<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/NCT02261389</url>
  </required_header>
  <id_info>
    <org_study_id>KRONOS</org_study_id>
    <secondary_id>PONS-S Italy</secondary_id>
    <nct_id>NCT02261389</nct_id>
  </id_info>
  <brief_title>Follow-up of Early Breast Cancer by Dynamic Evaluation of CEA and CA 15.3 Followed by 18FDG-PET</brief_title>
  <official_title>Three-monthly Dynamic Evaluation of CEA and CA 15.3 vs Usual Practice in the Follow-up of Early Breast Cancer Patients: a Randomized Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>IRCCS Azienda Ospedaliero-Universitaria di Bologna</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>PONS-S (Patientenorientierte Nachsorge-Stiftung), Augsburg, Germany</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Azienda ULSS 12 Veneziana</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Fondazione IRCCS Istituto Nazionale dei Tumori, Milano</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>IRCCS Azienda Ospedaliero-Universitaria di Bologna</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main purpose of follow-up in asymptomatic breast cancer patients during and after&#xD;
      adjuvant treatment is to detect breast cancer recurrence and metastatic disease.The aim of&#xD;
      this trial is to verify if, in asymptomatic patients, the serial measurement of serum CEA and&#xD;
      CA 15.3, with diagnostic imaging procedures (18FDG-PET) performed only in case of a critical&#xD;
      increase of serum CEA and CA 15.3 level, can anticipate the diagnosis of breast cancer local&#xD;
      and distant recurrence compared to the usual follow-up practice.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 2014</start_date>
  <completion_date type="Anticipated">December 2030</completion_date>
  <primary_completion_date type="Anticipated">November 2026</primary_completion_date>
  <phase>N/A</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>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time interval between date of randomization and date of diagnosis of disease distant recurrence</measure>
    <time_frame>Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months</time_frame>
    <description>Primary objective of the study is to verify if the experimental arm (serial measurement of serum CEA and CA 15.3 with diagnostic imaging procedures - i.e. 18FDG-PET- performed only in case of critical increase of serum markers level) can anticipate the diagnosis of breast cancer loco-regional (except for in-breast recurrence) or distant metastases compared to the control arm (usual follow-up practice).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Predefined critical difference of CEA and CA15-3</measure>
    <time_frame>Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months</time_frame>
    <description>Secondary objective is to evaluate the Positive Predictive Value (PPV) and the Negative Predictive Value (NPV) of CEA and CA15.3 dynamic changes in the diagnosis of breast cancer loco-regional (except for in-breast recurrence) or distant metastases.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory analysis in the different subtypes</measure>
    <time_frame>Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months</time_frame>
    <description>Secondary objective is to perform an exploratory analysis on diagnostic anticipation in the different subtypes (ER and HER2 status)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Imaging diagnostic tests evaluation</measure>
    <time_frame>Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months</time_frame>
    <description>Secondary objective is to measure how many imaging diagnostic tests will be avoided in the experimental arm compared to the control arm</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient quality of life evaluation</measure>
    <time_frame>Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months</time_frame>
    <description>Secondary objective is to compare the quality of life in the two arms</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">1507</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Arm A, usual follow-up practice</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Imaging studies and serum markers (CEA, CA 15.3, others) performed according to local practice</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B, tumor markers assessment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Serum CEA and CA 15.3 performed every 3 months. No imaging studies allowed in asymptomatic patients: imaging studies (18 FDG-PET) performed only in case of critical increase of CEA and /or CA 15.3 serum levels (+100% for CEA and +75% for CA15.3), even if in the normal range.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Arm B, tumor markers assessment</intervention_name>
    <description>Tumor markers assessment every three months through the study or until disease recurrence</description>
    <arm_group_label>Arm B, tumor markers assessment</arm_group_label>
    <other_name>CEA</other_name>
    <other_name>CA15-3</other_name>
    <other_name>18FDG-PET</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female ≥18 years.&#xD;
&#xD;
          -  Histologically confirmed stage I-III epithelial breast cancer.&#xD;
&#xD;
          -  Adequate surgery of breast and axilla:&#xD;
&#xD;
               1. patients must have undergone either a total mastectomy or breast conserving&#xD;
                  surgery&#xD;
&#xD;
               2. surgical margins of the resected specimen must be histologically free of invasive&#xD;
                  tumor.&#xD;
&#xD;
          -  Cohort 1: if chemotherapy and/or radiotherapy are indicated the patients must be&#xD;
             randomized between 1 month and 2 months from the end of chemotherapy and/or&#xD;
             radiotherapy; if only hormonal adjuvant therapy is indicated the patients must be&#xD;
             randomized within 3 months from the completion of surgery&#xD;
&#xD;
          -  Cohort 2: patients must be randomized in the trial after 5 years of follow-up without&#xD;
             relapse (but within year 6)&#xD;
&#xD;
          -  Signed informed consent obtained prior to any study-specific procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Histologically confirmed stage 0 epithelial breast cancer (carcinoma in situ).&#xD;
&#xD;
          -  Special histologies with a high or low risk of relapse (i.e. sarcoma and tubular&#xD;
             carcinoma)&#xD;
&#xD;
          -  T1a and T1b tumors with all the following characteristics: G1-2 and N0 and RE &gt; 10%,&#xD;
             RPg &gt; 10% and HER2 negative and Ki67≤14%&#xD;
&#xD;
          -  Evidence of distant metastases&#xD;
&#xD;
          -  Patients participating to other clinical trials requiring follow-up not equal to&#xD;
             standard&#xD;
&#xD;
          -  Previous history of cancer within 5 years from randomization (except for appropriately&#xD;
             treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, stage I uterine&#xD;
             cancer, or other non-breast malignancies with an outcome similar to those mentioned&#xD;
             above)&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Claudio Zamagni, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Azienda Ospedaliero-Universitaria di Bologna</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Azienda Sanitaria dell'Alto Adige - Ospedale di Bressanone</name>
      <address>
        <city>Bressanone</city>
        <state>Bolzano</state>
        <zip>39042</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Sanitaria dell'Alto Adige - Ospedale di Merano</name>
      <address>
        <city>Merano</city>
        <state>Bolzano</state>
        <zip>39012</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>ASL13 - Presidio Ospedaliero Mirano, U.O.C. Oncologia ed Ematologia Oncologica</name>
      <address>
        <city>Mirano</city>
        <state>Venezia</state>
        <zip>30035</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero-Universitaria di Bologna, Policlinico S. Orsola-Malpighi, SSD Oncologia Medica Addarii</name>
      <address>
        <city>Bologna</city>
        <zip>40138</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Sanitaria dell'Alto Adige - Ospedale Centrale di Bolzano</name>
      <address>
        <city>Bolzano</city>
        <zip>39100</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Azienda Ospedaliero-Universitaria di Ferrara</name>
      <address>
        <city>Ferrara</city>
        <zip>44124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IRCCS Azienda Ospedaliera S. Maria Nuova di Reggio Emilia</name>
      <address>
        <city>Reggio Emilia</city>
        <zip>42123</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>September 30, 2014</study_first_submitted>
  <study_first_submitted_qc>October 7, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 10, 2014</study_first_posted>
  <last_update_submitted>December 28, 2022</last_update_submitted>
  <last_update_submitted_qc>December 28, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 29, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>IRCCS Azienda Ospedaliero-Universitaria di Bologna</investigator_affiliation>
    <investigator_full_name>Claudio Zamagni MD</investigator_full_name>
    <investigator_title>MD Medical Oncologist</investigator_title>
  </responsible_party>
  <keyword>breast cancer</keyword>
  <keyword>follow-up</keyword>
  <keyword>tumor markers</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <!-- 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/NCT02261389
org study id: KRONOS
secondary id: PONS-S Italy
nct id: NCT02261389
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
The main purpose of follow-up in asymptomatic breast cancer patients during and after
      adjuvant treatment is to detect breast cancer recurrence and metastatic disease.The aim of
      this trial is to verify if, in asymptomatic patients, the serial measurement of serum CEA and
      CA 15.3, with diagnostic imaging procedures (18FDG-PET) performed only in case of a critical
      increase of serum CEA and CA 15.3 level, can anticipate the diagnosis of breast cancer local
      and distant recurrence compared to the usual follow-up practice.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Time interval between date of randomization and date of diagnosis of disease distant recurrence
time frame: Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months
description: Primary objective of the study is to verify if the experimental arm (serial measurement of serum CEA and CA 15.3 with diagnostic imaging procedures - i.e. 18FDG-PET- performed only in case of critical increase of serum markers level) can anticipate the diagnosis of breast cancer loco-regional (except for in-breast recurrence) or distant metastases compared to the control arm (usual follow-up practice).
measure: Predefined critical difference of CEA and CA15-3
time frame: Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months
description: Secondary objective is to evaluate the Positive Predictive Value (PPV) and the Negative Predictive Value (NPV) of CEA and CA15.3 dynamic changes in the diagnosis of breast cancer loco-regional (except for in-breast recurrence) or distant metastases.
measure: Exploratory analysis in the different subtypes
time frame: Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months
description: Secondary objective is to perform an exploratory analysis on diagnostic anticipation in the different subtypes (ER and HER2 status)
measure: Imaging diagnostic tests evaluation
time frame: Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months
description: Secondary objective is to measure how many imaging diagnostic tests will be avoided in the experimental arm compared to the control arm
measure: Patient quality of life evaluation
time frame: Participants will be followed from date of randomization until the date of first documented disease distant recurrence or date of death from any cause, whichever came first, assessed up to 60 months
description: Secondary objective is to compare the quality of life in the two arms
arm group label: Arm A, usual follow-up practice
arm group type: No Intervention
description: Imaging studies and serum markers (CEA, CA 15.3, others) performed according to local practice
arm group label: Arm B, tumor markers assessment
arm group type: Experimental
description: Serum CEA and CA 15.3 performed every 3 months. No imaging studies allowed in asymptomatic patients: imaging studies (18 FDG-PET) performed only in case of critical increase of CEA and /or CA 15.3 serum levels (+100% for CEA and +75% for CA15.3), even if in the normal range.
intervention type: Other
intervention name: Arm B, tumor markers assessment
description: Tumor markers assessment every three months through the study or until disease recurrence
arm group label: Arm B, tumor markers assessment
other name: CEA
other name: CA15-3
other name: 18FDG-PET
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Claudio Zamagni, MD
role: Principal Investigator
affiliation: Azienda Ospedaliero-Universitaria di Bologna
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Italy
responsible party type: Principal Investigator
investigator affiliation: IRCCS Azienda Ospedaliero-Universitaria di Bologna
investigator full name: Claudio Zamagni MD
investigator title: MD Medical Oncologist
mesh term: Breast Neoplasms