<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/NCT01662752</url>
  </required_header>
  <id_info>
    <org_study_id>C/32/2012</org_study_id>
    <nct_id>NCT01662752</nct_id>
  </id_info>
  <brief_title>Lymphatic Mapping for Sentinel Node Identification and Analysis</brief_title>
  <official_title>A Study to Assess Near Infrared Laparoscopy With Indocyanine Green (ICG) for Intraoperative Lymphatic Imaging and Sentinel Lymph Node Identification During Standard Surgical Resection for Colonic Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>London North West Healthcare NHS Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Imperial College London</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main objective of this study is to determine whether the first (sentinel) lymph nodes in&#xD;
      the drainage pathway of colonic tumour can be detected at the time of surgery using a new&#xD;
      technique. The detection method is to inject a fluorescent dye (indocyanine green) adjacent&#xD;
      to the tumour. The dye will then be seen as it fluoresces in the light form the near infrared&#xD;
      spectrum that can be used at the time of the laparoscopic (keyhole) surgery. An endoscope is&#xD;
      placed in the colon (colonoscopy) during surgery and the tracer fluorescent agent is injected&#xD;
      around the tumour. The mesentery in which the lymph nodes draining the tumour are located&#xD;
      will then be examined by laparoscopy as it is expected that fluorescence will be identified&#xD;
      within approximately 5 minutes of the injection. The first lymph node or nodes that take up&#xD;
      the fluorescent dye will then be marked by placing a clip or a stitch by them. After the&#xD;
      surgery has been completed and colon removed all lymph nodes can be examined microscopically&#xD;
      by the pathologist, paying a particular attention to whether any tumour cells are present in&#xD;
      the sentinel lymph nodes and whether the presence or the absence of tumour cells in that node&#xD;
      accurately reflects the tumour status of the rest of the specimen.&#xD;
&#xD;
      If this pilot demonstrates that sentinel lymph nodes can be reliably detected, we have&#xD;
      developed a technique which allows us to remove a small area (less than 5 cm) of the colon.&#xD;
      Using this procedure should decrease complications following traditional surgery. We however&#xD;
      also need a method that allows accurate assessment of the lymph nodes draining the tumour.&#xD;
      This pilot trial will examine our ability to detect such 'sentinel' lymph nodes so that we&#xD;
      can use their status (positive for cancer cells or negative) to determine whether a smaller&#xD;
      operation such as full thickness localised excision is adequate treatment for the patient and&#xD;
      that they can avoid a larger operation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Colorectal cancer is the third commonest cancer and second highest cause of cancer death in&#xD;
      the United Kingdom (UK). Introduction of the National Bowel Cancer Screening Program and&#xD;
      increasing awareness of symptoms of colorectal cancer will lead to an increase in numbers of&#xD;
      cancers detected at an early stage of the disease. Standard surgical management, however,&#xD;
      remains unchanged and that is segmental colectomy with en bloc mesenteric resection of the&#xD;
      regional lymph nodes as the metastatic status of these nodes remains the most important&#xD;
      factor for determining adjuvant treatment.&#xD;
&#xD;
      This of course was appropriate when the majority of the patients diagnosed with colorectal&#xD;
      cancer presented with symptomatic, locally advanced disease. Our practice, however, needs to&#xD;
      be reconsidered in the view of the recently published data from screening centres. Pilot&#xD;
      results demonstrate a significant shift towards an earlier stage of the disease in the&#xD;
      screened population and suggests that, in future, up to 50% of screen detected-cancers will&#xD;
      be T1 or T2 (i.e. early stage disease) 1. Less than 15% of patients with T1 and T2 disease&#xD;
      have nodal involvement 2 but current radiological techniques are not sensitive enough to&#xD;
      identify these patients pre-operatively. Instead, major surgery is performed in all patients&#xD;
      with T1 and T2 stage colonic cancer, and in up to 85%, en bloc mesenteric resection provides&#xD;
      no therapeutic benefit, as they have node negative disease. Major resection also exposes&#xD;
      patients to a significant risk of morbidity and mortality, along with late side effects.&#xD;
&#xD;
      The concept of sentinel lymph node mapping (SLNM) in colorectal cancer is not new and&#xD;
      although it has not had the same impact as in the clinical care of breast cancer, melanoma,&#xD;
      and more recently gastric cancer 3-6, some expert centres have suggested that it may be&#xD;
      clinically relevant 7, 8. The technique is based on the principle that the first possible&#xD;
      sites of metastasis along the lymphatic drainage route from the primary lesion are known as&#xD;
      sentinel lymph nodes (SLNs) and these can be detected using injection of dyes, radioisotopes&#xD;
      or a combination of both. Therefore, evaluation of the SLNs can result in an accurate&#xD;
      assessment of the nodal status in the entire lymphatic basin allowing a tailored surgical&#xD;
      treatment. Although this technique has transformed surgical care for melanoma and breast&#xD;
      cancer patients, its application in patients with colorectal cancer has been questioned due&#xD;
      to discrepancies in the reported results caused by the heterogeneous study designs employed,&#xD;
      variations in surgical experience and differing patient inclusion criteria 9-11.&#xD;
&#xD;
      Detailed analysis of studies performed to date shows that tumour and patient characterisation&#xD;
      as well as surgeons experience are key factors when assessing the utility of the technique 2,&#xD;
      12 and at least three nodes need to be found in order to maximise this 13. The main research&#xD;
      focus so far has been on optimising the technique itself. Initial research was performed&#xD;
      using blue dye, radioactive colloid or both in combination but this failed to achieve the&#xD;
      95-97% identification rates found in breast cancer and was also accompanied by unacceptable&#xD;
      false negative rates 14-17. Although many authors noted that their false negatives occurred&#xD;
      predominantly in patients with advanced disease (T3 and T4 cancers) 18-20, utilisation of&#xD;
      those identification agents has proven frustrating to date. Radioactive colloids require&#xD;
      involvement of a nuclear medicine physician, can be difficult to localise with a handheld&#xD;
      camera and cause signal interference if the SLN(s) is too close to the injection site. Blue&#xD;
      dyes however are difficult to localise in patients with a high body mass index (BMI), who&#xD;
      unfortunately comprise the majority of our patient population, thus producing only limited&#xD;
      (if any) visualisation of afferent lymphatic vessels and SLN(s).&#xD;
&#xD;
      In order to re-examine extensive research that has been reported on SLNM, a secondary&#xD;
      intention analysis of the two largest multicentre SLN databases was undertaken. This reported&#xD;
      that in 225 patients with T1 or T2 disease, accurate detection of SLNs was possible in 95%,&#xD;
      confirming that this staging technique should be most accurate in patients with early colonic&#xD;
      cancer 2. This improved with operator experience and when tumour size was smaller than 35 mm&#xD;
      in diameter. In 196 patients treated by experienced surgeons, 144 (73.4%), would have&#xD;
      correctly undergone localised full thickness resection if surgery had been based only on&#xD;
      their SLNs status and 49 (25.0%), would have required conventional resection either because&#xD;
      the SLNs were not identified, or due to detection of metastases. Only 3 patients (1.5%) would&#xD;
      have been inappropriately predicted to be node negative.&#xD;
&#xD;
      To overcome the aforementioned issues, a number of researchers have utilized optical imaging&#xD;
      using the near-infrared (NIR) fluorescence lymphatic tracer indocyanine green (ICG) which&#xD;
      enables real-time intraoperative visualisation of lymphatic channels and SLNs. The technique&#xD;
      performs as well as the combination of a radioactive tracer and blue dye in patients with&#xD;
      breast cancer 21, and has also been validated in patients with early gastric cancer 4-6.&#xD;
&#xD;
      ICG was initially recommended as a tattooing agent for colonic and pancreatic lesions to aid&#xD;
      perioperative localization 22-24, as there were no reports of complications such as focal&#xD;
      peritonitis, abscess formation, postoperative adhesions and ileus which had been seen with&#xD;
      the use of India ink 25-27. However, its use as a tattooing agent is limited to patients&#xD;
      undergoing surgery within 8 days after endoscopic injection, as the dye dissipates through&#xD;
      lymphatic channels due to its small molecular size 22. More recently, its fluorescence&#xD;
      properties have been utilised for intraoperative localisation of colorectal neoplasms and&#xD;
      associated SLNs 28-32 in patients undergoing surgery using either charge-coupled device (CCD)&#xD;
      or a NIR camera. Nagata et al. demonstrated that observation of ICG dye using a NIR camera&#xD;
      was far superior to that by conventional laparoscopy with identification of SLNs being five&#xD;
      times better 29. These results suggest that a SLNM technique using NIR with a fluorescent&#xD;
      tracer may be useful in patients with a high BMI who have large amounts of mesenteric adipose&#xD;
      tissue. All authors reporting the NIR technique have noted its success in colorectal&#xD;
      practice, without adverse effects with a comparable role to its use in early breast or&#xD;
      gastric cancer.&#xD;
&#xD;
      The ability to utilise this technique and confidently identify the SLNs has the potential to&#xD;
      transform the surgical care of patients with colonic neoplasia. The focus, however, must be&#xD;
      on patients with early disease, thus allowing those who have node negative disease to be&#xD;
      considered for localised full thickness resection of their primary cancer as definitive&#xD;
      surgical therapy. Unfortunately, studies published to date have included patients with T3&#xD;
      disease in their series 29, 31.&#xD;
&#xD;
      This pilot trial aims to apply a well-described technique using a NIR camera and ICG as the&#xD;
      tracer in order to clarify whether SLNs can be confidently identified in patients undergoing&#xD;
      conventional resection (segmental colectomy and en bloc mesenteric resection) for T1 and T2&#xD;
      colonic cancers. This protocol is based on extensive literature search of studies describing&#xD;
      the technique in patients with early gastric and colorectal cancers 5, 6, 29-31, 33-36.&#xD;
      Provided that the pilot trial is successful, and in order to obtain adequate power, a further&#xD;
      large multicentre trial will be required to determine whether the nodes visualised by NIR&#xD;
      mapping are representative of the patient's lymphatic basin metastatic status. Proven&#xD;
      concordance between the pathology of the SLNs and that of the standard nodal resection would&#xD;
      then justify a more limited surgical intervention, taking just the SLN(s), and allowing a&#xD;
      more precisely tailored operative intervention.&#xD;
&#xD;
      All patients in the pilot trial will undergo standard surgical treatment in addition to the&#xD;
      NIR SLNM technique.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 2013</start_date>
  <completion_date type="Actual">October 2015</completion_date>
  <primary_completion_date type="Actual">September 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Subjects in Which the SLN(s) Are Identified</measure>
    <time_frame>28 days</time_frame>
    <description>To establish whether it is possible to identify the first order draining mesocolic lymph nodes (sentinel lymph node(s) (SLNs) in patients with suspected T1 and T2 colonic cancer, using Indocyanine Green (ICG), a fluorescent mapping agent, and a laparoscopic near infrared imaging (NIR) system</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Sensitivity and Specificity of Tumour-bearing Status of SLN(s) as a Measure of Lymph Node Status When Assessed by Standard Techniques</measure>
    <time_frame>28 days</time_frame>
    <description>To assess the extent to which that the tumour-bearing status of SLN(s) identified corresponds with lymph node status as assessed by standard methods (pathological examination of excised nodes using H&amp;E and immunohistochemistry)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Frequency and Tumour-bearing Status of Aberrant SLN(s</measure>
    <time_frame>28 days</time_frame>
    <description>To estimate the proportion of patients with aberrant nodal drainage. i.e. the proportion with SLN(s) lying outside the standard resection field</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Indocyanine green</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Indocyanine green is used for intraoperative identification of sentinel lymph nodes in patients with early colonic cancer using near infrared laparoscopic imaging</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Indocyanine green</intervention_name>
    <description>Please see arm description</description>
    <arm_group_label>Indocyanine green</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients willing and able to give informed consent for participation in the study&#xD;
&#xD;
          2. Patients willing and able to comply with the study procedures&#xD;
&#xD;
          3. Male or Female, aged 18 years or above&#xD;
&#xD;
          4. Patients diagnosed with T1 or T2 colonic neoplasia on preoperative staging and require&#xD;
             laparoscopic surgical excision&#xD;
&#xD;
          5. If female, a negative pregnancy test for women of childbearing potential prior to&#xD;
             surgery&#xD;
&#xD;
          6. Patients who have clinically acceptable laboratory results pre-operatively with serum&#xD;
             creatinine of &lt;110 mg/dL&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients diagnosed with T3 or T4 disease on preoperative imaging&#xD;
&#xD;
          2. A patient who is pregnant, lactating or planning pregnancy during the course of the&#xD;
             study&#xD;
&#xD;
          3. Allergy to any of the compounds being used for lymphatic mapping including Indocyanine&#xD;
             green or sodium iodide&#xD;
&#xD;
          4. Patients with hyperthyroidism or those with thyroid adenomas&#xD;
&#xD;
          5. Patients with renal insufficiency (serum creatinine of &gt;110 mg/dL)&#xD;
&#xD;
          6. Patients in whom the use of ICG is contraindicated including development of adverse&#xD;
             events when previously or presently administered&#xD;
&#xD;
          7. Previous allergic reaction to shellfish&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Robin Kennedy, FRCS, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Imperial College London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>North West London Hospital</name>
      <address>
        <city>London</city>
        <state>UK</state>
        <zip>HA1 3UJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>August 2019</verification_date>
  <study_first_submitted>August 7, 2012</study_first_submitted>
  <study_first_submitted_qc>August 9, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 10, 2012</study_first_posted>
  <results_first_submitted>May 20, 2019</results_first_submitted>
  <results_first_submitted_qc>August 8, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">August 9, 2019</results_first_posted>
  <last_update_submitted>August 8, 2019</last_update_submitted>
  <last_update_submitted_qc>August 8, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 9, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Early colonic cancer</keyword>
  <keyword>Sentinel lymph node mapping</keyword>
  <keyword>Sentinel lymph node biopsy</keyword>
  <keyword>Near infrared imaging</keyword>
  <keyword>Indocyanine green</keyword>
  <keyword>Laparoscopic</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Indocyanine Green</title>
          <description>Single inject a fluorescent dye (indocyanine green) adjacent to the tumour. The dye will then be seen as it fluoresces in the light form the near infrared spectrum that can be used at the time of the laparoscopic (keyhole) surgery. An endoscope is placed in the colon (colonoscopy) during surgery and the tracer fluorescent agent is injected around the tumour. The mesentery in which the lymph nodes draining the tumour are located will then be examined by laparoscopy as it is expected that fluorescence will be identified within approximately 5 minutes of the injection.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Indocyanine Green</title>
          <description>Indocyanine green is used for intraoperative identification of sentinel lymph nodes in patients with early colonic cancer using near infrared laparoscopic imaging&#xD;
Indocyanine green: Please see arm description</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="30"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="66" spread="12.4"/>
                  </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>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United Kingdom</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Subjects in Which the SLN(s) Are Identified</title>
        <description>To establish whether it is possible to identify the first order draining mesocolic lymph nodes (sentinel lymph node(s) (SLNs) in patients with suspected T1 and T2 colonic cancer, using Indocyanine Green (ICG), a fluorescent mapping agent, and a laparoscopic near infrared imaging (NIR) system</description>
        <time_frame>28 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Indocyanine Green</title>
            <description>Indocyanine green is used for intraoperative identification of sentinel lymph nodes in patients with early colonic cancer using near infrared laparoscopic imaging&#xD;
Indocyanine green: Please see arm description</description>
          </group>
        </group_list>
        <measure>
          <title>Subjects in Which the SLN(s) Are Identified</title>
          <description>To establish whether it is possible to identify the first order draining mesocolic lymph nodes (sentinel lymph node(s) (SLNs) in patients with suspected T1 and T2 colonic cancer, using Indocyanine Green (ICG), a fluorescent mapping agent, and a laparoscopic near infrared imaging (NIR) system</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Sensitivity and Specificity of Tumour-bearing Status of SLN(s) as a Measure of Lymph Node Status When Assessed by Standard Techniques</title>
        <description>To assess the extent to which that the tumour-bearing status of SLN(s) identified corresponds with lymph node status as assessed by standard methods (pathological examination of excised nodes using H&amp;E and immunohistochemistry)</description>
        <time_frame>28 days</time_frame>
        <population>There were 10 patients with positive nodes hence this is the denominator for the sensitivity analysis. There were 20 patients with negative lymph nodes overall hence this is the denominator for the specificity analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Indocyanine Green</title>
            <description>Indocyanine green is used for intraoperative identification of sentinel lymph nodes in patients with early colonic cancer using near infrared laparoscopic imaging&#xD;
Indocyanine green: Please see arm description</description>
          </group>
        </group_list>
        <measure>
          <title>Sensitivity and Specificity of Tumour-bearing Status of SLN(s) as a Measure of Lymph Node Status When Assessed by Standard Techniques</title>
          <description>To assess the extent to which that the tumour-bearing status of SLN(s) identified corresponds with lymph node status as assessed by standard methods (pathological examination of excised nodes using H&amp;E and immunohistochemistry)</description>
          <population>There were 10 patients with positive nodes hence this is the denominator for the sensitivity analysis. There were 20 patients with negative lymph nodes overall hence this is the denominator for the specificity analysis.</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="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Sensitivity</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="10"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Specificity</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="20"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Frequency and Tumour-bearing Status of Aberrant SLN(s</title>
        <description>To estimate the proportion of patients with aberrant nodal drainage. i.e. the proportion with SLN(s) lying outside the standard resection field</description>
        <time_frame>28 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Indocyanine Green</title>
            <description>Indocyanine green is used for intraoperative identification of sentinel lymph nodes in patients with early colonic cancer using near infrared laparoscopic imaging&#xD;
Indocyanine green: Please see arm description</description>
          </group>
        </group_list>
        <measure>
          <title>Frequency and Tumour-bearing Status of Aberrant SLN(s</title>
          <description>To estimate the proportion of patients with aberrant nodal drainage. i.e. the proportion with SLN(s) lying outside the standard resection field</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 year</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Indocyanine Green</title>
          <description>Indocyanine green is used for intraoperative identification of sentinel lymph nodes in patients with early colonic cancer using near infrared laparoscopic imaging&#xD;
Indocyanine green: Please see arm description</description>
        </group>
      </group_list>
      <serious_events>
        <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="30"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</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="30" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Paroxysmal atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Constipations</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Distended abdomen</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Epigastric pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Hiccough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Ileus</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Febrile reaction</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Rigors</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Wound pain</sub_title>
                <counts group_id="E1" subjects_affected="29" subjects_at_risk="30"/>
              </event>
              <event>
                <sub_title>Postoperative ileus</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Low haemoglobin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Groin pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary retention</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Atelectasis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Low blood pressure</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
              </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>Professor Robin Kennedy</name_or_title>
      <organization>St Mark's Hospital</organization>
      <phone>+44(0)2082354046</phone>
      <email>robin.kennedy@nhs.net</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/NCT01662752
org study id: C/32/2012
nct id: NCT01662752
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The main objective of this study is to determine whether the first (sentinel) lymph nodes in
      the drainage pathway of colonic tumour can be detected at the time of surgery using a new
      technique. The detection method is to inject a fluorescent dye (indocyanine green) adjacent
      to the tumour. The dye will then be seen as it fluoresces in the light form the near infrared
      spectrum that can be used at the time of the laparoscopic (keyhole) surgery. An endoscope is
      placed in the colon (colonoscopy) during surgery and the tracer fluorescent agent is injected
      around the tumour. The mesentery in which the lymph nodes draining the tumour are located
      will then be examined by laparoscopy as it is expected that fluorescence will be identified
      within approximately 5 minutes of the injection. The first lymph node or nodes that take up
      the fluorescent dye will then be marked by placing a clip or a stitch by them. After the
      surgery has been completed and colon removed all lymph nodes can be examined microscopically
      by the pathologist, paying a particular attention to whether any tumour cells are present in
      the sentinel lymph nodes and whether the presence or the absence of tumour cells in that node
      accurately reflects the tumour status of the rest of the specimen.

      If this pilot demonstrates that sentinel lymph nodes can be reliably detected, we have
      developed a technique which allows us to remove a small area (less than 5 cm) of the colon.
      Using this procedure should decrease complications following traditional surgery. We however
      also need a method that allows accurate assessment of the lymph nodes draining the tumour.
      This pilot trial will examine our ability to detect such 'sentinel' lymph nodes so that we
      can use their status (positive for cancer cells or negative) to determine whether a smaller
      operation such as full thickness localised excision is adequate treatment for the patient and
      that they can avoid a larger operation.
Colorectal cancer is the third commonest cancer and second highest cause of cancer death in
      the United Kingdom (UK). Introduction of the National Bowel Cancer Screening Program and
      increasing awareness of symptoms of colorectal cancer will lead to an increase in numbers of
      cancers detected at an early stage of the disease. Standard surgical management, however,
      remains unchanged and that is segmental colectomy with en bloc mesenteric resection of the
      regional lymph nodes as the metastatic status of these nodes remains the most important
      factor for determining adjuvant treatment.

      This of course was appropriate when the majority of the patients diagnosed with colorectal
      cancer presented with symptomatic, locally advanced disease. Our practice, however, needs to
      be reconsidered in the view of the recently published data from screening centres. Pilot
      results demonstrate a significant shift towards an earlier stage of the disease in the
      screened population and suggests that, in future, up to 50% of screen detected-cancers will
      be T1 or T2 (i.e. early stage disease) 1. Less than 15% of patients with T1 and T2 disease
      have nodal involvement 2 but current radiological techniques are not sensitive enough to
      identify these patients pre-operatively. Instead, major surgery is performed in all patients
      with T1 and T2 stage colonic cancer, and in up to 85%, en bloc mesenteric resection provides
      no therapeutic benefit, as they have node negative disease. Major resection also exposes
      patients to a significant risk of morbidity and mortality, along with late side effects.

      The concept of sentinel lymph node mapping (SLNM) in colorectal cancer is not new and
      although it has not had the same impact as in the clinical care of breast cancer, melanoma,
      and more recently gastric cancer 3-6, some expert centres have suggested that it may be
      clinically relevant 7, 8. The technique is based on the principle that the first possible
      sites of metastasis along the lymphatic drainage route from the primary lesion are known as
      sentinel lymph nodes (SLNs) and these can be detected using injection of dyes, radioisotopes
      or a combination of both. Therefore, evaluation of the SLNs can result in an accurate
      assessment of the nodal status in the entire lymphatic basin allowing a tailored surgical
      treatment. Although this technique has transformed surgical care for melanoma and breast
      cancer patients, its application in patients with colorectal cancer has been questioned due
      to discrepancies in the reported results caused by the heterogeneous study designs employed,
      variations in surgical experience and differing patient inclusion criteria 9-11.

      Detailed analysis of studies performed to date shows that tumour and patient characterisation
      as well as surgeons experience are key factors when assessing the utility of the technique 2,
      12 and at least three nodes need to be found in order to maximise this 13. The main research
      focus so far has been on optimising the technique itself. Initial research was performed
      using blue dye, radioactive colloid or both in combination but this failed to achieve the
      95-97% identification rates found in breast cancer and was also accompanied by unacceptable
      false negative rates 14-17. Although many authors noted that their false negatives occurred
      predominantly in patients with advanced disease (T3 and T4 cancers) 18-20, utilisation of
      those identification agents has proven frustrating to date. Radioactive colloids require
      involvement of a nuclear medicine physician, can be difficult to localise with a handheld
      camera and cause signal interference if the SLN(s) is too close to the injection site. Blue
      dyes however are difficult to localise in patients with a high body mass index (BMI), who
      unfortunately comprise the majority of our patient population, thus producing only limited
      (if any) visualisation of afferent lymphatic vessels and SLN(s).

      In order to re-examine extensive research that has been reported on SLNM, a secondary
      intention analysis of the two largest multicentre SLN databases was undertaken. This reported
      that in 225 patients with T1 or T2 disease, accurate detection of SLNs was possible in 95%,
      confirming that this staging technique should be most accurate in patients with early colonic
      cancer 2. This improved with operator experience and when tumour size was smaller than 35 mm
      in diameter. In 196 patients treated by experienced surgeons, 144 (73.4%), would have
      correctly undergone localised full thickness resection if surgery had been based only on
      their SLNs status and 49 (25.0%), would have required conventional resection either because
      the SLNs were not identified, or due to detection of metastases. Only 3 patients (1.5%) would
      have been inappropriately predicted to be node negative.

      To overcome the aforementioned issues, a number of researchers have utilized optical imaging
      using the near-infrared (NIR) fluorescence lymphatic tracer indocyanine green (ICG) which
      enables real-time intraoperative visualisation of lymphatic channels and SLNs. The technique
      performs as well as the combination of a radioactive tracer and blue dye in patients with
      breast cancer 21, and has also been validated in patients with early gastric cancer 4-6.

      ICG was initially recommended as a tattooing agent for colonic and pancreatic lesions to aid
      perioperative localization 22-24, as there were no reports of complications such as focal
      peritonitis, abscess formation, postoperative adhesions and ileus which had been seen with
      the use of India ink 25-27. However, its use as a tattooing agent is limited to patients
      undergoing surgery within 8 days after endoscopic injection, as the dye dissipates through
      lymphatic channels due to its small molecular size 22. More recently, its fluorescence
      properties have been utilised for intraoperative localisation of colorectal neoplasms and
      associated SLNs 28-32 in patients undergoing surgery using either charge-coupled device (CCD)
      or a NIR camera. Nagata et al. demonstrated that observation of ICG dye using a NIR camera
      was far superior to that by conventional laparoscopy with identification of SLNs being five
      times better 29. These results suggest that a SLNM technique using NIR with a fluorescent
      tracer may be useful in patients with a high BMI who have large amounts of mesenteric adipose
      tissue. All authors reporting the NIR technique have noted its success in colorectal
      practice, without adverse effects with a comparable role to its use in early breast or
      gastric cancer.

      The ability to utilise this technique and confidently identify the SLNs has the potential to
      transform the surgical care of patients with colonic neoplasia. The focus, however, must be
      on patients with early disease, thus allowing those who have node negative disease to be
      considered for localised full thickness resection of their primary cancer as definitive
      surgical therapy. Unfortunately, studies published to date have included patients with T3
      disease in their series 29, 31.

      This pilot trial aims to apply a well-described technique using a NIR camera and ICG as the
      tracer in order to clarify whether SLNs can be confidently identified in patients undergoing
      conventional resection (segmental colectomy and en bloc mesenteric resection) for T1 and T2
      colonic cancers. This protocol is based on extensive literature search of studies describing
      the technique in patients with early gastric and colorectal cancers 5, 6, 29-31, 33-36.
      Provided that the pilot trial is successful, and in order to obtain adequate power, a further
      large multicentre trial will be required to determine whether the nodes visualised by NIR
      mapping are representative of the patient's lymphatic basin metastatic status. Proven
      concordance between the pathology of the SLNs and that of the standard nodal resection would
      then justify a more limited surgical intervention, taking just the SLN(s), and allowing a
      more precisely tailored operative intervention.

      All patients in the pilot trial will undergo standard surgical treatment in addition to the
      NIR SLNM technique.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Subjects in Which the SLN(s) Are Identified
time frame: 28 days
description: To establish whether it is possible to identify the first order draining mesocolic lymph nodes (sentinel lymph node(s) (SLNs) in patients with suspected T1 and T2 colonic cancer, using Indocyanine Green (ICG), a fluorescent mapping agent, and a laparoscopic near infrared imaging (NIR) system
measure: Sensitivity and Specificity of Tumour-bearing Status of SLN(s) as a Measure of Lymph Node Status When Assessed by Standard Techniques
time frame: 28 days
description: To assess the extent to which that the tumour-bearing status of SLN(s) identified corresponds with lymph node status as assessed by standard methods (pathological examination of excised nodes using H&E and immunohistochemistry)
measure: Frequency and Tumour-bearing Status of Aberrant SLN(s
time frame: 28 days
description: To estimate the proportion of patients with aberrant nodal drainage. i.e. the proportion with SLN(s) lying outside the standard resection field
arm group label: Indocyanine green
arm group type: Other
description: Indocyanine green is used for intraoperative identification of sentinel lymph nodes in patients with early colonic cancer using near infrared laparoscopic imaging
intervention type: Drug
intervention name: Indocyanine green
description: Please see arm description
arm group label: Indocyanine green
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Robin Kennedy, FRCS, MS
role: Principal Investigator
affiliation: Imperial College London
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 