Efficacy of a Fibrin Sealant for the Prevention of Lymphocele After Lymphadenectomy
Condition: Lymphocele
MeSH terms: Lymphocele
Study type: Interventional
Phase: Phase 3

Summary: 
      Objective:

      Lymphocele (LC) is a potential complication of lymph node removal. The objective of this
      study was to assess the efficacy of the Tissucol Duo® (Baxter AG Industriestrasse 67 A-1221
      Vienna, Austria) fibrin sealant in decreasing the incidence of LC after pelvic laparoscopic
      lymph node dissection using harmonic shears.

      Material and Methods:

      This prospective double blind randomised study was conducted between February 2012 and June
      2016 in Donostia University Hospital (Spain). Overall, 74 patients diagnosed with
      gynaecological cancer gave written informed consent and were included in the study. After
      bilateral pelvic lymphadenectomy, the fibrin sealant was used following manufacturer's
      instructions in one hemipelvis but not the other. Overall, the product was applied in 41
      (55.4%) left and 33 (44.6%) right hemipelvises. The primary objective of the study was to
      determine the incidence of LC after surgery in symptomatic and asymptomatic patients. Imaging
      (ultrasound, computed tomography and magnetic resonance) was performed to detect LC at 3, 6
      and 12 months after surgery.
    

Detailed description: 
      This prospective double blind randomized study was conducted by the Gynaecological Cancer
      Unit of Donostia University Hospital (San Sebastian, Basque Country, Spain) between February
      2012 and June 2016. The study was approved on 24 August 2012 by the clinical research ethics
      committee of our hospital (study reference number ONC-1111).

      All patients diagnosed with gynaecological (cervical, endometrial or ovarian) cancer due to
      undergo transperitoneal bilateral laparoscopic pelvic lymphadenectomy (LPL) as part of their
      surgical treatment were invited to participate. Our treatment protocol is based on clinical
      guidelines of the European Society Gynaecology and Oncology and the Spanish Society of
      Gynaecology and Obstetrics (SEGO).

      The inclusion criteria were that the patient had endometrial, cervical, or ovarian cancer,
      underwent PL, an expected survival of more than 12 weeks and appropriate bone marrow, kidney
      and liver function, as well as that they agreed to participate and signed the informed
      consent form. Patients were excluded if they had previously received radiotherapy or
      chemotherapy, haematological disorders including coagulation defects, a history of
      thromboembolic disease or lymphatic system disorders (lymphedema or lymphocele), or allergy
      to aprotinin, as well as if they declined to participate or did not sign the informed consent
      form.

      After standard preoperative assessment, patients were randomly assigned to having Tissucol
      Duo® applied to the surgical bed in only the right or only the left hemipelvis after
      bilateral LPL. The patient, doctors who performed the follow-up and initially the surgeon
      were blinded to the randomization sequence and site of application. That is, the surgeon was
      only told to which hemipelvis the sealant was to be applied when he considered that the
      surgical procedure had been completed. Following the manufacturer´s instructions, 5 ml of
      sealant was sprayed evenly across the entire surgical bed in only one hemipelvis (the treated
      hemipelvis). Using this protocol, the investigators sought to minimise intervention bias, in
      that the surgeon did not know where he was going to spray the sealant until the end of the
      LPL procedure. The investigators decided to treat only one hemipelvis in each patient,
      thereby allowing patients to serve as their own controls, in order to compare outcomes with
      and without the sealant in the same body with the same clinical characteristics and reduce
      the influence of other factors beyond the treatment.

      All the patients received antithrombotic and antibiotic prophylaxis according to our usual
      protocols and were operated on by the same surgical team, all procedures being carried out
      using ultrasonic shears (Harmonic®, Ethicon, Cincinnati, OH, USA) In patients with
      endometrial cancer, we also carried out retroperitoneal aortocaval lymphadenectomy as part of
      surgical staging (para-aortic lymph node dissection PALND, as described by Querleu) up to the
      left renal vein, followed by type A radical hysterectomy (Querleu-Morrow 2011/EORT) and
      opening of the retroperitoneal space after the surgical intervention. In patients with
      cervical cancer, after LPL and intraoperative lymph node biopsy, the surgeons completed
      surgery with transperitoneal aortic lymphadenectomy if the biopsy was positive or radical
      hysterectomy (type B1 or C1) if it was negative.

      The limits of the dissection of the LPL were: the psoas muscle laterally, the obliterated
      umbilical artery medially, the crossing of the ureter over the common iliac artery cranially,
      and the crossing of the circumflex iliac vein over the external iliac artery caudally. The
      caudal limit of the aortocaval dissection was the bifurcation of the aorta, with the cranial
      limit being the level of both renal veins, and all lymphatic tissue was removed from the
      paracaval, interaortocaval, paraaortic and presacral regions between the ureters.

      Data were collected on the following variables: age, body weight, height, type of tumour,
      tumour stage (FIGO), surgical procedure, duration of surgery, intra and postoperative
      complications, length of hospital stay, readmission, and number of lymph nodes obtained in
      each area, as well as the presence, location, size and symptoms of LCs and changes over time
      in these parameters.

      Routine follow-up assessments conducted at 3, 6 and 12 months after surgery included imaging,
      ultrasound, computed tomography or magnetic resonance, depending on which was indicated for
      monitoring the patient's cancer. The imaging findings were used to assess the incidence of
      LC, defined as the accumulation of lymphatic fluid, in particular along the iliac vessels,
      the observer for this examination being blind to patient group allocation. These follow-up
      findings were compared to imaging (ultrasound, computed tomography or magnetic resonance)
      results prior to the surgery.

      The sample size was calculated assuming an overall incidence of LC after LPL of 30%, based on
      previous studies. The investigators estimated that a sample of at least 39 hemipelvises for
      each study arm was needed to declare a 34% (Tinelli et al) lower incidence of LC with the
      treatment as significant with an alpha of 0.05 and beta of 0.1.

      All the patient clinical and surgical data were entered into a Microsoft Access 2010
      database. Once cleaned, data were imported into IBM SPSS Statistics for Windows, version 21.0
      (Armonk, NY, USA) for statistical analysis. Data were summarised using the mean and standard
      deviation for quantitative variables and absolute and relative frequencies expressed as
      percentages for qualitative variables.

      The analysis was performed per protocol. To assess the efficacy of the intervention,
      chi-square or Fisher's exact tests were used to compare the rate of LC in the two groups
      (intervention and control), while Student's t test for unpaired samples was used to compare
      parametric variables between groups. Significance was set at a value of p <0.05.
    

Intervention name(s): Fibrin sealant hemipelvis; Control hemipelvis
Intervention type(s): Biological; Biological
Intervention description(s): Following the manufacturer´s instructions, 5 ml of sealant was sprayed evenly across the entire surgical bed in only one hemipelvis (the treated hemipelvis) after pelvis bilateral lymphadenectomy.; Contralateral hemipelvis not treated with fibrin sealant
Intervention MeSH terms: Fibrin Tissue Adhesive
Allocation: Randomized
Intervention model: Single Group Assignment
Intervention model description: After standard preoperative assessment, patients were randomly assigned to having Tissucol Duo® applied to the surgical bed in only the right or only the left hemipelvis after bilateral pelvic lymphadenectomy. Following the manufacturer´s instructions, 5 ml of sealant was sprayed evenly across the entire surgical bed in only one hemipelvis (the treated hemipelvis). We decided to treat only one hemipelvis in each patient, thereby allowing patients to serve as their own controls, in order to compare outcomes with and without the sealant in the same body with the same clinical characteristics and reduce the influence of other factors beyond the treatment.
Masking: Single (Outcomes Assessor)
Primary purpose: Prevention
Keywords: Fibrin Tissue Adhesive; Lymph node dissection