Original Article
Prevention of Lymphoceles Using FloSeal and CoSeal After Laparoscopic Lymphadenectomy in Patients With Gynecologic Malignancies Christhardt K€ ohler, MD, Sarah Kyeyamwa, MD, Simone Marnitz, MD, Audrey Tsunoda, MD, Filiberto Vercelino, MD, Achim Schneider, MD, MPH, and Giovanni Favero, MD* From the Department of Operative and Oncologic Gynecology, Asklepios Clinic, Hamburg, Germany (Drs. K€ohler and Favero), Department of Gynecology, Charite Universitt of Gynec, Berlin, Germany (Drs. Kyeyamwa and Vercelino), Department of Radiooncology, Charite Universitt of Radio, Berlin, Germany (Dr. Marnitz), Department of Gynecologic Oncology, Cancer Centre Barretos, Barretos, Brazil (Dr. Tsunoda), and Institute for Cytologie and Dyplasia, F€ uytologie and Dyp, Berlin, Germany (Dr. Schneider).
ABSTRACT Introduction: Pelvic 6 para-aortic lymphadenectomy (LAE) is an essential element of staging and treatment of different gynecologic malignancies. However, LAE can induce asymptomatic and symptomatic pelvic lymphoceles (LCs) in a considerable percentage of patients. Therapy of symptomatic LCs may cause additional morbidity. The best strategy to reduce the rate of LCs has not established yet. Materials and Methods: Between January 2011 and May 2012, transperitoneal laparoscopic pelvic 6 para-aortic LAE was performed at the Department of Gynecology at Charite University Hospital Berlin in 238 patients with cervical, endometrial, ovarian, or groin-positive vulvar cancer. The application of FloSeal (Baxter, Deerfield, IL) and CoSeal (Baxter) was used in 25 patients (group A) as an alternative to routine pelvic drainage after LAE. A case-control comparison was performed on 25 patients (group B) with bilateral drainage after complete LAE. The primary objective of this pilot study was to evaluate the feasibility and safety of the method. As a secondary objective, we evaluated the incidence of LCs and symptomatic LCs in both groups. The detection of LCs was performed during oncologic follow-up by sonography, computed tomographic imaging, or magnetic resonance imaging. Measurements and Main Results: Pelvic (n 5 50) or pelvic 1 para-aortic (n 5 42) LAE was performed in 44 patients with cervical, 2 with endometrial, 1 with ovarian, and 2 with groin-positive vulvar cancer, respectively. In group B (n 5 25), systematic bilateral pelvic drainage was placed after finishing LAE, whereas in group A (n 5 25) LAE areas were sealed with 5 mL FloSeal on each side and sprayed with CoSeal afterward without placing drains. In 14 of 50 patients (28%), LCs were detected. In a subgroup of patients with cervical cancer (88% of the cohort), symptomatic LCs occurred in 11% in group A and 18% in group B. Operative revision of symptomatic LCs was necessary in 5% and 18% in groups A and B, respectively (p 5 .66). Mean Hospital stay was significant shorter in group A (6 days) versus B (8 days) (p 5 .027). Conclusion: The results of this case-controlled pilot study indicate that the application of FloSeal and CoSeal after transperitoneal LAE is feasible and safe, may reduce hospital stay, and may potentially decrease the rate of symptomatic LCs in patients with gynecologic malignancies. Journal of Minimally Invasive Gynecology (2015) 22, 451–455 Ó 2015 AAGL. All rights reserved. Keywords:
DISCUSS
Gynecologic malignancies; Laparoscopic lymphadenectomy; Prevention of lymphoceles
You can discuss this article with its authors and with other AAGL members at http://www.AAGL.org/jmig-22-3-JMIG-D-14-00522
Use your Smartphone to scan this QR code and connect to the discussion forum for this article now* * Download a free QR Code scanner by searching for ‘‘QR scanner’’ in your smartphone’s app store or app marketplace.
The authors declare no conflict of interest. Corresponding author: Giovanni Favero, MD, PhD, Department of Operative and Oncologic Gynecology, Asklepios Clinic Hamburg, Eißendorfer Pferdeweg 52, 21075 Hamburg, Germany. 1553-4650/$ - see front matter Ó 2015 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2014.12.007
E-mail: [email protected] Submitted October 18, 2014. Accepted for publication December 4, 2014. Available at www.sciencedirect.com and www.jmig.org
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Pelvic 6 para-aortic lymphadenectomy (LAE) is currently part of staging and treatment in patients with endometrial, cervical, ovarian, fallopian tube, and groin-positive vulvar cancer. However, the therapeutic benefit of LAE in different entities is discussed controversially. Two randomized trials in patients with endometrial cancer failed to show an oncologic benefit, but there are also arguments for systematic LAE [1–4]. In advanced cervical cancer patients, retrospective studies showed a survival benefit of lymph node dissection and debulking [1,2]. However, because of the small number of patients and methodical problems, the only randomized study in this field was insufficient [3]. Also, in ovarian cancer, the oncologic value is still under discussion [4]. Two randomized studies of the German Gynecologic Oncology Group (Uterus 11 and Ovar OP.3-LION) will provide answers for ovarian and advanced cervical cancer in the future. In inguinal-positive vulvar cancer patients, pelvic LAE can omit pelvic radiation in a substantial percentage of patients, but this approach is also investigational [5]. Systematic LAE may cause intraoperative and postoperative complications [6–8]. Among the postoperative findings, lymphoceles (LCs) are quite frequent with incidence rates between 0% and 60% [9,10]. Potential complications associated with LCs are pelvic infection, impaired micturition, slow resumption of bowel movement, pain and/or heaviness in the pelvis, and lymphedema or leg swelling, but LCs may also cause lifethreatening conditions [11]. Indeed, the presence of an LC and the treatment involved may also delay the initiation of adjuvant therapies [12]. For this reason, different methods of LC prevention are described in the literature. The spectrum comprises technical aspects like leaving the peritoneum open after LAE or leaving the vaginal vault open, the placement of drainages, omentoplastic procedures, the use of biological glues or new energy sources, and postoperative octreotide therapy in urologic cancers [13–24]. However, in most studies, there is a mixture of open and laparoscopic procedures, different tumor entities, placement of drainages, and use of fibrin glue or not. Therefore, the aim of the present study was to evaluate the potential benefits of the application of FloSeal (Baxter, Deerfield, IL) and CoSeal (Baxter) in patients after laparoscopic transperitoneal LAE without closure of the peritoneum. Material and Methods Twenty-five applications of FloSeal and CoSeal were made available by Baxter for the development of a pilot case-control study aiming to investigate the prevention of LCs after laparoscopic lymphadenectomy in patients with gynecologic malignancies. Between January 2011 and May 2012, 238 patients with cervical, endometrial, ovarian, or groin-positive vulvar cancer underwent transperitoneal laparoscopic pelvic 6 para-aortic LAE at the Department of Gynecology at Charite University Hospital, Berlin, Germany. After institutional review board approval, the application
Journal of Minimally Invasive Gynecology, Vol 22, No 3, March/April 2015
of FloSeal and CoSeal was offered to consecutive patients with indication for laparoscopic retroperitoneal lymphadenectomy (group A). Women were extensively counseled before consenting to surgery, and only those patients who agreed to the procedure and signed a written informed consent form were included in the study. FloSeal is a patented combination of gelatin granules and human thrombin. CoSeal is a fully synthetic sealant consisting of 2 polyethylene glycol polymers that rapidly cross-link to human proteins in tissue. The primary objective of this pilot study was to evaluate the feasibility and safety of the method. As a secondary objective, we evaluated the incidence of LCs and symptomatic LCs by confronting the operative outcomes in the study group with the results from a historic cohort of patients, respecting the same oncologic and epidemiologic characteristics in which the sealing substances were not used (group B). Pelvic and para-aortic LAE was performed in a standardized technique that was described previously [10]. After pelvic at was-aortic LAE, sealing of the lymph node dissection area was performed with 5 mL FloSeal on the para-aortic and each pelvic side, and afterward it was sprayed with CoSeal. No drainage was used in any patient. The case-control group was composed of 25 patients (group B) operated on in the same period and fashion. In these patients, bilateral pelvic drainage after complete LAE was placed routinely. The detection of LCs was performed during routine postoperative and cancer follow-up, including clinical symptoms, pelvic examinations, and imaging (sonography, computed tomographic imaging, or magnetic resonance imaging). The surveillance was performed 1 and 4 weeks after surgery and then every 3 months during the first year.
Statistical Analysis Continuous variables are presented as mean and standard deviation. Categoric variables are presented as numbers of cases or percentages. Frequencies were compared using the t test, chi-square test, Fisher exact test, and Mann-Whitney U test. For all statistical tests, p values less than .05 were considered significant.
Results Transperitoneal pelvic (n 5 50) LAE in combination with para-aortic LAE (n 5 44) was performed as part of laparoscopic staging or laparoscopic treatment in 44 (88%), 3 (6%), 2 (4%), and 1 (2%) patient with cervical, endometrial, inguinal-positive vulvar, and early ovarian cancer, respectively. Additional operation steps performed together with LAE are provided in Tables 1 and 2. The median age in both groups was 47 (26–72) years. There was also no significant difference between groups A and B in terms of duration of operation (193 vs 191 minutes, p 5 .528), mean estimated blood loss (122 vs 108 mL, p 5 .432), median number of removed lymph nodes (31 vs 34, p 5 .969), or rate of adjuvant therapy (16 vs 22, p 5 .095). Any casualty related to surgery, intraoperative complication, or conversion to laparotomy occurred in both groups. The overall incidence of LC was 28% in the entire cohort. In patients with cervical cancer (88% of the
K€ ohler et al.
FloSeal and CoSeal for Reduction of Lymphoceles
Table 1 Operations performed FloSeal/ CoSeal VALRH 1 pelvic/para-aortic LAE Trachelectomy 1 pelvic LAE Pelvic/para-aortic LAE LAVH 1 pelvic/para-aortic LAE Vulvectomy 1 groin 1 pelvic LAE Total
Control group
Total
2 2 4 3 2 5 19 19 38 0 1 1 1 1 2 25 25 50 p 5 .669 (Fisher test)
LAE 5 lymphadenectomy; LAVH 5 laparoscopic-assisted vaginal hysterectomy; VALRH 5 vaginal-assisted laparoscopic radical hysterectomy.
entire cohort), we could find trends for a lower rate of LC (32% vs 36%, p 5 .627) and symptomatic LC in group A (11% vs 18%, p 5 .453), but they were not statistically significant. On the other hand, hospital stay was significantly shorter in group A (6 vs 8 days, p 5 .026). Invasive intervention because of symptomatic LCs was necessary in only 1 patient in group A in contrast to 4 patients in group B (5% vs 18%, p 5 .668). Initially, all patients were similarly treated by image-guided (sonography or computed tomographic imaging) aspiration and placement of percutaneous drainage. In all cases, the obtained fluid was sent for laboratory analysis to exclude urinary or intestinal leakage. One woman (group B) presented a refractory symptomatic LC and underwent laparoscopic LC marsupialization. Discussion The incidence of LCs after LAE in patients with gynecologic malignancies is described in the literature up to 60%, among these LCs with symptoms between 4.9% and 23% [12–14,18,20,25,26]. Therefore, our rate of asymptomatic and symptomatic LCs meets this spectrum. Table 2 Federation Internationale de Gynecologie et d’Obstetrique (FIGO) stages of patients in both groups
FIGO
FloSeal/CoSeal group
Control group
Cervical cancer IB1 Cervical cancer IB2 Cervical cancer IIA Cervical cancer IIB Cervical cancer IIIB Endometrial cancer IA G3 Endometrial cancer IB G2/3 Vulvar cancer IIIA/B Ovarian cancer IA Total
9 1 1 8 1 1 2 1 1 25
5 2 3 11 2 0 1 1 0 25
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Although therapy for symptomatic LCs is established by puncture (with or without installation of ethanol, tetracycline, doxycycline, bleomycin, or povidone-iodine) or reoperation with fenestration of LCs with success rates between 90% and 100%, the best method for prevention is not established yet [14,15,27–31]. There are different risk factors for the occurrence of LCs that are controversially discussed in the literature. Achouri et al [12] found a lower risk for LCs in patients with endometrial cancer but a higher risk in younger patients and after the removal of 1 or more positive pelvic lymph nodes. In contrast, in their study, there was no correlation with surgical approach (open vs laparoscopic), body mass index (BMI), and performance of aortocaval LAE. However, symptomatic LCs seem to occur more often after open surgery (15% vs 1.4%) compared with the laparoscopic approach as shown by Ghezzi et al [32]. In this study, the placement of drainages was inconsistent depending on the surgeon’s judgment. The removal of more than 14 lymph nodes was significantly associated with more postoperative complications, including the formation of LCs, in a study by Franchi et al [33] including 133 patients operated on using the abdominal approach for endometrial cancer. Gallotta et al [26] showed a significantly lower incidence of LCs using the Ligaclip, (Ethicon, Sommerville, NJ) in a small randomized trial after laparoscopic LAE in 30 patients (endometrial cancer, n 5 15; cervical cancer, n 5 15). However, there was no correlation to BMI, lymph node number, or tumor entity. In contrast, in Kim et al’s study [34], BMI, lymph node number, and postoperative radiotherapy were associated with a higher frequency for LCs in 264 patients with ovarian, endometrial, or cervical cancer. In our study, the occurrence of LCs was not correlated with BMI, lymph node number, or rate of adjuvant therapy. The patient cohorts in available studies seldom comprise only 1 gynecologic tumor entity but often a mixture of different cancers [12,18–20,22–26,32,34,35]. In our series, predominately (88%) patients with cervical cancer were included, and distribution in both groups is well balanced. The surgical approach was also different in published studies. Few data are available for exclusive laparoscopic LAE, some data for the combination of open and laparoscopic LAE, and (especially in older studies) most frequently the abdominal approach was the only one used [12,13,17–20,22–26,32,34,35]. Our present study encompasses only patients after transperitoneal laparoscopic LAE. Different methods for the prevention of LCs are described. Yamamoto et al [19] reported a lower incidence of LCs when leaving the vaginal vault open at the end of surgery. The precondition for this approach is simultaneous hysterectomy during surgery, which was not performed in the majority of patients in our study. There is strong evidence that the placement of drainages, which is often used for the control of hemostasis, has no benefit for the prevention of LC formation in patients with gynecologic malignancies and is
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associated with a higher risk of development of symptomatic LCs [21]. Benedetti-Panici et al [20] showed in a randomized trial that hospital stay was shorter without drain placement (11 vs 7 days) and the rate of symptomatic LCs was lower (23% vs 7%). These results verify data from Patsner [22] on 120 patients (LC with drain 7%, without 2%). One of the criticisms of the present study is the fact that the patients in the control group systematically received drainage. Indeed, it could be a potential risk factor for LCs and, consequently, a possible bias. However, the magnitude of this effect in the outcomes is uncertain. We particularly do not believe that this fact jeopardizes the quality of the data related to complications. There is also good evidence that leaving the peritoneum open after LAE has a protective effect against LC formation as shown in a randomized study by Suzuki et al [18] in open surgery. Data were confirmed in a retrospective study on 180 patients by Park et al [17] in 2010. The latter authors showed a significantly shorter hospital stay (22 vs 11 days) and a lower LC rate (6% vs 30%) after nonclosure of the peritoneum over the LAE area. However, interpretation has to be done with caution because of the modification of other factors. Patients in the group with peritoneal closure were operated on by the open approach using monopolar cautery, whereas patients in the other group were operated on laparoscopically without peritonization and bipolar cautery. Single-institutional studies report on the reduction of LCs by performing omentoplasty after radical hysterectomy and pelvic LAE using the Ligaclip or ligation of lymph vessels or the use of ultrasonic shears [13,14,23,26,35]. Promising results using fibrin-coated patches or fibrin glue (Tachosil-Takeda. Japan, Tachocomb-Takeda, Japan, Tissomat - Baxter, Deerfield, IL, and Tissocul-Baxter, Deerfield, IL) after axillary lymph node dissection, groin dissection (LC incidence 25% vs 62.5% without Tachosil), or pelvic LAE in urologic cancer patients suggested that the application of fibrin glue can also be a useful tool to reduce LCs in patients with gynecologic malignancies [36–38]. However, there are also studies with negative results in this field. Berger et al [39] could not find a significant difference with respect to axillary drainage time, drainage volume, length of hospital stay, or seroma formation in a randomized trial using Tachocomb after axillary LAE. Another randomized trial after pelvic LAE in 93 patients and the application of fibrin glue in half of the patients did not find a statistically significant lower rate of LCs (6% vs 9%) but did indicate the usefulness of fibrin glue [24]. The potential benefit of fibrin application was cancelled because drainages were always placed and there was routine closure of the peritoneum. In a recently published study by Tinelli et al [25], there was a significantly lower rate of symptomatic LCs (17.2% vs 7.6%) after pelvic LAE in patients with endometrial cancer stages I and II using Tachosil, but the placement of drainages was obligatory in this study. The combination of consequent laparoscopic LAE in patients with gynecologic malignancies and the use of FloSeal/
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CoSeal without drainage, as done in our study, has never been described before. The operative results obtained in the present pilot study show that its use is technically feasible and safe. A potential reduction in operative complications, particularly LCs, may be considered. Despite the absence of statistical significance, in patients with cervical cancer, we found relevant trends for lower rates of complications, such as LCs (32% vs 36%), symptomatic LCs in group A (11% vs 18%), and the need for invasive intervention (5% vs 18%). We suppose that these parameters did not reach statistical significance because of the small number of included patients. Moreover, the length of hospital stay was significantly shorter, suggesting also that the use of these substances may reduce the morbidity associated with the procedure. In fact, only large prospective trials can confirm the apparent better outcomes obtained with FloSeal and CoSeal application. In our opinion, the incorporation of these substances into oncologic endoscopic procedures does not necessarily raise the costs. Probably, the reduction in surgery-related morbidity might compensate the initial investments. To illustrate, the only LC in the study group was treated with percutaneous drainage alone, and, in group B, 3 symptomatic LCs were managed with percutaneous puncture and 1 demanded surgical exploration. Consequently, the mean cost per patient of treating symptomatic LCs was certainly higher in the non-FloSeal/CoSeal group. A shorter hospital stay would also have a positive influence on costs. Although the objective of this article was not to evaluate financial aspects or viability, the method may provide economic advantages and be cost-effective. In conclusion, this is the first study exclusively encompassing patients after laparoscopic transperitoneal LAE without closure of the peritoneum und the use of FloSeal and CoSeal for the prevention of LCs. The outcomes observed in this pilot study show that the application of these substances is feasible and safe and may reduce surgeryrelated morbidity, particularly regarding cervical cancer. These facts should be motivation for larger randomized trials to be performed.
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Prevention of Lymphoceles Using FloSeal and CoSeal After Laparoscopic Lymphadenectomy in Patients With Gynecologic Malignancies Christhardt K€ ohler, MD, Sarah Kyeyamwa, MD, Simone Marnitz, MD, Audrey Tsunoda, MD, Filiberto Vercelino, MD, Achim Schneider, MD, MPH, and Giovanni Favero, MD* From the Department of Operative and Oncologic Gynecology, Asklepios Clinic, Hamburg, Germany (Drs. K€ohler and Favero), Department of Gynecology, Charite Universitt of Gynec, Berlin, Germany (Drs. Kyeyamwa and Vercelino), Department of Radiooncology, Charite Universitt of Radio, Berlin, Germany (Dr. Marnitz), Department of Gynecologic Oncology, Cancer Centre Barretos, Barretos, Brazil (Dr. Tsunoda), and Institute for Cytologie and Dyplasia, F€ uytologie and Dyp, Berlin, Germany (Dr. Schneider).
ABSTRACT Introduction: Pelvic 6 para-aortic lymphadenectomy (LAE) is an essential element of staging and treatment of different gynecologic malignancies. However, LAE can induce asymptomatic and symptomatic pelvic lymphoceles (LCs) in a considerable percentage of patients. Therapy of symptomatic LCs may cause additional morbidity. The best strategy to reduce the rate of LCs has not established yet. Materials and Methods: Between January 2011 and May 2012, transperitoneal laparoscopic pelvic 6 para-aortic LAE was performed at the Department of Gynecology at Charite University Hospital Berlin in 238 patients with cervical, endometrial, ovarian, or groin-positive vulvar cancer. The application of FloSeal (Baxter, Deerfield, IL) and CoSeal (Baxter) was used in 25 patients (group A) as an alternative to routine pelvic drainage after LAE. A case-control comparison was performed on 25 patients (group B) with bilateral drainage after complete LAE. The primary objective of this pilot study was to evaluate the feasibility and safety of the method. As a secondary objective, we evaluated the incidence of LCs and symptomatic LCs in both groups. The detection of LCs was performed during oncologic follow-up by sonography, computed tomographic imaging, or magnetic resonance imaging. Measurements and Main Results: Pelvic (n 5 50) or pelvic 1 para-aortic (n 5 42) LAE was performed in 44 patients with cervical, 2 with endometrial, 1 with ovarian, and 2 with groin-positive vulvar cancer, respectively. In group B (n 5 25), systematic bilateral pelvic drainage was placed after finishing LAE, whereas in group A (n 5 25) LAE areas were sealed with 5 mL FloSeal on each side and sprayed with CoSeal afterward without placing drains. In 14 of 50 patients (28%), LCs were detected. In a subgroup of patients with cervical cancer (88% of the cohort), symptomatic LCs occurred in 11% in group A and 18% in group B. Operative revision of symptomatic LCs was necessary in 5% and 18% in groups A and B, respectively (p 5 .66). Mean Hospital stay was significant shorter in group A (6 days) versus B (8 days) (p 5 .027). Conclusion: The results of this case-controlled pilot study indicate that the application of FloSeal and CoSeal after transperitoneal LAE is feasible and safe, may reduce hospital stay, and may potentially decrease the rate of symptomatic LCs in patients with gynecologic malignancies. Journal of Minimally Invasive Gynecology (2015) 22, 451–455 Ó 2015 AAGL. All rights reserved. Keywords:
DISCUSS
Gynecologic malignancies; Laparoscopic lymphadenectomy; Prevention of lymphoceles
You can discuss this article with its authors and with other AAGL members at http://www.AAGL.org/jmig-22-3-JMIG-D-14-00522
Use your Smartphone to scan this QR code and connect to the discussion forum for this article now* * Download a free QR Code scanner by searching for ‘‘QR scanner’’ in your smartphone’s app store or app marketplace.
The authors declare no conflict of interest. Corresponding author: Giovanni Favero, MD, PhD, Department of Operative and Oncologic Gynecology, Asklepios Clinic Hamburg, Eißendorfer Pferdeweg 52, 21075 Hamburg, Germany. 1553-4650/$ - see front matter Ó 2015 AAGL. All rights reserved. http://dx.doi.org/10.1016/j.jmig.2014.12.007
E-mail: [email protected] Submitted October 18, 2014. Accepted for publication December 4, 2014. Available at www.sciencedirect.com and www.jmig.org
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Pelvic 6 para-aortic lymphadenectomy (LAE) is currently part of staging and treatment in patients with endometrial, cervical, ovarian, fallopian tube, and groin-positive vulvar cancer. However, the therapeutic benefit of LAE in different entities is discussed controversially. Two randomized trials in patients with endometrial cancer failed to show an oncologic benefit, but there are also arguments for systematic LAE [1–4]. In advanced cervical cancer patients, retrospective studies showed a survival benefit of lymph node dissection and debulking [1,2]. However, because of the small number of patients and methodical problems, the only randomized study in this field was insufficient [3]. Also, in ovarian cancer, the oncologic value is still under discussion [4]. Two randomized studies of the German Gynecologic Oncology Group (Uterus 11 and Ovar OP.3-LION) will provide answers for ovarian and advanced cervical cancer in the future. In inguinal-positive vulvar cancer patients, pelvic LAE can omit pelvic radiation in a substantial percentage of patients, but this approach is also investigational [5]. Systematic LAE may cause intraoperative and postoperative complications [6–8]. Among the postoperative findings, lymphoceles (LCs) are quite frequent with incidence rates between 0% and 60% [9,10]. Potential complications associated with LCs are pelvic infection, impaired micturition, slow resumption of bowel movement, pain and/or heaviness in the pelvis, and lymphedema or leg swelling, but LCs may also cause lifethreatening conditions [11]. Indeed, the presence of an LC and the treatment involved may also delay the initiation of adjuvant therapies [12]. For this reason, different methods of LC prevention are described in the literature. The spectrum comprises technical aspects like leaving the peritoneum open after LAE or leaving the vaginal vault open, the placement of drainages, omentoplastic procedures, the use of biological glues or new energy sources, and postoperative octreotide therapy in urologic cancers [13–24]. However, in most studies, there is a mixture of open and laparoscopic procedures, different tumor entities, placement of drainages, and use of fibrin glue or not. Therefore, the aim of the present study was to evaluate the potential benefits of the application of FloSeal (Baxter, Deerfield, IL) and CoSeal (Baxter) in patients after laparoscopic transperitoneal LAE without closure of the peritoneum. Material and Methods Twenty-five applications of FloSeal and CoSeal were made available by Baxter for the development of a pilot case-control study aiming to investigate the prevention of LCs after laparoscopic lymphadenectomy in patients with gynecologic malignancies. Between January 2011 and May 2012, 238 patients with cervical, endometrial, ovarian, or groin-positive vulvar cancer underwent transperitoneal laparoscopic pelvic 6 para-aortic LAE at the Department of Gynecology at Charite University Hospital, Berlin, Germany. After institutional review board approval, the application
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of FloSeal and CoSeal was offered to consecutive patients with indication for laparoscopic retroperitoneal lymphadenectomy (group A). Women were extensively counseled before consenting to surgery, and only those patients who agreed to the procedure and signed a written informed consent form were included in the study. FloSeal is a patented combination of gelatin granules and human thrombin. CoSeal is a fully synthetic sealant consisting of 2 polyethylene glycol polymers that rapidly cross-link to human proteins in tissue. The primary objective of this pilot study was to evaluate the feasibility and safety of the method. As a secondary objective, we evaluated the incidence of LCs and symptomatic LCs by confronting the operative outcomes in the study group with the results from a historic cohort of patients, respecting the same oncologic and epidemiologic characteristics in which the sealing substances were not used (group B). Pelvic and para-aortic LAE was performed in a standardized technique that was described previously [10]. After pelvic at was-aortic LAE, sealing of the lymph node dissection area was performed with 5 mL FloSeal on the para-aortic and each pelvic side, and afterward it was sprayed with CoSeal. No drainage was used in any patient. The case-control group was composed of 25 patients (group B) operated on in the same period and fashion. In these patients, bilateral pelvic drainage after complete LAE was placed routinely. The detection of LCs was performed during routine postoperative and cancer follow-up, including clinical symptoms, pelvic examinations, and imaging (sonography, computed tomographic imaging, or magnetic resonance imaging). The surveillance was performed 1 and 4 weeks after surgery and then every 3 months during the first year.
Statistical Analysis Continuous variables are presented as mean and standard deviation. Categoric variables are presented as numbers of cases or percentages. Frequencies were compared using the t test, chi-square test, Fisher exact test, and Mann-Whitney U test. For all statistical tests, p values less than .05 were considered significant.
Results Transperitoneal pelvic (n 5 50) LAE in combination with para-aortic LAE (n 5 44) was performed as part of laparoscopic staging or laparoscopic treatment in 44 (88%), 3 (6%), 2 (4%), and 1 (2%) patient with cervical, endometrial, inguinal-positive vulvar, and early ovarian cancer, respectively. Additional operation steps performed together with LAE are provided in Tables 1 and 2. The median age in both groups was 47 (26–72) years. There was also no significant difference between groups A and B in terms of duration of operation (193 vs 191 minutes, p 5 .528), mean estimated blood loss (122 vs 108 mL, p 5 .432), median number of removed lymph nodes (31 vs 34, p 5 .969), or rate of adjuvant therapy (16 vs 22, p 5 .095). Any casualty related to surgery, intraoperative complication, or conversion to laparotomy occurred in both groups. The overall incidence of LC was 28% in the entire cohort. In patients with cervical cancer (88% of the
K€ ohler et al.
FloSeal and CoSeal for Reduction of Lymphoceles
Table 1 Operations performed FloSeal/ CoSeal VALRH 1 pelvic/para-aortic LAE Trachelectomy 1 pelvic LAE Pelvic/para-aortic LAE LAVH 1 pelvic/para-aortic LAE Vulvectomy 1 groin 1 pelvic LAE Total
Control group
Total
2 2 4 3 2 5 19 19 38 0 1 1 1 1 2 25 25 50 p 5 .669 (Fisher test)
LAE 5 lymphadenectomy; LAVH 5 laparoscopic-assisted vaginal hysterectomy; VALRH 5 vaginal-assisted laparoscopic radical hysterectomy.
entire cohort), we could find trends for a lower rate of LC (32% vs 36%, p 5 .627) and symptomatic LC in group A (11% vs 18%, p 5 .453), but they were not statistically significant. On the other hand, hospital stay was significantly shorter in group A (6 vs 8 days, p 5 .026). Invasive intervention because of symptomatic LCs was necessary in only 1 patient in group A in contrast to 4 patients in group B (5% vs 18%, p 5 .668). Initially, all patients were similarly treated by image-guided (sonography or computed tomographic imaging) aspiration and placement of percutaneous drainage. In all cases, the obtained fluid was sent for laboratory analysis to exclude urinary or intestinal leakage. One woman (group B) presented a refractory symptomatic LC and underwent laparoscopic LC marsupialization. Discussion The incidence of LCs after LAE in patients with gynecologic malignancies is described in the literature up to 60%, among these LCs with symptoms between 4.9% and 23% [12–14,18,20,25,26]. Therefore, our rate of asymptomatic and symptomatic LCs meets this spectrum. Table 2 Federation Internationale de Gynecologie et d’Obstetrique (FIGO) stages of patients in both groups
FIGO
FloSeal/CoSeal group
Control group
Cervical cancer IB1 Cervical cancer IB2 Cervical cancer IIA Cervical cancer IIB Cervical cancer IIIB Endometrial cancer IA G3 Endometrial cancer IB G2/3 Vulvar cancer IIIA/B Ovarian cancer IA Total
9 1 1 8 1 1 2 1 1 25
5 2 3 11 2 0 1 1 0 25
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Although therapy for symptomatic LCs is established by puncture (with or without installation of ethanol, tetracycline, doxycycline, bleomycin, or povidone-iodine) or reoperation with fenestration of LCs with success rates between 90% and 100%, the best method for prevention is not established yet [14,15,27–31]. There are different risk factors for the occurrence of LCs that are controversially discussed in the literature. Achouri et al [12] found a lower risk for LCs in patients with endometrial cancer but a higher risk in younger patients and after the removal of 1 or more positive pelvic lymph nodes. In contrast, in their study, there was no correlation with surgical approach (open vs laparoscopic), body mass index (BMI), and performance of aortocaval LAE. However, symptomatic LCs seem to occur more often after open surgery (15% vs 1.4%) compared with the laparoscopic approach as shown by Ghezzi et al [32]. In this study, the placement of drainages was inconsistent depending on the surgeon’s judgment. The removal of more than 14 lymph nodes was significantly associated with more postoperative complications, including the formation of LCs, in a study by Franchi et al [33] including 133 patients operated on using the abdominal approach for endometrial cancer. Gallotta et al [26] showed a significantly lower incidence of LCs using the Ligaclip, (Ethicon, Sommerville, NJ) in a small randomized trial after laparoscopic LAE in 30 patients (endometrial cancer, n 5 15; cervical cancer, n 5 15). However, there was no correlation to BMI, lymph node number, or tumor entity. In contrast, in Kim et al’s study [34], BMI, lymph node number, and postoperative radiotherapy were associated with a higher frequency for LCs in 264 patients with ovarian, endometrial, or cervical cancer. In our study, the occurrence of LCs was not correlated with BMI, lymph node number, or rate of adjuvant therapy. The patient cohorts in available studies seldom comprise only 1 gynecologic tumor entity but often a mixture of different cancers [12,18–20,22–26,32,34,35]. In our series, predominately (88%) patients with cervical cancer were included, and distribution in both groups is well balanced. The surgical approach was also different in published studies. Few data are available for exclusive laparoscopic LAE, some data for the combination of open and laparoscopic LAE, and (especially in older studies) most frequently the abdominal approach was the only one used [12,13,17–20,22–26,32,34,35]. Our present study encompasses only patients after transperitoneal laparoscopic LAE. Different methods for the prevention of LCs are described. Yamamoto et al [19] reported a lower incidence of LCs when leaving the vaginal vault open at the end of surgery. The precondition for this approach is simultaneous hysterectomy during surgery, which was not performed in the majority of patients in our study. There is strong evidence that the placement of drainages, which is often used for the control of hemostasis, has no benefit for the prevention of LC formation in patients with gynecologic malignancies and is
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associated with a higher risk of development of symptomatic LCs [21]. Benedetti-Panici et al [20] showed in a randomized trial that hospital stay was shorter without drain placement (11 vs 7 days) and the rate of symptomatic LCs was lower (23% vs 7%). These results verify data from Patsner [22] on 120 patients (LC with drain 7%, without 2%). One of the criticisms of the present study is the fact that the patients in the control group systematically received drainage. Indeed, it could be a potential risk factor for LCs and, consequently, a possible bias. However, the magnitude of this effect in the outcomes is uncertain. We particularly do not believe that this fact jeopardizes the quality of the data related to complications. There is also good evidence that leaving the peritoneum open after LAE has a protective effect against LC formation as shown in a randomized study by Suzuki et al [18] in open surgery. Data were confirmed in a retrospective study on 180 patients by Park et al [17] in 2010. The latter authors showed a significantly shorter hospital stay (22 vs 11 days) and a lower LC rate (6% vs 30%) after nonclosure of the peritoneum over the LAE area. However, interpretation has to be done with caution because of the modification of other factors. Patients in the group with peritoneal closure were operated on by the open approach using monopolar cautery, whereas patients in the other group were operated on laparoscopically without peritonization and bipolar cautery. Single-institutional studies report on the reduction of LCs by performing omentoplasty after radical hysterectomy and pelvic LAE using the Ligaclip or ligation of lymph vessels or the use of ultrasonic shears [13,14,23,26,35]. Promising results using fibrin-coated patches or fibrin glue (Tachosil-Takeda. Japan, Tachocomb-Takeda, Japan, Tissomat - Baxter, Deerfield, IL, and Tissocul-Baxter, Deerfield, IL) after axillary lymph node dissection, groin dissection (LC incidence 25% vs 62.5% without Tachosil), or pelvic LAE in urologic cancer patients suggested that the application of fibrin glue can also be a useful tool to reduce LCs in patients with gynecologic malignancies [36–38]. However, there are also studies with negative results in this field. Berger et al [39] could not find a significant difference with respect to axillary drainage time, drainage volume, length of hospital stay, or seroma formation in a randomized trial using Tachocomb after axillary LAE. Another randomized trial after pelvic LAE in 93 patients and the application of fibrin glue in half of the patients did not find a statistically significant lower rate of LCs (6% vs 9%) but did indicate the usefulness of fibrin glue [24]. The potential benefit of fibrin application was cancelled because drainages were always placed and there was routine closure of the peritoneum. In a recently published study by Tinelli et al [25], there was a significantly lower rate of symptomatic LCs (17.2% vs 7.6%) after pelvic LAE in patients with endometrial cancer stages I and II using Tachosil, but the placement of drainages was obligatory in this study. The combination of consequent laparoscopic LAE in patients with gynecologic malignancies and the use of FloSeal/
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CoSeal without drainage, as done in our study, has never been described before. The operative results obtained in the present pilot study show that its use is technically feasible and safe. A potential reduction in operative complications, particularly LCs, may be considered. Despite the absence of statistical significance, in patients with cervical cancer, we found relevant trends for lower rates of complications, such as LCs (32% vs 36%), symptomatic LCs in group A (11% vs 18%), and the need for invasive intervention (5% vs 18%). We suppose that these parameters did not reach statistical significance because of the small number of included patients. Moreover, the length of hospital stay was significantly shorter, suggesting also that the use of these substances may reduce the morbidity associated with the procedure. In fact, only large prospective trials can confirm the apparent better outcomes obtained with FloSeal and CoSeal application. In our opinion, the incorporation of these substances into oncologic endoscopic procedures does not necessarily raise the costs. Probably, the reduction in surgery-related morbidity might compensate the initial investments. To illustrate, the only LC in the study group was treated with percutaneous drainage alone, and, in group B, 3 symptomatic LCs were managed with percutaneous puncture and 1 demanded surgical exploration. Consequently, the mean cost per patient of treating symptomatic LCs was certainly higher in the non-FloSeal/CoSeal group. A shorter hospital stay would also have a positive influence on costs. Although the objective of this article was not to evaluate financial aspects or viability, the method may provide economic advantages and be cost-effective. In conclusion, this is the first study exclusively encompassing patients after laparoscopic transperitoneal LAE without closure of the peritoneum und the use of FloSeal and CoSeal for the prevention of LCs. The outcomes observed in this pilot study show that the application of these substances is feasible and safe and may reduce surgeryrelated morbidity, particularly regarding cervical cancer. These facts should be motivation for larger randomized trials to be performed.
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