Mean cost per patient	€327 ($455)	€553 ($760)

$ conversion rates as of March 2011.

CT=computed tomography.

Discussion

PLA is important for obtaining information regarding lymph node status in patients who undergo surgery for clinically localized prostate cancer. The optimal extent of PLA and presurgical clinical parameters to identify candidates for extended PLA are still under discussion. Extended PLA has a high incidence of complications. In the recent study by Musch and associates,³ the rate of complications that was attributable to PLA was 6.5%. Other studies report overall complication rates ranging from 4.1% to 17.4%, respectively.^4,6

–11 Intraoperative complications that were attributable to PLA, such as vessel or nerve lesions, were rare events in all recent reports.

In the series of Musch and colleagues,³ the most frequent postoperative complication was the development of symptomatic lymphoceles (5.3%). Reported incidence ranges from 1.6% to 9.1%, the differences most likely attributable to the different definitions of lymphocele formation applied in the studies. The most important risk factor for lymphocele formation was the extent of PLA, the risk being higher as the number of removed lymph nodes increased.

Lymphoceles may pose a problem for patients, especially if they become symptomatic. The complications mainly include thromboembolic events from compression of the pelvic vessels, secondary infection, or urinary obstruction. Another important aspect is the higher incidence of reintervention.³

None of these studies, however, focused on the prevention of lymphoceles. Different surgical approaches such as a transperitoneal approach, ligation, or clamping of the lymphatics with small clips have been described.^12,13 Stolzenburg and coworkers¹² described the surgical technique of bilateral peritoneal fenestration as a feasible way the reduce the incidence of symptomatic lymphoceles. Recently, a prospective study tested the ability of TachoSil surgical patch to decrease the morbidity of PLA and reported that the number of symptomatic lymphoceles was decreased in patients in whom TachoSil was applied.⁵

In our institution, FloSeal was used for the same purpose. FloSeal is a two-component hemostatic sealant, consisting of a bovine-derived gelatin matrix and a human-derived thrombin. The gelatin matrix consists of cross-linked gelatin granules and the thrombin component contains lyophilized thrombin. Its main indication is for use as an adjunct for hemostasis in all kinds of bleeding and has been proven to be effective in a wide range of surgical fields including cardiac,^14,15 vascular,^16,17 renal,¹⁸ hepatic,¹⁹ gynecologic,²⁰ and spinal surgery,²¹ pediatric adenoidectomy,²² and endoscopic sinus surgery.^23,24

Why should FloSeal work in patients after PLA? When hydrated by blood and thrombin, the cross-linked gelatin granules allow conformation to irregular wound geometries, thereby maintaining contiguous contact. Furthermore, the granules swell by up to 20% within 10 minutes when exposed to blood, which may offer a tamponade effect. FloSeal may promote the conversion of fibrinogen into fibrin with its thrombin component, thereby reducing lymphorrhea and forming a fibrin clot embedding the gelatin particles, which has been shown after axillary lymph node dissections.^25,26 These properties may have a preventive effect on pelvic lymphocele formation, as demonstrated for TachoSil by Han and associates.²⁵ In laparoscopic surgery, FloSeal is easier to apply because it is a paste, and no subsequent local compression, as with TachoSil, is needed. Another point is that the laparoscopic application to the relatively large wound area may pose some difficulties.²⁷

In 32 of our patients, FloSeal was applied to the obturator fossa immediately after lymphadenectomy, whereas in 110 patients, no FloSeal was used after PLA. The two groups were comparable in terms of pathologic features, number of resected nodes, and method of surgery. The number of nodes removed was not statistically different between the different surgical approaches or between the FloSeal and non-FloSeal groups. The low number of removed lymph nodes reported in this study could be because of the method of submission and examination of the removed nodes. We routinely perform en bloc submission, which leads to a significantly lower lymph node count compared with separate package submission.^28,29

The number of symptomatic lymphoceles was lower in the FloSeal group, although the reduction was not statistically significant (P=0.149), possibly because of the relatively small sample size. Moreover, the only symptomatic lymphocele in this group could be managed with a percutaneous drainage, whereas six patients needed laparoscopic intervention in the non-FloSeal group.

When calculating the overall and individual costs, the use of FloSeal was more cost-effective.

Limitations of this study include the low number of patients in both groups, a relatively high number of symptomatic lymphoceles for limited PLA, and its retrospective and single-center design. Another possible factor influencing the results could be the timing of FloSeal administration. Application was always done before performing the ERP, assuming that because of the high extraperitoneal CO₂ pressure during surgery, local molding to the irregular wound geometries is facilitated and its effectiveness could be increased. In contrast, further manipulation in the lymphadenectomy area in case of bleeding during the course of surgery could negatively influence the effectiveness of FloSeal. Because all our cases were performed in this fashion and because of the retrospective character, this important question cannot be answered. Further multicenter prospective studies are needed to confirm these first results.

Conclusions

The results of this study suggest that the use of FloSeal may be effective in reducing the likelihood of lymphocele formation after PLA performed in conjunction with ERP. In addition, these data suggest that FloSeal is cost effective by reducing the need for diagnostic CT scans, laparoscopic fenestration, and subsequent prolonged hospitalization. These findings warrant further investigation in multicenter prospective studies.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

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