<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/NCT02233374</url>
  </required_header>
  <id_info>
    <org_study_id>14-NSCCRO-P001</org_study_id>
    <nct_id>NCT02233374</nct_id>
  </id_info>
  <brief_title>Predicting RadIotherapy ReSponse of Rectal Cancer With MRI and PET</brief_title>
  <acronym>PRISM</acronym>
  <official_title>Predicting RadIotherapy ReSponse of Rectal Cancer With MRI and PET</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Royal North Shore Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Royal North Shore Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to investigate if PET/CT and MRI scans performed early in&#xD;
      treatment and six weeks after treatment can predict the response of rectal cancer following&#xD;
      chemotherapy and radiotherapy. This will help doctors to better tailor treatments for rectal&#xD;
      cancer in the future.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Bowel cancer is the second most prevalent cancer in Australia with rectal cancer the most&#xD;
      common subgroup, representing 5% of all cancer diagnoses in 2008 [1]. Rectal cancer also&#xD;
      accounts for 4.6% of all cancer deaths in New South Wales [1]. All rectal cancer that is T3/4&#xD;
      or node positive on pre-operative assessment should be considered for pre-operative therapy,&#xD;
      which has been shown to significantly improve local control compared to postoperative&#xD;
      chemoradiation. [2]. Pre-operative chemoradiation is standard pre-operative treatment at the&#xD;
      Northern Sydney Cancer Centre with approximately 40 patients/year receiving this treatment.&#xD;
      Surgery is normally performed 6-8 weeks following chemoradiation.&#xD;
&#xD;
      One of the unique opportunities with rectal cancer is that histopathological analysis of the&#xD;
      resected specimen gives an accurate assessment of the response of the tumour to pre-operative&#xD;
      chemoradiation. Those tumours having a pathologic complete response (pCR) are known to have&#xD;
      an excellent long-term outcome.&#xD;
&#xD;
      Data from the department of Radiation Oncology at Northern Sydney Cancer Centre demonstrates&#xD;
      that only 17% of patients experience a pCR, which is in keeping with other series [4]. In&#xD;
      this study of 48 patients, 38% showed evidence of tumour shrinkage 2 weeks into treatment as&#xD;
      demonstrated on a Cone Beam CT scan taken during radiotherapy. 44% of these patients&#xD;
      demonstrated a pCR following surgery. In the remaining 62%, none of these patients had a pCR.&#xD;
      This confirms the principle that early response during radiation based only on gross tumour&#xD;
      shrinkage can be a powerful predictor of subsequent response.&#xD;
&#xD;
      Assessing response during Cone Beam CT is very subjective and not possible on all patients.&#xD;
      Furthermore it may be possible to better predict those likely to have a complete response&#xD;
      with alternate imaging modalities. There is emerging data that functional and microstructural&#xD;
      imaging modalities can also be used to predict and assess treatment response prior to, during&#xD;
      and following the delivery of pre-operative chemoradiation for locally advanced rectal cancer&#xD;
      [5].&#xD;
&#xD;
      Diffusion-weighted magnetic resonance imaging (DWI) is a microstructural imaging technique&#xD;
      that characterizes tissue based on differences in the movement of water molecules. These&#xD;
      differences can be quantified using the apparent diffusion coefficient (ADC). The ADC has&#xD;
      been shown to differentiate post-treatment inflammation and necrosis from recurrent or&#xD;
      persistent tumoural tissue in rectal cancer with high specificity [6]. Pre-treatment ADC&#xD;
      assessment with DWI has a sensitivity of 100% and specificity of 86% for detection of pCR&#xD;
      (p=0.003) whilst treatment induced changes in ADC (measured at week 2 chemoradiation) have a&#xD;
      sensitivity and specificity of 100% for predicting pCR (p=0.0006) [5]. Prediction of response&#xD;
      should be improved further with the use of PET imaging. A staging 18F-FDG&#xD;
      (18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose ) PET/CT has been demonstrated to provide&#xD;
      new findings compared to contrast-enhanced CT of the thorax/abdomen/pelvis resulting in a&#xD;
      change in the stage of disease and alteration of treatment strategy in 14% of patients [7].&#xD;
      F-FDG PET/CT can be more predictive of histological response and outcome than anatomic&#xD;
      imaging alone [8]. Whilst PET Response Criteria in Solid Tumors (PERCIST) has not been shown&#xD;
      to have predictive power on the response to neoadjuvant therapy, PET Residual Disease in&#xD;
      Solid Tumor (PREDIST) criteria has been shown to correlate to pCR (p = 0.004) [9].&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 2014</start_date>
  <completion_date type="Actual">December 2018</completion_date>
  <primary_completion_date type="Actual">December 2018</primary_completion_date>
  <phase>N/A</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>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Predictive value of PET/CT and MRI 2 weeks into chemo-irradiation for developing a pathologic complete response at surgery.</measure>
    <time_frame>2 years</time_frame>
    <description>Predictive value of PET/CT and MRI 2 weeks into chemo-irradiation for developing a pathologic complete response at surgery (Grade 0 - no viable cancer cells seen in the resection specimen).&#xD;
The standard grading system employed by pathologists at Royal North Shore Hospital will be used to measure tumour regression. This is the system recommended by the RCPA synoptic report for colorectal cancer, based on Ryan R, Gibbons D, Hyland JMP, et al. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology 2005; 47:141-6.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Feasibility of conducting additional PET and MRI scans at 6 weeks post-treatment.</measure>
    <time_frame>2 years</time_frame>
    <description>This will be assessed in terms of whether PET and MR imaging approximately 6 weeks after chemo-irradiation adds any additional predictive value to imaging performed 2 weeks into treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Utility of adding PET scan to the baseline staging of patients</measure>
    <time_frame>2 years</time_frame>
    <description>This will be measured by whether PET 2 weeks into treatment (combined with already utilised MRI) can independently predict the likelihood of a pathological complete response at surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pathologic response according to Tumour Regression Grade (TRG)</measure>
    <time_frame>2.5 years</time_frame>
    <description>A scoring system will be developed based on the degree of response from the PET and MRI scan at 2 weeks incorporating tumour shrinkage (PET and MR), reduction in SUV (PET) and reduction in diffusion (MR) that can best predict the &quot;responders&quot; and &quot;non-responders&quot;.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Impact of pCR rates on long term disease control</measure>
    <time_frame>5 years</time_frame>
    <description>Measured in terms of loco-regional or distant recurrence by 3 years.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">27</enrollment>
  <condition>Rectal Neoplasms</condition>
  <arm_group>
    <arm_group_label>Assessing response with MRI + PET.</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Pre-operative chemo/RT as per standard treatment. Intensity Modulated Radiotherapy (IMRT) / Volumetric Arc Therapy (VMAT) 45Gray/25 fractions with simultaneous integrated Boost of 50Gray/25 fractions + concurrent capecitabine chemotherapy.&#xD;
Intervention 1 'Early MRI and PET/CT - 2 weeks after commencing chemo/RT' involves additional Multiparametric MRI + PET/CT 2 weeks into chemo/RT Intervention 2 :\'Late MRI and PET/CT 6 weeks post chemo/RT' involves additional Multiparametric MRI + PET/CT 6 weeks post chemo/RT</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Early MRI and PET/CT - 2 weeks after commencing chemo/RT</intervention_name>
    <description>Patients will have an early MRI and PET/CT - 2 weeks after commencing chemo/RT. A limited range PET/CT will look at parameters: SUVmaxm PERCIST, RECIST 1.1, ΔSUV (PET1-2), ΔSUV (early -late), Glycolytic tumour volume (GTV). MRI T2 (1-3mm slice as per NS Radiology protocol and ESGAR guideline) will look at parameters: DWI &amp; ADC value (preferably on a single camera with reproducible ADC value), Local Staging, MRF involvement, EMVI, nodal status, MR volumetry, and desmoplastic reaction.</description>
    <arm_group_label>Assessing response with MRI + PET.</arm_group_label>
    <other_name>Imaging</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Late MRI and PET/CT 6 weeks post chemo/RT</intervention_name>
    <description>Patients will have late a MRI and PET/CT 6 weeks post chemo/RT. A whole body PET/CT will look at parameters: SUVmaxm PERCIST, RECIST 1.1, ΔSUV (PET1-2), ΔSUV (early -late), Glycolytic tumour volume (GTV). MRI T2 (1-3mm slice as per NS Radiology protocol and ESGAR guideline) will look at parameters: DWI &amp; ADC value (preferably on a single camera with reproducible ADC value), Local Staging, MRF involvement, EMVI, nodal status, MR volumetry, and desmoplastic reaction.</description>
    <arm_group_label>Assessing response with MRI + PET.</arm_group_label>
    <other_name>Imaging</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age &gt; 18 years&#xD;
&#xD;
          -  T3/4 or node positive rectal cancer&#xD;
&#xD;
          -  Suitable for pre-operative chemo-irradiation and surgical resection&#xD;
&#xD;
          -  No contraindication to MRI (pacemaker, severe claustrophobia)&#xD;
&#xD;
          -  Gross visible disease on MRI&#xD;
&#xD;
          -  No contraindications to PET/CT&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Karnofsky&#xD;
             Performance Status &gt; 70%)&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  - Previous radiotherapy to pelvis&#xD;
&#xD;
          -  Unable/unwilling to have MRI&#xD;
&#xD;
          -  Unable/unwilling to have PET/CT&#xD;
&#xD;
          -  Pregnancy, lactation or inadequate contraception&#xD;
&#xD;
          -  Known allergic reaction to FDG PET contrast&#xD;
&#xD;
          -  Pacemaker or implanted defibrillator&#xD;
&#xD;
          -  Patients with a history of psychological illness or condition such as to interfere&#xD;
             with the patient's ability to understand requirements of the study.&#xD;
&#xD;
          -  Unwilling or unable to give informed consent&#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>Andrew Kneebone, MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Royal North Shore Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Northern Sydney Cancer Centre, Royal North Shore Hospital</name>
      <address>
        <city>St Leonards</city>
        <state>New South Wales</state>
        <zip>2065</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>August 13, 2014</study_first_submitted>
  <study_first_submitted_qc>September 2, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 8, 2014</study_first_posted>
  <last_update_submitted>October 26, 2022</last_update_submitted>
  <last_update_submitted_qc>October 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">October 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Royal North Shore Hospital</investigator_affiliation>
    <investigator_full_name>Professor Andrew Kneebone</investigator_full_name>
    <investigator_title>Associate Professor Andrew Kneebone</investigator_title>
  </responsible_party>
  <keyword>Rectal Cancer</keyword>
  <keyword>Magnetic Resonance Imaging</keyword>
  <keyword>Positron Emission Tomography</keyword>
  <keyword>pathologic complete response</keyword>
  <keyword>Diffusion-weighted magnetic resonance imaging</keyword>
  <keyword>Microstructural Imaging</keyword>
  <keyword>FDG PET</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rectal Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02233374
org study id: 14-NSCCRO-P001
nct id: NCT02233374
lead sponsor: 
has dmc: Yes
The purpose of this study is to investigate if PET/CT and MRI scans performed early in
      treatment and six weeks after treatment can predict the response of rectal cancer following
      chemotherapy and radiotherapy. This will help doctors to better tailor treatments for rectal
      cancer in the future.
Bowel cancer is the second most prevalent cancer in Australia with rectal cancer the most
      common subgroup, representing 5% of all cancer diagnoses in 2008 [1]. Rectal cancer also
      accounts for 4.6% of all cancer deaths in New South Wales [1]. All rectal cancer that is T3/4
      or node positive on pre-operative assessment should be considered for pre-operative therapy,
      which has been shown to significantly improve local control compared to postoperative
      chemoradiation. [2]. Pre-operative chemoradiation is standard pre-operative treatment at the
      Northern Sydney Cancer Centre with approximately 40 patients/year receiving this treatment.
      Surgery is normally performed 6-8 weeks following chemoradiation.

      One of the unique opportunities with rectal cancer is that histopathological analysis of the
      resected specimen gives an accurate assessment of the response of the tumour to pre-operative
      chemoradiation. Those tumours having a pathologic complete response (pCR) are known to have
      an excellent long-term outcome.

      Data from the department of Radiation Oncology at Northern Sydney Cancer Centre demonstrates
      that only 17% of patients experience a pCR, which is in keeping with other series [4]. In
      this study of 48 patients, 38% showed evidence of tumour shrinkage 2 weeks into treatment as
      demonstrated on a Cone Beam CT scan taken during radiotherapy. 44% of these patients
      demonstrated a pCR following surgery. In the remaining 62%, none of these patients had a pCR.
      This confirms the principle that early response during radiation based only on gross tumour
      shrinkage can be a powerful predictor of subsequent response.

      Assessing response during Cone Beam CT is very subjective and not possible on all patients.
      Furthermore it may be possible to better predict those likely to have a complete response
      with alternate imaging modalities. There is emerging data that functional and microstructural
      imaging modalities can also be used to predict and assess treatment response prior to, during
      and following the delivery of pre-operative chemoradiation for locally advanced rectal cancer
      [5].

      Diffusion-weighted magnetic resonance imaging (DWI) is a microstructural imaging technique
      that characterizes tissue based on differences in the movement of water molecules. These
      differences can be quantified using the apparent diffusion coefficient (ADC). The ADC has
      been shown to differentiate post-treatment inflammation and necrosis from recurrent or
      persistent tumoural tissue in rectal cancer with high specificity [6]. Pre-treatment ADC
      assessment with DWI has a sensitivity of 100% and specificity of 86% for detection of pCR
      (p=0.003) whilst treatment induced changes in ADC (measured at week 2 chemoradiation) have a
      sensitivity and specificity of 100% for predicting pCR (p=0.0006) [5]. Prediction of response
      should be improved further with the use of PET imaging. A staging 18F-FDG
      (18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose ) PET/CT has been demonstrated to provide
      new findings compared to contrast-enhanced CT of the thorax/abdomen/pelvis resulting in a
      change in the stage of disease and alteration of treatment strategy in 14% of patients [7].
      F-FDG PET/CT can be more predictive of histological response and outcome than anatomic
      imaging alone [8]. Whilst PET Response Criteria in Solid Tumors (PERCIST) has not been shown
      to have predictive power on the response to neoadjuvant therapy, PET Residual Disease in
      Solid Tumor (PREDIST) criteria has been shown to correlate to pCR (p = 0.004) [9].
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Predictive value of PET/CT and MRI 2 weeks into chemo-irradiation for developing a pathologic complete response at surgery.
time frame: 2 years
description: Predictive value of PET/CT and MRI 2 weeks into chemo-irradiation for developing a pathologic complete response at surgery (Grade 0 - no viable cancer cells seen in the resection specimen).
The standard grading system employed by pathologists at Royal North Shore Hospital will be used to measure tumour regression. This is the system recommended by the RCPA synoptic report for colorectal cancer, based on Ryan R, Gibbons D, Hyland JMP, et al. Pathological response following long-course neoadjuvant chemoradiotherapy for locally advanced rectal cancer. Histopathology 2005; 47:141-6.
measure: Feasibility of conducting additional PET and MRI scans at 6 weeks post-treatment.
time frame: 2 years
description: This will be assessed in terms of whether PET and MR imaging approximately 6 weeks after chemo-irradiation adds any additional predictive value to imaging performed 2 weeks into treatment.
measure: Utility of adding PET scan to the baseline staging of patients
time frame: 2 years
description: This will be measured by whether PET 2 weeks into treatment (combined with already utilised MRI) can independently predict the likelihood of a pathological complete response at surgery.
measure: Pathologic response according to Tumour Regression Grade (TRG)
time frame: 2.5 years
description: A scoring system will be developed based on the degree of response from the PET and MRI scan at 2 weeks incorporating tumour shrinkage (PET and MR), reduction in SUV (PET) and reduction in diffusion (MR) that can best predict the "responders" and "non-responders".
measure: Impact of pCR rates on long term disease control
time frame: 5 years
description: Measured in terms of loco-regional or distant recurrence by 3 years.
arm group label: Assessing response with MRI + PET.
arm group type: Experimental
description: Pre-operative chemo/RT as per standard treatment. Intensity Modulated Radiotherapy (IMRT) / Volumetric Arc Therapy (VMAT) 45Gray/25 fractions with simultaneous integrated Boost of 50Gray/25 fractions + concurrent capecitabine chemotherapy.
Intervention 1 'Early MRI and PET/CT - 2 weeks after commencing chemo/RT' involves additional Multiparametric MRI + PET/CT 2 weeks into chemo/RT Intervention 2 :\'Late MRI and PET/CT 6 weeks post chemo/RT' involves additional Multiparametric MRI + PET/CT 6 weeks post chemo/RT
intervention type: Other
intervention name: Early MRI and PET/CT - 2 weeks after commencing chemo/RT
description: Patients will have an early MRI and PET/CT - 2 weeks after commencing chemo/RT. A limited range PET/CT will look at parameters: SUVmaxm PERCIST, RECIST 1.1, ΔSUV (PET1-2), ΔSUV (early -late), Glycolytic tumour volume (GTV). MRI T2 (1-3mm slice as per NS Radiology protocol and ESGAR guideline) will look at parameters: DWI & ADC value (preferably on a single camera with reproducible ADC value), Local Staging, MRF involvement, EMVI, nodal status, MR volumetry, and desmoplastic reaction.
arm group label: Assessing response with MRI + PET.
other name: Imaging
intervention type: Other
intervention name: Late MRI and PET/CT 6 weeks post chemo/RT
description: Patients will have late a MRI and PET/CT 6 weeks post chemo/RT. A whole body PET/CT will look at parameters: SUVmaxm PERCIST, RECIST 1.1, ΔSUV (PET1-2), ΔSUV (early -late), Glycolytic tumour volume (GTV). MRI T2 (1-3mm slice as per NS Radiology protocol and ESGAR guideline) will look at parameters: DWI & ADC value (preferably on a single camera with reproducible ADC value), Local Staging, MRF involvement, EMVI, nodal status, MR volumetry, and desmoplastic reaction.
arm group label: Assessing response with MRI + PET.
other name: Imaging
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrew Kneebone, MBBS
role: Principal Investigator
affiliation: Royal North Shore Hospital
facility: 
country: Australia
responsible party type: Principal Investigator
investigator affiliation: Royal North Shore Hospital
investigator full name: Professor Andrew Kneebone
investigator title: Associate Professor Andrew Kneebone
mesh term: Rectal Neoplasms
sharing ipd: No