<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/NCT02231086</url>
  </required_header>
  <id_info>
    <org_study_id>NL49960.018.14</org_study_id>
    <secondary_id>2014-002794-11</secondary_id>
    <nct_id>NCT02231086</nct_id>
  </id_info>
  <brief_title>Adjuvant HIPEC in High Risk Colon Cancer</brief_title>
  <acronym>COLOPEC</acronym>
  <official_title>Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Colon Cancer at High Risk of Peritoneal Carcinomatosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>ZonMw: The Netherlands Organisation for Health Research and Development</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Dutch Health Care Insurance Board</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study aims to determine the oncological effectiveness of adjuvant HIPEC, using&#xD;
      intraperitoneal oxaliplatin with concomitant i.v. 5-FU/LV, following a curative resection of&#xD;
      a T4 or intra-abdominally perforated Colon cancer in preventing the development of peritoneal&#xD;
      carcinomatosis in addition to the standard adjuvant systemic treatment.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      The hypothesis is that adjuvant HIPEC preceding routine adjuvant systemic therapy using i.p.&#xD;
      oxaliplatin with concomitant i.v. 5-FU/LV following a curative resection of a T4 or&#xD;
      intra-abdominally perforated colon cancer reduces the development of peritoneal&#xD;
      carcinomatosis in comparison to standard adjuvant systemic treatment alone.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      The peritoneum is the second most common site of recurrence in patients with colon cancer.&#xD;
      Early detection of peritoneal carcinomatosis (PC) by imaging is difficult and adjuvant&#xD;
      systemic treatment does not seem to affect peritoneal dissemination in contrast to&#xD;
      haematogenous dissemination in the liver or lungs. Of all patients eventually presenting with&#xD;
      clinically apparent PC, only a quarter have potentially curable disease. The curative option&#xD;
      is cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC), but the&#xD;
      effectiveness depends highly on the extent of disease and is associated with a considerable&#xD;
      complication rate. These clinical problems underline the need for effective adjuvant&#xD;
      intraperitoneal therapy in high risk colon cancer patients in order to prevent the&#xD;
      development of PC with treatment at a subclinical stage.&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      This will be a multicentre study in which 176 eligible patients will be randomized to&#xD;
      adjuvant HIPEC followed by adjuvant systemic chemotherapy in the experimental arm, or the&#xD;
      standard adjuvant systemic chemotherapy alone in the control arm. Adjuvant HIPEC will be&#xD;
      performed preferably simultaneously or within 10 days after resection of the primary tumour,&#xD;
      either by laparoscopy or open approach, similar to the technique used for resection of the&#xD;
      primary tumour. If adjuvant HIPEC cannot be performed within 10 days (i.e. complicated&#xD;
      postoperative course), the procedure will be delayed until 5 to 8 weeks postoperatively.&#xD;
      Subsequently, patients will receive routine adjuvant chemotherapy (CAPOX) within 3 weeks from&#xD;
      HIPEC. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in&#xD;
      both arms of the study in patients without evidence of disease based on routine follow-up&#xD;
      using CT imaging and CEA. If peritoneal carcinomatosis is found during staging laparoscopy,&#xD;
      CR/ HIPEC will be performed in patients with a maximum of 5 involved regions and without&#xD;
      evidence of systemic disease.&#xD;
&#xD;
      Study population:&#xD;
&#xD;
      Patients who underwent intentionally curative resection for a T4N0-2M0 or intra-abdominally&#xD;
      perforated colon cancer.&#xD;
&#xD;
      Intervention:&#xD;
&#xD;
      Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under&#xD;
      general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal&#xD;
      cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic&#xD;
      dialysis fluid at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before the&#xD;
      beginning of HIPEC, 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be administered&#xD;
      intravenously to potentiate oxaliplatin activity. Oxaliplatin (460 mg/m2) is added to the&#xD;
      perfusate after attaining at least 42 degrees inflow temperature with a total of 30 minutes&#xD;
      perfusion time.&#xD;
&#xD;
      Outcomes:&#xD;
&#xD;
      Primary endpoint is peritoneal recurrence-free survival at 18 months. Secondary endpoints are&#xD;
      number of participants with adverse events as a measure of safety and tolerability, incidence&#xD;
      of PC at end of follow-up with or without concomitant liver/lung metastases, percentage of&#xD;
      false negative CT at 18 months (second look laparoscopy/laparotomy as gold standard),&#xD;
      disease-free survival, overall survival, quality of life and costs.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 2015</start_date>
  <completion_date type="Actual">June 1, 2019</completion_date>
  <primary_completion_date type="Actual">September 2018</primary_completion_date>
  <phase>Phase 3</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>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Peritoneal Recurrence Free Survival at 18 Months</measure>
    <time_frame>18 months</time_frame>
    <description>Peritoneal recurrence-free survival at 18 months determined by CT and CEA. If CEA was normal and CT did not show any signs of peritoneal metastase at 18 months, a diagnostic laparoscopy was performed in those patients who consented to this intervention. Complete peritoneal staging was performed during laparoscopy, and biopsies were taken from suspicious lesions. If no peritoneal lesions were seen or biopsies were negative, this indicated that the patient was free from peritoneal recurrence.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Treatment Related Toxicity of Adjuvant HIPEC</measure>
    <time_frame>30 days after adjuvant HIPEC</time_frame>
    <description>Toxicity directly related to adjuvant HIPEC included 30-day complication rate, re-intervention rate, and re-admission rate.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospital Stay for Simultaneous and Staged HIPEC, Either Open or Laparoscopic</measure>
    <time_frame>10 weeks</time_frame>
    <description>Hospital stay for simultaneous and staged HIPEC, either open or laparoscopic.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>False-negative Rate of CT-scan for Peritoneal Metastases</measure>
    <time_frame>5 years</time_frame>
    <description>The presence or absence of peritoneal metastasis on CT-scan will be compared to the findings during diagnostic laparoscopy, histological biopsy or fine needle aspiration cytology.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patterns of Dissemination (Peritoneal Plus or Minus Distant Metastases)</measure>
    <time_frame>5 years</time_frame>
    <description>Patterns of dissemination (peritoneal plus or minus distant metastases).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease-free Survival</measure>
    <time_frame>5 years</time_frame>
    <description>Disease-free survival.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>5 years</time_frame>
    <description>Overall survival.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life Questionnaire Survey 5- Year Follow-up</measure>
    <time_frame>5 years</time_frame>
    <description>Quality of life questionnaire survey 5- year follow-up.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">204</enrollment>
  <condition>Colorectal Neoplasms</condition>
  <condition>Peritoneal Neoplasms</condition>
  <arm_group>
    <arm_group_label>Standard adjuvant systemic chemotherapy</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Adjuvant HIPEC (open/laparoscopic)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (&lt;10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Adjuvant HIPEC (open/laparoscopic)</intervention_name>
    <description>Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before the beginning of HIPEC, 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be administered intravenously to potentiate oxaliplatin activity. Oxaliplatin (460 mg/m2) is added to the perfusate after attaining at least 42 degrees inflow temperature with a total of 30 minutes perfusion time.</description>
    <arm_group_label>Adjuvant HIPEC (open/laparoscopic)</arm_group_label>
    <other_name>I.V. leucovorin 20 mg/m2 (maximum 40 mg)</other_name>
    <other_name>I.V. 5-fluorouracil 400 mg/m2 (maximum 800 mg)</other_name>
    <other_name>Intraperitoneal oxaliplatin 460 mg/m2 (maximum 920 mg)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Standard adjuvant systemic chemotherapy</intervention_name>
    <description>Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months.</description>
    <arm_group_label>Adjuvant HIPEC (open/laparoscopic)</arm_group_label>
    <arm_group_label>Standard adjuvant systemic chemotherapy</arm_group_label>
    <other_name>adjuvant capecitabine and oxaliplatin (CAPOX)</other_name>
    <other_name>adjuvant 5-FU and oxaliplatin (FOLFOX)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Diagnostic laparoscopy</intervention_name>
    <description>Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.</description>
    <arm_group_label>Adjuvant HIPEC (open/laparoscopic)</arm_group_label>
    <arm_group_label>Standard adjuvant systemic chemotherapy</arm_group_label>
    <other_name>Diagnostic laparoscopic surgery</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  age between 18 and 75 years&#xD;
&#xD;
          -  Intention to start routine adjuvant systemic therapy&#xD;
&#xD;
          -  adequate clinical condition to undergo simultaneous HIPEC or re- laparoscopy or&#xD;
             re-laparotomy with HIPEC within either 10 days or between week 5-8 from --primary&#xD;
             resection&#xD;
&#xD;
          -  written informed consent&#xD;
&#xD;
          -  white blood cell count of at least 3000/mm3, platelet count of at least 100.000/mm3&#xD;
&#xD;
          -  no bleeding diathesis or coagulopathy&#xD;
&#xD;
          -  normal creatinine or creatinine clearance of at least 50 ml/min&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  postoperative complications that interfere with adjuvant HIPEC within 8 weeks (i.e.&#xD;
             persisting intra-abdominal abscess, significant fascial dehiscence, enteric fistula)&#xD;
&#xD;
          -  no intention to start routine adjuvant systemic therapy&#xD;
&#xD;
          -  liver and/or lung metastases&#xD;
&#xD;
          -  pregnant or lactating women&#xD;
&#xD;
          -  unstable or uncompensated respiratory or cardiac disease&#xD;
&#xD;
          -  serious active infections&#xD;
&#xD;
          -  other concurrent chemotherapy&#xD;
&#xD;
          -  hypersensitivity to fluorouracil, folinic acid or another substance of leucovorin or&#xD;
             oxaliplatin&#xD;
&#xD;
          -  stomatitis, ulceration in the mouth or gastrointestinal tract.&#xD;
&#xD;
          -  severe diarrhea&#xD;
&#xD;
          -  severe hepatic and / or renal dysfunction.&#xD;
&#xD;
          -  plasma bilirubin concentrations greater than 85 μmol/l.&#xD;
&#xD;
          -  pernicious anemia or other anaemias due to vitamin B12 deficiency.&#xD;
&#xD;
          -  peripheral sensory neuropathy with functional impairment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Pieter J. Tanis, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Academic Medical Center</name>
      <address>
        <city>Amsterdam</city>
        <zip>1105 AZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Antoni van Leeuwenhoek hospital</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Free University Medical Center</name>
      <address>
        <city>Amsterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Catharina hospital</name>
      <address>
        <city>Eindhoven</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Centre Groningen</name>
      <address>
        <city>Groningen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Antonius hospital</name>
      <address>
        <city>Nieuwegein</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Radboud University Medical Center</name>
      <address>
        <city>Nijmegen</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Erasmus Medical Center</name>
      <address>
        <city>Rotterdam</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Medical Center Utrecht</name>
      <address>
        <city>Utrecht</city>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>August 22, 2014</study_first_submitted>
  <study_first_submitted_qc>August 30, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 4, 2014</study_first_posted>
  <results_first_submitted>July 23, 2021</results_first_submitted>
  <results_first_submitted_qc>August 18, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">September 16, 2021</results_first_posted>
  <last_update_submitted>August 18, 2021</last_update_submitted>
  <last_update_submitted_qc>August 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">September 16, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</investigator_affiliation>
    <investigator_full_name>P.J. Tanis</investigator_full_name>
    <investigator_title>M.D. Ph.D</investigator_title>
  </responsible_party>
  <keyword>Chemotherapy, Adjuvant</keyword>
  <keyword>Laparoscopy</keyword>
  <keyword>Peritoneal Lavage</keyword>
  <keyword>HIPEC</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Colorectal Neoplasms</mesh_term>
    <mesh_term>Peritoneal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 5, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/86/NCT02231086/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Standard Adjuvant Systemic Chemotherapy</title>
          <description>Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months.&#xD;
Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.</description>
        </group>
        <group group_id="P2">
          <title>Adjuvant HIPEC (Open/Laparoscopic)</title>
          <description>Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (&lt;10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="102"/>
                <participants group_id="P2" count="102"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="63"/>
                <participants group_id="P2" count="65"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="39"/>
                <participants group_id="P2" count="37"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Intention-to-treat Baseline population</population>
      <group_list>
        <group group_id="B1">
          <title>Standard Adjuvant Systemic Chemotherapy</title>
          <description>Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months.&#xD;
Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.</description>
        </group>
        <group group_id="B2">
          <title>Adjuvant HIPEC (Open/Laparoscopic)</title>
          <description>Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (&lt;10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis flui</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="102"/>
            <count group_id="B2" value="100"/>
            <count group_id="B3" value="202"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="102"/>
                    <count group_id="B2" value="100"/>
                    <count group_id="B3" value="202"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="67"/>
                    <measurement group_id="B2" value="67"/>
                    <measurement group_id="B3" value="134"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="33"/>
                    <measurement group_id="B3" value="68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="102"/>
                    <count group_id="B2" value="100"/>
                    <count group_id="B3" value="202"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61" lower_limit="54" upper_limit="68"/>
                    <measurement group_id="B2" value="61.5" lower_limit="56" upper_limit="68"/>
                    <measurement group_id="B3" value="61" lower_limit="55" upper_limit="68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="102"/>
                    <count group_id="B2" value="100"/>
                    <count group_id="B3" value="202"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="50"/>
                    <measurement group_id="B2" value="47"/>
                    <measurement group_id="B3" value="97"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="52"/>
                    <measurement group_id="B2" value="53"/>
                    <measurement group_id="B3" value="105"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <description>Intention-to-treat Baseline population</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Netherlands</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="102"/>
                    <count group_id="B2" value="100"/>
                    <count group_id="B3" value="202"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="102"/>
                    <measurement group_id="B2" value="100"/>
                    <measurement group_id="B3" value="202"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Peritoneal Recurrence Free Survival at 18 Months</title>
        <description>Peritoneal recurrence-free survival at 18 months determined by CT and CEA. If CEA was normal and CT did not show any signs of peritoneal metastase at 18 months, a diagnostic laparoscopy was performed in those patients who consented to this intervention. Complete peritoneal staging was performed during laparoscopy, and biopsies were taken from suspicious lesions. If no peritoneal lesions were seen or biopsies were negative, this indicated that the patient was free from peritoneal recurrence.</description>
        <time_frame>18 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Standard Adjuvant Systemic Chemotherapy</title>
            <description>Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months.&#xD;
Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.</description>
          </group>
          <group group_id="O2">
            <title>Adjuvant HIPEC (Open/Laparoscopic)</title>
            <description>Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (&lt;10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid</description>
          </group>
        </group_list>
        <measure>
          <title>Peritoneal Recurrence Free Survival at 18 Months</title>
          <description>Peritoneal recurrence-free survival at 18 months determined by CT and CEA. If CEA was normal and CT did not show any signs of peritoneal metastase at 18 months, a diagnostic laparoscopy was performed in those patients who consented to this intervention. Complete peritoneal staging was performed during laparoscopy, and biopsies were taken from suspicious lesions. If no peritoneal lesions were seen or biopsies were negative, this indicated that the patient was free from peritoneal recurrence.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="102"/>
                <count group_id="O2" value="100"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="79"/>
                    <measurement group_id="O2" value="80"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Treatment Related Toxicity of Adjuvant HIPEC</title>
        <description>Toxicity directly related to adjuvant HIPEC included 30-day complication rate, re-intervention rate, and re-admission rate.</description>
        <time_frame>30 days after adjuvant HIPEC</time_frame>
        <population>Only measured in experimental group</population>
        <group_list>
          <group group_id="O1">
            <title>Standard Adjuvant Systemic Chemotherapy</title>
            <description>Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months.&#xD;
Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.</description>
          </group>
          <group group_id="O2">
            <title>Adjuvant HIPEC (Open/Laparoscopic)</title>
            <description>Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (&lt;10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid</description>
          </group>
        </group_list>
        <measure>
          <title>Treatment Related Toxicity of Adjuvant HIPEC</title>
          <description>Toxicity directly related to adjuvant HIPEC included 30-day complication rate, re-intervention rate, and re-admission rate.</description>
          <population>Only measured in experimental group</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="87"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Hospital Stay for Simultaneous and Staged HIPEC, Either Open or Laparoscopic</title>
        <description>Hospital stay for simultaneous and staged HIPEC, either open or laparoscopic.</description>
        <time_frame>10 weeks</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>False-negative Rate of CT-scan for Peritoneal Metastases</title>
        <description>The presence or absence of peritoneal metastasis on CT-scan will be compared to the findings during diagnostic laparoscopy, histological biopsy or fine needle aspiration cytology.</description>
        <time_frame>5 years</time_frame>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Patterns of Dissemination (Peritoneal Plus or Minus Distant Metastases)</title>
        <description>Patterns of dissemination (peritoneal plus or minus distant metastases).</description>
        <time_frame>5 years</time_frame>
        <posting_date>02/2022</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Disease-free Survival</title>
        <description>Disease-free survival.</description>
        <time_frame>5 years</time_frame>
        <posting_date>02/2022</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Overall survival.</description>
        <time_frame>5 years</time_frame>
        <posting_date>02/2022</posting_date>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Quality of Life Questionnaire Survey 5- Year Follow-up</title>
        <description>Quality of life questionnaire survey 5- year follow-up.</description>
        <time_frame>5 years</time_frame>
        <posting_date>02/2022</posting_date>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>All postoperative complications after resection of the primary tumor and after adjuvant HIPEC, as well as adverse events occuring during adjuvant chemotherapy were collected, until 30 days after last trial related intervention, for an average of 2 years.</time_frame>
      <desc>We used standard definitions for AE and SAE</desc>
      <group_list>
        <group group_id="E1">
          <title>Standard Adjuvant Systemic Chemotherapy</title>
          <description>Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Standard adjuvant systemic chemotherapy: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months.&#xD;
Diagnostic laparoscopy: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.</description>
        </group>
        <group group_id="E2">
          <title>Adjuvant HIPEC (Open/Laparoscopic)</title>
          <description>Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (&lt;10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.&#xD;
Adjuvant HIPEC (open/laparoscopic): Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis flui</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="46" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="95" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>venous thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>cardiac</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Obstructive ileus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>Paralytic ileus</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>Gastroparesis</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="15" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>cardiopulmonary resuscitation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>abscess</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>line sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>chemical peritonitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>encapsulating peritoneal sclerosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Electrolyte disorder</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>parenteral feeding</sub_title>
                <counts group_id="E1" subjects_affected="9" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="22" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Neoplasms benign, malignant and unspecified (incl cysts and polyps)</title>
            <event_list>
              <event>
                <sub_title>nodal metastasis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>delirium</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>dehydration</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>urologic</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="8" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>ovarian cyst</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>pneumonia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>pulmonary embolism</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Anastomotic leakage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>wound infection</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="7" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>colonic stenosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>gastric perforation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="102" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="100" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="73" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="68" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>vomiting</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="27" subjects_at_risk="100"/>
              </event>
              <event>
                <sub_title>mucositis</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>fatigue</sub_title>
                <counts group_id="E1" subjects_affected="58" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="58" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>anorexia</sub_title>
                <counts group_id="E1" subjects_affected="20" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="13" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>peripheral sensible neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="73" subjects_at_risk="102"/>
                <counts group_id="E2" subjects_affected="68" subjects_at_risk="100"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Prof. dr. P.J. Tanis</name_or_title>
      <organization>Amsterdam UMC</organization>
      <phone>+31-20-4444444</phone>
      <email>p.j.tanis@amsterdamumc.nl</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02231086
org study id: NL49960.018.14
secondary id: 2014-002794-11
nct id: NCT02231086
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
This study aims to determine the oncological effectiveness of adjuvant HIPEC, using
      intraperitoneal oxaliplatin with concomitant i.v. 5-FU/LV, following a curative resection of
      a T4 or intra-abdominally perforated Colon cancer in preventing the development of peritoneal
      carcinomatosis in addition to the standard adjuvant systemic treatment.

      Hypothesis:

      The hypothesis is that adjuvant HIPEC preceding routine adjuvant systemic therapy using i.p.
      oxaliplatin with concomitant i.v. 5-FU/LV following a curative resection of a T4 or
      intra-abdominally perforated colon cancer reduces the development of peritoneal
      carcinomatosis in comparison to standard adjuvant systemic treatment alone.
Background:

      The peritoneum is the second most common site of recurrence in patients with colon cancer.
      Early detection of peritoneal carcinomatosis (PC) by imaging is difficult and adjuvant
      systemic treatment does not seem to affect peritoneal dissemination in contrast to
      haematogenous dissemination in the liver or lungs. Of all patients eventually presenting with
      clinically apparent PC, only a quarter have potentially curable disease. The curative option
      is cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC), but the
      effectiveness depends highly on the extent of disease and is associated with a considerable
      complication rate. These clinical problems underline the need for effective adjuvant
      intraperitoneal therapy in high risk colon cancer patients in order to prevent the
      development of PC with treatment at a subclinical stage.

      Study design:

      This will be a multicentre study in which 176 eligible patients will be randomized to
      adjuvant HIPEC followed by adjuvant systemic chemotherapy in the experimental arm, or the
      standard adjuvant systemic chemotherapy alone in the control arm. Adjuvant HIPEC will be
      performed preferably simultaneously or within 10 days after resection of the primary tumour,
      either by laparoscopy or open approach, similar to the technique used for resection of the
      primary tumour. If adjuvant HIPEC cannot be performed within 10 days (i.e. complicated
      postoperative course), the procedure will be delayed until 5 to 8 weeks postoperatively.
      Subsequently, patients will receive routine adjuvant chemotherapy (CAPOX) within 3 weeks from
      HIPEC. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in
      both arms of the study in patients without evidence of disease based on routine follow-up
      using CT imaging and CEA. If peritoneal carcinomatosis is found during staging laparoscopy,
      CR/ HIPEC will be performed in patients with a maximum of 5 involved regions and without
      evidence of systemic disease.

      Study population:

      Patients who underwent intentionally curative resection for a T4N0-2M0 or intra-abdominally
      perforated colon cancer.

      Intervention:

      Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under
      general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal
      cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic
      dialysis fluid at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before the
      beginning of HIPEC, 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be administered
      intravenously to potentiate oxaliplatin activity. Oxaliplatin (460 mg/m2) is added to the
      perfusate after attaining at least 42 degrees inflow temperature with a total of 30 minutes
      perfusion time.

      Outcomes:

      Primary endpoint is peritoneal recurrence-free survival at 18 months. Secondary endpoints are
      number of participants with adverse events as a measure of safety and tolerability, incidence
      of PC at end of follow-up with or without concomitant liver/lung metastases, percentage of
      false negative CT at 18 months (second look laparoscopy/laparotomy as gold standard),
      disease-free survival, overall survival, quality of life and costs.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Peritoneal Recurrence Free Survival at 18 Months
time frame: 18 months
description: Peritoneal recurrence-free survival at 18 months determined by CT and CEA. If CEA was normal and CT did not show any signs of peritoneal metastase at 18 months, a diagnostic laparoscopy was performed in those patients who consented to this intervention. Complete peritoneal staging was performed during laparoscopy, and biopsies were taken from suspicious lesions. If no peritoneal lesions were seen or biopsies were negative, this indicated that the patient was free from peritoneal recurrence.
measure: Treatment Related Toxicity of Adjuvant HIPEC
time frame: 30 days after adjuvant HIPEC
description: Toxicity directly related to adjuvant HIPEC included 30-day complication rate, re-intervention rate, and re-admission rate.
measure: Hospital Stay for Simultaneous and Staged HIPEC, Either Open or Laparoscopic
time frame: 10 weeks
description: Hospital stay for simultaneous and staged HIPEC, either open or laparoscopic.
measure: False-negative Rate of CT-scan for Peritoneal Metastases
time frame: 5 years
description: The presence or absence of peritoneal metastasis on CT-scan will be compared to the findings during diagnostic laparoscopy, histological biopsy or fine needle aspiration cytology.
measure: Patterns of Dissemination (Peritoneal Plus or Minus Distant Metastases)
time frame: 5 years
description: Patterns of dissemination (peritoneal plus or minus distant metastases).
measure: Disease-free Survival
time frame: 5 years
description: Disease-free survival.
measure: Overall Survival
time frame: 5 years
description: Overall survival.
measure: Quality of Life Questionnaire Survey 5- Year Follow-up
time frame: 5 years
description: Quality of life questionnaire survey 5- year follow-up.
arm group label: Standard adjuvant systemic chemotherapy
arm group type: Active Comparator
description: Standard adjuvant systemic chemotherapy according to the Dutch colon cancer guideline, using a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) schedule. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.
arm group label: Adjuvant HIPEC (open/laparoscopic)
arm group type: Experimental
description: Adjuvant HIPEC will be performed simultaneously with primary tumor resection, or as a staged procedure (<10 days or 5-8 weeks postoperatively). The chemotherapy during oxaliplatin-HIPEC consists of an intravenous phase with leucovorin 20 mg/m2 (maximum 40 mg) and 5-fluorouracil 400 mg/m2 (maximum 800 mg) and an intraperitoneal phase with oxaliplatin 460 mg/m2 (maximal 920 mg). Standard adjuvant systemic chemotherapy according to the national guideline will be given within 3 weeks from HIPEC. Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively.
intervention type: Procedure
intervention name: Adjuvant HIPEC (open/laparoscopic)
description: Adjuvant HIPEC procedure: access to the abdominal cavity by laparoscopy or laparotomy under general anaesthesia, adhesiolysis if necessary, complete staging of the intra-abdominal cavity, positioning of in- and outflow catheters, perfusion with a minimum of 2l isotonic dialysis fluid at a flow rate of 1-2l/min and an inflow temperature of 42-43˚C. Before the beginning of HIPEC, 5-fluorouracil 400 mg/m2 and leucovorin 20 mg/m2 will be administered intravenously to potentiate oxaliplatin activity. Oxaliplatin (460 mg/m2) is added to the perfusate after attaining at least 42 degrees inflow temperature with a total of 30 minutes perfusion time.
arm group label: Adjuvant HIPEC (open/laparoscopic)
other name: I.V. leucovorin 20 mg/m2 (maximum 40 mg)
other name: I.V. 5-fluorouracil 400 mg/m2 (maximum 800 mg)
other name: Intraperitoneal oxaliplatin 460 mg/m2 (maximum 920 mg)
intervention type: Drug
intervention name: Standard adjuvant systemic chemotherapy
description: Colon cancer patients with a high risk of developing PC, but do not have (yet) proven macroscopic peritoneal metastasis, are standardly treated with adjuvant systemic chemotherapy. Standard adjuvant systemic chemotherapy consists in the Netherlands of a capecitabine and oxaliplatin (CAPOX) or 5-FU and oxaliplatin (FOLFOX) for a total of 6 months.
arm group label: Adjuvant HIPEC (open/laparoscopic)
arm group label: Standard adjuvant systemic chemotherapy
other name: adjuvant capecitabine and oxaliplatin (CAPOX)
other name: adjuvant 5-FU and oxaliplatin (FOLFOX)
intervention type: Procedure
intervention name: Diagnostic laparoscopy
description: Presence or absence of peritoneal recurrence will be evaluated by laparoscopy in case of negative routine examination (CEA and CT thorax/abdomen) at 18 months postoperatively in both study arms.
arm group label: Adjuvant HIPEC (open/laparoscopic)
arm group label: Standard adjuvant systemic chemotherapy
other name: Diagnostic laparoscopic surgery
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Pieter J. Tanis, M.D., Ph.D.
role: Principal Investigator
affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
facility: 
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country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
investigator full name: P.J. Tanis
investigator title: M.D. Ph.D
mesh term: Neoplasms
mesh term: Colorectal Neoplasms
mesh term: Peritoneal Neoplasms
mesh term: Leucovorin
mesh term: Fluorouracil
mesh term: Capecitabine
mesh term: Oxaliplatin
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 