<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03305757</url>
  </required_header>
  <id_info>
    <org_study_id>14-T-21</org_study_id>
    <nct_id>NCT03305757</nct_id>
  </id_info>
  <brief_title>Seroma Reduction After Mastectomy</brief_title>
  <acronym>SAM</acronym>
  <official_title>A Multi-center, Double Blinded Randomized Controlled Trial Evaluating Closure of the Dead Space After Mastectomy Using Sutures or Tissue Glue Versus Conventional Closure. Protocol for the Seroma Reduction After Mastectomy (SAM) Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Zuyderland Medisch Centrum</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Zuyderland Medisch Centrum</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Rationale: Seroma formation and its sequelae form the mainstay of complications in breast&#xD;
      cancer surgery. Seroma has an incidence of 3% to 85%. Complications vary from delayed wound&#xD;
      healing, infection, skin flap necrosis, patient discomfort and repeated visits to the out&#xD;
      patient clinic. The key to reducing seroma formations seems to partly lie in the obliteration&#xD;
      of dead space. The use of electrocautery has been demonstrated to increase seroma formation&#xD;
      following mastectomy, however no other surgical devices (laser scalpel, argon diathermy and&#xD;
      ultrasonic scalpel) or substances have proven to be superior in seroma reduction.&#xD;
&#xD;
      No prospective randomized controlled trials have been able to demonstrate which techniques&#xD;
      are superior in reducing seroma and as a consequence patient discomfort in patients&#xD;
      undergoing mastectomy. In a previous retrospective observational study these investigators&#xD;
      demonstrated that mastectomy flap fixation significantly reduced seroma formation and the&#xD;
      number of seroma aspirations. In a pilot study that was recently performed in one of the&#xD;
      investigators hospitals, ARTISS tissue glue was used for skin flap fixation and showed&#xD;
      promising results. The investigators hypothesize that obliteration of the dead space&#xD;
      following mastectomy will significantly reduce seroma formation, its complications and the&#xD;
      discomfort it causes patients undergoing mastectomy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. INTRODUCTION AND RATIONALE&#xD;
&#xD;
           Seroma formation is a common side effect after surgery for breast cancer, with an&#xD;
           incidence of 3% to 85%. Seroma is a collection of serous fluid that contains blood&#xD;
           plasma and/ or lymph fluid. Some surgeons regard seroma formation as a necessary evil&#xD;
           after breast cancer surgery. Seroma formation and its sequelae form the mainstay of&#xD;
           complications in breast cancer surgery. Complications vary from delayed wound healing,&#xD;
           infection, skin flap necrosis, patient discomfort and repeated visits to the out patient&#xD;
           clinic to deal with seroma and its sequelae.&#xD;
&#xD;
           The key to reducing seroma formations seems to partly lie in the obliteration of dead&#xD;
           space. However, the techniques used to achieve this goal are subjects of much&#xD;
           controversy and debate. In a randomized controlled study it was difficult to elucidate&#xD;
           whether reducing the dead space or ligation of lymphatics or a combination of both were&#xD;
           responsible of reduction of seroma formation.&#xD;
&#xD;
           The use of electrocautery has been demonstrated to increase seroma formation following&#xD;
           mastectomy, however no other surgical devices (laser scalpel, argon diathermy and&#xD;
           ultrasonic scalpel) or substances have proven to be superior in seroma reduction. Seroma&#xD;
           formation after axillary dissection for breast cancer cannot be avoided but hopefully it&#xD;
           can be minimized by mechanical dead space closure. This systematic review highlights the&#xD;
           fact that seroma formation is multifactorial and prevention of seroma is difficult at&#xD;
           present. Certain prospective trials have been performed that demonstrate that flap&#xD;
           anchoring and therefore dead space reduction could be very beneficial. The trial&#xD;
           performed by Laurence et al analysed flap fixation and closed suction drainage. In this&#xD;
           study there was no difference in seroma rates, but patients without drains were&#xD;
           discharged earlier. In the trial performed by Sakkary et al the amount of fluid drained&#xD;
           was significantly less in the flap fixation group however patient discomfort (seroma&#xD;
           aspirations and out patient visits) were not assessed.&#xD;
&#xD;
           A Cochrane review was published in 2013 regarding Fibrin Glue (Tissuecol), Fibrin Glue&#xD;
           did not influence the incidence of postoperative seroma, the mean volume of seroma,&#xD;
           wound infections, complications and the length of hospital stays in people undergoing&#xD;
           breast cancer surgery. Due to significant methodological and clinical diversity among&#xD;
           the included studies this conclusion may be considered weak and biased. Therefore, a&#xD;
           major multicentre and high-quality RCT is required to validate these findings. ARTISS&#xD;
           tissue glue is a two-component fibrin sealant matrix of human fibrinogen and human&#xD;
           thrombin wich has the advantage of setting in 60 seconds. This means that the surgeon&#xD;
           has 60 seconds to correctly position the skin flaps before the tissue sealant sets,&#xD;
&#xD;
           The investigators hypothesize that obliteration of the dead space following mastectomy&#xD;
           will significantly reduce seroma formation. This study aims to reduce seroma formation&#xD;
           after mastectomy, proving that obliteration of dead space following mastectomy is vital&#xD;
           in preventing seroma formation and its sequelae.&#xD;
&#xD;
           The investigators current standard of treatment for patients undergoing mastectomy in&#xD;
           Atrium Medical Centre Heerlen is flap fixation using interrupted Vicryl sutures and&#xD;
           closed suction drainage. In Orbis Medical Centre Sittard current standard of wound&#xD;
           closure in patients undergoing mastectomy is ARTISS Tissue Glue.&#xD;
&#xD;
           A retrospective study (13-N-77) has been conducted in our centre in which flap fixation&#xD;
           seemed to be an effective surgical technique in reducing dead space and therefore seroma&#xD;
           formation in patients undergoing mastectomy for invasive breast cancer. Patients&#xD;
           undergoing flap fixation required fewer seroma aspirations and had fewer seroma related&#xD;
           complications (infection).&#xD;
&#xD;
        2. OBJECTIVES&#xD;
&#xD;
      Primary Objective:&#xD;
&#xD;
      To assess:&#xD;
&#xD;
      1. The number of seroma aspirations&#xD;
&#xD;
      Secondary Objective(s):&#xD;
&#xD;
      To assess:&#xD;
&#xD;
        1. The number of out patient clinic visits&#xD;
&#xD;
        2. Infection rate&#xD;
&#xD;
        3. Shoulder function&#xD;
&#xD;
        4. Cosmesis&#xD;
&#xD;
        5. Quality of life, costs and cost-effectiveness (cost/QALY)&#xD;
&#xD;
      3. STUDY DESIGN&#xD;
&#xD;
      Study design is a double-blind randomized controlled trial. All patients are &gt; 18 years and&#xD;
      will be enrolled after obtaining informed consent in the surgical out patient clinics of&#xD;
      Zuyderland Medical Center (Heerlen and Sittard), Maastricht University Medical Center, St&#xD;
      Jans Gasthuis, Weert and Albert Schweitser Hospital, Dordrecht. All patients have an&#xD;
      indication to undergo mastectomy due to invasive breast cancer or DCIS.&#xD;
&#xD;
      Follow up will be performed until 1 year after surgery. Patients will be evaluated in the out&#xD;
      patient clinic 2 weeks, 6 weeks, 3 months, 6 months and 12 months postoperatively.&#xD;
&#xD;
      Study population:&#xD;
&#xD;
      Female patients &gt; 18 years diagnosed with invasive breast cancer or DCIS with an indication&#xD;
      to perform mastectomy&#xD;
&#xD;
      Intervention:&#xD;
&#xD;
        1. Conventional mastectomy with closed suction drainage&#xD;
&#xD;
        2. Mastectomy with flap fixation using absorbable sutures and closed suction drainage&#xD;
&#xD;
        3. Mastectomy with flap fixation using ARTISS tissue glue and closed suction drainage&#xD;
&#xD;
      Main study parameters/endpoints:&#xD;
&#xD;
      Primary endpoint: Number of seroma aspirations&#xD;
&#xD;
      Nature and extent of the burden and risks associated with participation, benefit and group&#xD;
      relatedness: Patients will be informed about the study before inclusion in the out patient&#xD;
      clinic. Informed consent will be obtained in the out patient clinic a week after patients&#xD;
      were initially informed. Postoperative check ups will de done more frequently.&#xD;
&#xD;
      Standard postoperative check ups:&#xD;
&#xD;
      2 weeks, 3 months, 12 months&#xD;
&#xD;
      Additional study postoperative check ups:&#xD;
&#xD;
      6 weeks, 6 months Therefore patients will be required to undergo two additional check ups.&#xD;
      During out patients' visits, patients will hand in questionnaires regarding shoulder function&#xD;
      and a questionnaire scale regarding cosmesis.&#xD;
&#xD;
      Patients will be clinically examined as they usually would be.&#xD;
&#xD;
      Out-patient follow up identical for all three groups&#xD;
&#xD;
      2 weeks post operatively, DASH + cosmesis questionnaire, clinical assessment seroma 6 weeks&#xD;
      post operatively, DASH + cosmesis questionnaire + EQ-5D, clinical assessment seroma 3 months&#xD;
      post operatively, DASH + cosmesis questionnaire + EQ-5D + cost questionnaire, clinical&#xD;
      assessment seroma 6 months post operatively, DASH + cosmesis questionnaire + EQ-5D + cost&#xD;
      questionnaire, clinical assessment seroma 12 months post operatively, DASH + cosmesis&#xD;
      questionnaire +EQ-5D + cost questionnaire, clinical assessment seroma&#xD;
&#xD;
      EXIT FROM TRIAL 1 YEAR POST OPERATIVELY 4. STUDY POPULATION 4.1 Population (base ) All&#xD;
      patients will be recruited from the surgical breast cancer clinic after evaluation for&#xD;
      invasive breast cancer or DCIS. Patients will be recruited from two breast cancer clinics,&#xD;
      treating 500 patients annually for breast cancer. Patients undergoing mastectomy or modified&#xD;
      radical mastectomy are eligible for inclusion.&#xD;
&#xD;
      4.2 Inclusion criteria Older than 18 years Female sex Indication for mastectomy or modified&#xD;
      radical mastectomy&#xD;
&#xD;
      4.3 Exclusion criteria Patients undergoing breast conserving therapy Patients undergoing&#xD;
      direct breast reconstruction Unable to comprehend implications and extent of study and sign&#xD;
      for informed consent&#xD;
&#xD;
      4.4 Sample size calculation The number of seroma aspirations is not normally distributed.&#xD;
      Therefore, sample size estimations based on normally distributed continuous variables cannot&#xD;
      be used. It is possible to use formulas based on non-parametric analysis methods, estimating&#xD;
      the chance of a random patient in the treatment group having fewer aspirations than a random&#xD;
      patient in the control group. However, since the majority of patients will have the same&#xD;
      number of aspirations (i.e. 0), this method of sample size estimation does not seem to be&#xD;
      applicable to our study.&#xD;
&#xD;
      Sample size estimation based on ordinal regression is in line with the data distribution and&#xD;
      limited possibilities (maximum number of aspirations in the observational retrospective study&#xD;
      was 4) of the outcome variable (Walters SJ. Health Qual Life Outcomes 2004: 2(1); 26). Using&#xD;
      alpha=0.025 (correction for 2 comparisons with 3 study groups), beta=0.10, and a proportional&#xD;
      odds ratio=2.67 (corresponding to an absolute difference of 20% in the need for seroma&#xD;
      punctions), the sample size is estimated at 112 patients per study group.&#xD;
&#xD;
      5. TREATMENT OF SUBJECTS Group 1: conventional treatment and closed suction drainage Group 2:&#xD;
      flap fixation with vicryl sutures and closed suction drainage Group 3: Artiss tissue glue and&#xD;
      closed suction drainage&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2014</start_date>
  <completion_date type="Actual">August 31, 2019</completion_date>
  <primary_completion_date type="Actual">August 31, 2019</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Study design is a double-blind randomized controlled trial. All patients are &gt; 18 years and will be enrolled after obtaining informed consent in the surgical out patient clinics of Zuyderland Medical Center (Heerlen and Sittard), Maastricht University Medical Center, St Jans Gasthuis, Weert and Albert Schweitser Hospital, Dordrecht. All patients have an indication to undergo mastectomy due to invasive breast cancer or DCIS.&#xD;
Follow up will be performed until 1 year after surgery. Patients will be evaluated in the out patient clinic 2 weeks, 6 weeks, 3 months, 6 months and 12 months postoperatively.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
    <masking_description>Randomisation is achieved using a web based randomization programme (RANDI2). Randomization will take place on the day of surgery, after the start of the operation and 30 minutes before wound closure. Blocked randomisation will take place with randomly selected block sizes (6/9/12) with an allocation ratio of 1:1:1. Randomisation will be stratified per site. Both patients and surgeons will be blinded. Patients will be informed preoperatively that their post-operative check ups will NOT be performed by the surgeon that performed the surgery. Randomisation will take place 30 minutes before wound closure in the operating theatre. Post-operatively, patients will not be evaluated by their own surgeon. The OR report will contain the following information (in Dutch) so as to ensure that blinding of the physicians will not be compromised.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of seroma aspirations</measure>
    <time_frame>1 year following surgery</time_frame>
    <description>Number of seroma aspirations performed post mastectomy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of out patient clinic visits</measure>
    <time_frame>1 year following surgery</time_frame>
    <description>Number of out patient clinic visits</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Infection rate</measure>
    <time_frame>1 year following surgery</time_frame>
    <description>Post operative surgical site infections</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Shoulder function</measure>
    <time_frame>1 year following surgery</time_frame>
    <description>Shoulder function as measured by the disability of arm, shoulder and hand (DASH score)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cosmesis</measure>
    <time_frame>1 year following surgery</time_frame>
    <description>Subjective post operative cosmesis after mastectomy by questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact on Quality of life</measure>
    <time_frame>1 year following surgery</time_frame>
    <description>QALY (EQ-5D)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cost effectiveness</measure>
    <time_frame>1 year following surgery</time_frame>
    <description>Cost effectiveness as assessed by a validated cost effectiveness questionnaire</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">339</enrollment>
  <condition>Seroma</condition>
  <condition>Aspiration</condition>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>conventional wound closure</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The skin flaps will not undergo further treatment in this group.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>flap fixation with vicryl sutures</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The skin flaps will be sutured on to the pectoral muscle after having performed the mastectomy.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Artiss tissue glue</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>ARTISS tissue glue will be applied to the skin flaps after mastectomy</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Artiss</intervention_name>
    <description>Application of ARTISS Glue to skin flaps after mastectomy</description>
    <arm_group_label>Artiss tissue glue</arm_group_label>
    <other_name>Artiss glue</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>vicryl sutures</intervention_name>
    <description>Flap fixation with vicryl sutures after mastectomy</description>
    <arm_group_label>flap fixation with vicryl sutures</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Conventional</intervention_name>
    <description>Conventional closure after mastectomy</description>
    <arm_group_label>conventional wound closure</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Older than 18 years&#xD;
&#xD;
          -  Female sex&#xD;
&#xD;
          -  Indication for mastectomy or modified radical mastectomy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients undergoing breast conserving therapy&#xD;
&#xD;
          -  Patients undergoing direct breast reconstruction&#xD;
&#xD;
          -  Unable to comprehend implications and extent of study and sign for informed consent&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Female</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>James van Bastelaar, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Zuyderland Medisch Centrum</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Zuyderland Medisch Centrum</name>
      <address>
        <city>Sittard</city>
        <state>Limburg</state>
        <zip>6162 BG</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <results_reference>
    <citation>van Bastelaar J, Beckers A, Snoeijs M, Beets G, Vissers Y. Flap fixation reduces seroma in patients undergoing mastectomy: a significant implication for clinical practice. World J Surg Oncol. 2016 Mar 8;14:66. doi: 10.1186/s12957-016-0830-8.</citation>
    <PMID>26952040</PMID>
  </results_reference>
  <verification_date>December 2019</verification_date>
  <study_first_submitted>January 23, 2017</study_first_submitted>
  <study_first_submitted_qc>October 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 10, 2017</study_first_posted>
  <last_update_submitted>December 2, 2019</last_update_submitted>
  <last_update_submitted_qc>December 2, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 3, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Zuyderland Medisch Centrum</investigator_affiliation>
    <investigator_full_name>James van Bastelaar</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Seroma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03305757
org study id: 14-T-21
nct id: NCT03305757
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Rationale: Seroma formation and its sequelae form the mainstay of complications in breast
      cancer surgery. Seroma has an incidence of 3% to 85%. Complications vary from delayed wound
      healing, infection, skin flap necrosis, patient discomfort and repeated visits to the out
      patient clinic. The key to reducing seroma formations seems to partly lie in the obliteration
      of dead space. The use of electrocautery has been demonstrated to increase seroma formation
      following mastectomy, however no other surgical devices (laser scalpel, argon diathermy and
      ultrasonic scalpel) or substances have proven to be superior in seroma reduction.

      No prospective randomized controlled trials have been able to demonstrate which techniques
      are superior in reducing seroma and as a consequence patient discomfort in patients
      undergoing mastectomy. In a previous retrospective observational study these investigators
      demonstrated that mastectomy flap fixation significantly reduced seroma formation and the
      number of seroma aspirations. In a pilot study that was recently performed in one of the
      investigators hospitals, ARTISS tissue glue was used for skin flap fixation and showed
      promising results. The investigators hypothesize that obliteration of the dead space
      following mastectomy will significantly reduce seroma formation, its complications and the
      discomfort it causes patients undergoing mastectomy.
1. INTRODUCTION AND RATIONALE

           Seroma formation is a common side effect after surgery for breast cancer, with an
           incidence of 3% to 85%. Seroma is a collection of serous fluid that contains blood
           plasma and/ or lymph fluid. Some surgeons regard seroma formation as a necessary evil
           after breast cancer surgery. Seroma formation and its sequelae form the mainstay of
           complications in breast cancer surgery. Complications vary from delayed wound healing,
           infection, skin flap necrosis, patient discomfort and repeated visits to the out patient
           clinic to deal with seroma and its sequelae.

           The key to reducing seroma formations seems to partly lie in the obliteration of dead
           space. However, the techniques used to achieve this goal are subjects of much
           controversy and debate. In a randomized controlled study it was difficult to elucidate
           whether reducing the dead space or ligation of lymphatics or a combination of both were
           responsible of reduction of seroma formation.

           The use of electrocautery has been demonstrated to increase seroma formation following
           mastectomy, however no other surgical devices (laser scalpel, argon diathermy and
           ultrasonic scalpel) or substances have proven to be superior in seroma reduction. Seroma
           formation after axillary dissection for breast cancer cannot be avoided but hopefully it
           can be minimized by mechanical dead space closure. This systematic review highlights the
           fact that seroma formation is multifactorial and prevention of seroma is difficult at
           present. Certain prospective trials have been performed that demonstrate that flap
           anchoring and therefore dead space reduction could be very beneficial. The trial
           performed by Laurence et al analysed flap fixation and closed suction drainage. In this
           study there was no difference in seroma rates, but patients without drains were
           discharged earlier. In the trial performed by Sakkary et al the amount of fluid drained
           was significantly less in the flap fixation group however patient discomfort (seroma
           aspirations and out patient visits) were not assessed.

           A Cochrane review was published in 2013 regarding Fibrin Glue (Tissuecol), Fibrin Glue
           did not influence the incidence of postoperative seroma, the mean volume of seroma,
           wound infections, complications and the length of hospital stays in people undergoing
           breast cancer surgery. Due to significant methodological and clinical diversity among
           the included studies this conclusion may be considered weak and biased. Therefore, a
           major multicentre and high-quality RCT is required to validate these findings. ARTISS
           tissue glue is a two-component fibrin sealant matrix of human fibrinogen and human
           thrombin wich has the advantage of setting in 60 seconds. This means that the surgeon
           has 60 seconds to correctly position the skin flaps before the tissue sealant sets,

           The investigators hypothesize that obliteration of the dead space following mastectomy
           will significantly reduce seroma formation. This study aims to reduce seroma formation
           after mastectomy, proving that obliteration of dead space following mastectomy is vital
           in preventing seroma formation and its sequelae.

           The investigators current standard of treatment for patients undergoing mastectomy in
           Atrium Medical Centre Heerlen is flap fixation using interrupted Vicryl sutures and
           closed suction drainage. In Orbis Medical Centre Sittard current standard of wound
           closure in patients undergoing mastectomy is ARTISS Tissue Glue.

           A retrospective study (13-N-77) has been conducted in our centre in which flap fixation
           seemed to be an effective surgical technique in reducing dead space and therefore seroma
           formation in patients undergoing mastectomy for invasive breast cancer. Patients
           undergoing flap fixation required fewer seroma aspirations and had fewer seroma related
           complications (infection).

        2. OBJECTIVES

      Primary Objective:

      To assess:

      1. The number of seroma aspirations

      Secondary Objective(s):

      To assess:

        1. The number of out patient clinic visits

        2. Infection rate

        3. Shoulder function

        4. Cosmesis

        5. Quality of life, costs and cost-effectiveness (cost/QALY)

      3. STUDY DESIGN

      Study design is a double-blind randomized controlled trial. All patients are > 18 years and
      will be enrolled after obtaining informed consent in the surgical out patient clinics of
      Zuyderland Medical Center (Heerlen and Sittard), Maastricht University Medical Center, St
      Jans Gasthuis, Weert and Albert Schweitser Hospital, Dordrecht. All patients have an
      indication to undergo mastectomy due to invasive breast cancer or DCIS.

      Follow up will be performed until 1 year after surgery. Patients will be evaluated in the out
      patient clinic 2 weeks, 6 weeks, 3 months, 6 months and 12 months postoperatively.

      Study population:

      Female patients > 18 years diagnosed with invasive breast cancer or DCIS with an indication
      to perform mastectomy

      Intervention:

        1. Conventional mastectomy with closed suction drainage

        2. Mastectomy with flap fixation using absorbable sutures and closed suction drainage

        3. Mastectomy with flap fixation using ARTISS tissue glue and closed suction drainage

      Main study parameters/endpoints:

      Primary endpoint: Number of seroma aspirations

      Nature and extent of the burden and risks associated with participation, benefit and group
      relatedness: Patients will be informed about the study before inclusion in the out patient
      clinic. Informed consent will be obtained in the out patient clinic a week after patients
      were initially informed. Postoperative check ups will de done more frequently.

      Standard postoperative check ups:

      2 weeks, 3 months, 12 months

      Additional study postoperative check ups:

      6 weeks, 6 months Therefore patients will be required to undergo two additional check ups.
      During out patients' visits, patients will hand in questionnaires regarding shoulder function
      and a questionnaire scale regarding cosmesis.

      Patients will be clinically examined as they usually would be.

      Out-patient follow up identical for all three groups

      2 weeks post operatively, DASH + cosmesis questionnaire, clinical assessment seroma 6 weeks
      post operatively, DASH + cosmesis questionnaire + EQ-5D, clinical assessment seroma 3 months
      post operatively, DASH + cosmesis questionnaire + EQ-5D + cost questionnaire, clinical
      assessment seroma 6 months post operatively, DASH + cosmesis questionnaire + EQ-5D + cost
      questionnaire, clinical assessment seroma 12 months post operatively, DASH + cosmesis
      questionnaire +EQ-5D + cost questionnaire, clinical assessment seroma

      EXIT FROM TRIAL 1 YEAR POST OPERATIVELY 4. STUDY POPULATION 4.1 Population (base ) All
      patients will be recruited from the surgical breast cancer clinic after evaluation for
      invasive breast cancer or DCIS. Patients will be recruited from two breast cancer clinics,
      treating 500 patients annually for breast cancer. Patients undergoing mastectomy or modified
      radical mastectomy are eligible for inclusion.

      4.2 Inclusion criteria Older than 18 years Female sex Indication for mastectomy or modified
      radical mastectomy

      4.3 Exclusion criteria Patients undergoing breast conserving therapy Patients undergoing
      direct breast reconstruction Unable to comprehend implications and extent of study and sign
      for informed consent

      4.4 Sample size calculation The number of seroma aspirations is not normally distributed.
      Therefore, sample size estimations based on normally distributed continuous variables cannot
      be used. It is possible to use formulas based on non-parametric analysis methods, estimating
      the chance of a random patient in the treatment group having fewer aspirations than a random
      patient in the control group. However, since the majority of patients will have the same
      number of aspirations (i.e. 0), this method of sample size estimation does not seem to be
      applicable to our study.

      Sample size estimation based on ordinal regression is in line with the data distribution and
      limited possibilities (maximum number of aspirations in the observational retrospective study
      was 4) of the outcome variable (Walters SJ. Health Qual Life Outcomes 2004: 2(1); 26). Using
      alpha=0.025 (correction for 2 comparisons with 3 study groups), beta=0.10, and a proportional
      odds ratio=2.67 (corresponding to an absolute difference of 20% in the need for seroma
      punctions), the sample size is estimated at 112 patients per study group.

      5. TREATMENT OF SUBJECTS Group 1: conventional treatment and closed suction drainage Group 2:
      flap fixation with vicryl sutures and closed suction drainage Group 3: Artiss tissue glue and
      closed suction drainage
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Study design is a double-blind randomized controlled trial. All patients are > 18 years and will be enrolled after obtaining informed consent in the surgical out patient clinics of Zuyderland Medical Center (Heerlen and Sittard), Maastricht University Medical Center, St Jans Gasthuis, Weert and Albert Schweitser Hospital, Dordrecht. All patients have an indication to undergo mastectomy due to invasive breast cancer or DCIS.
Follow up will be performed until 1 year after surgery. Patients will be evaluated in the out patient clinic 2 weeks, 6 weeks, 3 months, 6 months and 12 months postoperatively.
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
masking description: Randomisation is achieved using a web based randomization programme (RANDI2). Randomization will take place on the day of surgery, after the start of the operation and 30 minutes before wound closure. Blocked randomisation will take place with randomly selected block sizes (6/9/12) with an allocation ratio of 1:1:1. Randomisation will be stratified per site. Both patients and surgeons will be blinded. Patients will be informed preoperatively that their post-operative check ups will NOT be performed by the surgeon that performed the surgery. Randomisation will take place 30 minutes before wound closure in the operating theatre. Post-operatively, patients will not be evaluated by their own surgeon. The OR report will contain the following information (in Dutch) so as to ensure that blinding of the physicians will not be compromised.
measure: Number of seroma aspirations
time frame: 1 year following surgery
description: Number of seroma aspirations performed post mastectomy
measure: Number of out patient clinic visits
time frame: 1 year following surgery
description: Number of out patient clinic visits
measure: Infection rate
time frame: 1 year following surgery
description: Post operative surgical site infections
measure: Shoulder function
time frame: 1 year following surgery
description: Shoulder function as measured by the disability of arm, shoulder and hand (DASH score)
measure: Cosmesis
time frame: 1 year following surgery
description: Subjective post operative cosmesis after mastectomy by questionnaire
measure: Impact on Quality of life
time frame: 1 year following surgery
description: QALY (EQ-5D)
measure: Cost effectiveness
time frame: 1 year following surgery
description: Cost effectiveness as assessed by a validated cost effectiveness questionnaire
arm group label: conventional wound closure
arm group type: Active Comparator
description: The skin flaps will not undergo further treatment in this group.
arm group label: flap fixation with vicryl sutures
arm group type: Experimental
description: The skin flaps will be sutured on to the pectoral muscle after having performed the mastectomy.
arm group label: Artiss tissue glue
arm group type: Experimental
description: ARTISS tissue glue will be applied to the skin flaps after mastectomy
intervention type: Drug
intervention name: Artiss
description: Application of ARTISS Glue to skin flaps after mastectomy
arm group label: Artiss tissue glue
other name: Artiss glue
intervention type: Procedure
intervention name: vicryl sutures
description: Flap fixation with vicryl sutures after mastectomy
arm group label: flap fixation with vicryl sutures
intervention type: Procedure
intervention name: Conventional
description: Conventional closure after mastectomy
arm group label: conventional wound closure
criteria: 
gender: Female
gender based: Yes
gender description: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: James van Bastelaar, MD
role: Principal Investigator
affiliation: Zuyderland Medisch Centrum
facility: 
country: Netherlands
citation: van Bastelaar J, Beckers A, Snoeijs M, Beets G, Vissers Y. Flap fixation reduces seroma in patients undergoing mastectomy: a significant implication for clinical practice. World J Surg Oncol. 2016 Mar 8;14:66. doi: 10.1186/s12957-016-0830-8.
PMID: 26952040
responsible party type: Principal Investigator
investigator affiliation: Zuyderland Medisch Centrum
investigator full name: James van Bastelaar
investigator title: MD
mesh term: Seroma
sharing ipd: No