<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/NCT02251353</url>
  </required_header>
  <id_info>
    <org_study_id>IMET</org_study_id>
    <nct_id>NCT02251353</nct_id>
  </id_info>
  <brief_title>Intervention to Hepatic and Pulmonary Metastasis in Breast Cancer Patients</brief_title>
  <acronym>IMET</acronym>
  <official_title>Intervention to Hepatic and Pulmonary Metastasis in Breast Cancer Patients: Prospective, Observational, Multi-institutional Registration Study - IMET</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Federation of Breast Diseases Societies</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Federation of Breast Diseases Societies</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The number of intervention performed for metastatic breast cancer has dramatically increased&#xD;
      over the past 2 decades. Hepatectomy and pulmonary resection for stage IV colorectal cancer&#xD;
      is now considered the standard of care for resectable patients with isolated hepatic and/or&#xD;
      pulmonary disease and acceptable performance status. However, the indications for resection /&#xD;
      intervention of breast cancer origin metastases are not as clearly defined. The aim of this&#xD;
      study to focus on emerging data for the intervention (resection and/or radiofrequency&#xD;
      ablation (RFA), transcatheter arterial chemoembolization (TACE), cyberKnife stereotactic&#xD;
      radiosurgery) of breast cancer metastatic disease to the lung and liver, with a focus on&#xD;
      indications for resection / intervention.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Purpose Despite breast cancer being the most common cancer in women in the developed world,&#xD;
      only a minority of patients (&lt; 10%) has stage IV disease at diagnosis (1). In addition,&#xD;
      20-30% of patients with early breast cancer will experience distant metastatic relapse (2).&#xD;
      Due to advances in available multimodality therapies and a better understanding of tumor&#xD;
      biology, survival of stage IV patients is constantly improving (3-5).&#xD;
&#xD;
      Clinically, oligometastatic breast cancer is characterized by solitary/few detectable&#xD;
      lesions, usually limited to single organs, in which local therapy with curative intent could&#xD;
      impact survival. This population of 'potentially curable' stage IV disease is estimated to be&#xD;
      1-10% of newly diagnosed patients with metastatic breast cancer (5). A multimodal approach is&#xD;
      endorsed for these selected patients (5,6). The identification of patients with truly&#xD;
      oligometastatic disease is challenging. Most published series refer to an era before modern&#xD;
      imaging (i.e. positron emission tomography-computed tomography), and thus many patients were&#xD;
      probably understaged, potentially leading to underestimation of the global effect of an&#xD;
      aggressive local management.&#xD;
&#xD;
      Patients with oligometastatic disease can be divided into 3 cohorts (7,8): 1) patients who&#xD;
      present with oligometastases; 2) patients with residual oligometastases after systemic&#xD;
      therapy; and 3) those with relapsed oligometastases after curative locoregional therapy.&#xD;
      These different groups have possibly distinct prognoses, and may need differential&#xD;
      approaches.&#xD;
&#xD;
      Several series have reported on lung and liver metastases resection in oligometastatic breast&#xD;
      cancer and most data are from small series of patients collected over many years. The largest&#xD;
      dataset comes from the International Registry of Lung Metastases and presents results of lung&#xD;
      metastasectomy in 467 breast cancer patients (9). Complete resection was possible in 84% of&#xD;
      patients and led to a median survival of 37 months (5-year OS = 38%, 10-year OS = 22%).&#xD;
      Identified prognostic factors for lung resection include disease-free interval and number of&#xD;
      metastases (disease-free interval &gt;36 months and solitary metastases being the most&#xD;
      favorable), ER status, size of metastases, completeness of resection, and use of anatomical&#xD;
      resection (as opposite to wedge resection) (9-19). Obviously, the reported data refer to a&#xD;
      subset of patients who were selected for favorable prognostic factors, and any comparison&#xD;
      with surgically untreated patients is threatened by serious biases.&#xD;
&#xD;
      Pulmonary resection in metastatic breast cancer patients, apart from its potential&#xD;
      therapeutic value, is also an important diagnostic tool, especially in patients with a&#xD;
      suspected first recurrence, allowing for differential diagnosis with second primary lung&#xD;
      cancers and benign lesions (19,20). The proportion of lesions proved not to be breast cancer&#xD;
      metastases in various series ranges from 7% to 66% (9,14,18,21). As the morbidity and&#xD;
      mortality of pulmonary resection has decreased substantially over the last decades, this&#xD;
      potentially beneficial procedure can be discussed in a selected group of patients (9,19,21).&#xD;
&#xD;
      Surgery to remove liver metastases is an accepted treatment modality in patients with&#xD;
      colorectal cancer (22). Its role in breast cancer is, however, much less recognized. Liver is&#xD;
      a common metastatic breast cancer site, but only 5% of patients have isolated liver&#xD;
      involvement. In various series of hepatic resection for breast cancer metastases, the&#xD;
      reported median survival ranged from 14.5 to 63 months and the 5-year survival from 14% to&#xD;
      61%, in general, comparing well with nonsurgically treated patients. Most of the reported&#xD;
      series, however, describe extremely selected patients, constituting 1% or less of metastatic&#xD;
      breast cancer patients treated over the respective periods of time (22-26). As an example, in&#xD;
      the one of the important series, all patients were asymptomatic and identified through&#xD;
      intensive surveillance programs (27). Patients with isolated liver metastasis can potentially&#xD;
      be managed with local treatments (surgery, radiofrequency ablation (RFA), transcatheter&#xD;
      arterial chemoembolization (TACE), cyberKnife stereotactic radiosurgery). In contrast to&#xD;
      liver colorectal metastases, local treatment for breast cancer liver metastasis is not&#xD;
      considered a therapeutic option due to common involvement of additional organs; nevertheless,&#xD;
      in some selected patients, local approaches have been associated with long-term survival&#xD;
      (10,29,30).&#xD;
&#xD;
      Because patients who are potentially eligible for this therapeutic strategy represent only&#xD;
      1%-3% of the total metastatic breast cancer population, a large global collaboration is&#xD;
      needed to confirm its impact on long-term survival or cure and to ensure adequate statistical&#xD;
      power and strength of the results. Enrolled patients must have comparable clinical and&#xD;
      biological characteristics, extent of staging, and frequency of monitoring to avoid selection&#xD;
      biases and stage migration, which can substantially affect the outcome.&#xD;
&#xD;
      The number of intervention performed for metastatic breast cancer has dramatically increased&#xD;
      over the past 2 decades. Hepatectomy and pulmonary resection for stage IV colorectal cancer&#xD;
      is now considered the standard of care for resectable patients with isolated hepatic and/or&#xD;
      pulmonary disease and acceptable performance status. However, the indications for resection /&#xD;
      intervention of breast cancer origin metastases are not as clearly defined. The aim of this&#xD;
      study to focus on emerging data for the intervention (resection and/or radiofrequency&#xD;
      ablation (RFA), transcatheter arterial chemoembolization (TACE), cyberKnife stereotactic&#xD;
      radiosurgery) of breast cancer metastatic disease to the lung and liver, with a focus on&#xD;
      indications for resection / intervention.&#xD;
&#xD;
      Patient acquisition and data collection All patient should be female. All following&#xD;
      demographic, clinical and tumour specific data will be collected: patient age, performance&#xD;
      status according to the WHO classification at the time of first presentation to the hospital,&#xD;
      stage, type and receptor status (ER, PR, HER-2) of the primary tumour, tumor load in the lung&#xD;
      and/or liver (uni-or bilateral affection, number of metastases, diameter of the largest&#xD;
      tumour size), chronology of the metastases (metachronous or synchronous), presence of further&#xD;
      metastatic (synchronous metastases) or recurrent (metachronous) extrahepatic tumour growth&#xD;
      and lymph node involvement in the mediastinal region or hepatoduodenal ligament. In addition,&#xD;
      treatment-related and follow-up data will be documented: Intervention method (surgical&#xD;
      resection, cryosurgery, laser-induced thermotherapy, radio-frequency ablation, ethanol&#xD;
      injection, cyber-knife), median follow-up, incidence of tumour recurrence, time to&#xD;
      recurrence, overall survival, and the administration of chemotherapy. Survival will be&#xD;
      calculated from the date of diagnosis of the lung and/or liver metastases.&#xD;
&#xD;
      Definitions Lung and/or liver metastases will be defined as metachronous if the interval&#xD;
      between resection of the primary tumour and first diagnosis of metastases is longer than 3&#xD;
      months. General physical condition of study patients will be measured by the performance&#xD;
      status according to the WHO classification.&#xD;
&#xD;
      Prior and during the treatment, all patients will be undergone evaluation with complete&#xD;
      medical history, physical examination, baseline blood tests, and imaging evaluations&#xD;
      (positron emission tomography (PET-CT) and/or radiography, bone scintigraphy, computed&#xD;
      tomography scan, magnetic resonance imaging, ultrasonography). Effects of the treatment will&#xD;
      be monitoring by imaging analyses at every 3 months for lesions detected at diagnosis of lung&#xD;
      and/or hepatic metastasis or every 6 months without detectable lesions before the treatment.&#xD;
&#xD;
      R0 resection is a complete resection with no microscopic residual tumor, while R1 resection&#xD;
      means a complete resection with no grossly visual tumor as defined by surgeon, but&#xD;
      microscopic cancer may be left behind. R2 resection indicates a partial resection with&#xD;
      grossly visible tumor left behind.&#xD;
&#xD;
      Effects of the treatment were assessed by analyses of maximum response, according to either&#xD;
      the criteria of the World Health Organization (WHO) (30) or the Response Evaluation Criteria&#xD;
      in Solid Tumors (RECIST) version 1.0 (31) since its announcement in 2004. Responses in bone&#xD;
      metastases were evaluated using the methods reported by MD Anderson Cancer Center (32,33),&#xD;
      with CR as clear evidence of complete bone recalcification with attainment of near-normal&#xD;
      bone architecture or normalization of scan, and partial response as radio- logical evidence&#xD;
      of sclerosis in lytic lesions or marked improvement of bone scan. In recent years, MRI was&#xD;
      performed when available, and the imaging information was taken into account in evaluation of&#xD;
      bone metastases. Responses in pleural fluids were determined as: CR for radiological&#xD;
      demonstration of complete disappearance of pleural fluid, and PR for 50% or more decrease.&#xD;
      For study inclusion, pathological diagnosis of the primary lesions had to be obtained,&#xD;
      whereas tissue or cellular pathology of the metastatic lesions was preferred but not&#xD;
      mandatory. In patients who performed surgical resection, a complete histopathological&#xD;
      response will be defined as the absence of vital tumour cells. Detection of tumour necrosis&#xD;
      or scar formation within the tumour tissue will be regarded as a partial pathohistological&#xD;
      response.&#xD;
&#xD;
      Ethics committee approval in Istanbul University Istanbul Medical Faculty can be obtained to&#xD;
      participate for this study.&#xD;
&#xD;
      Statistical analysis The characteristics of the patients with assessable data will be&#xD;
      compared with X2 test or Wilcoxon rank-sum tests. Overall survival (OS) will be defined as&#xD;
      duration from diagnosis of the metastasis to last visit or death. Progression free interval&#xD;
      (PFI) will be defined as duration from diagnosis of the metastasis to the point when disease&#xD;
      progression will be detected. Complete response (CR) will be achieved by a systemic therapy&#xD;
      or no evidence of clinical disease (NED) after a local therapy considered relapse-free, and&#xD;
      the duration between induction of relapse free status and the point of relapse detection will&#xD;
      be defined as the relapse free interval (RFI); survival time after induction of relapse-free&#xD;
      status without relapse will be defined as relapse free survival (RFS). Unrelated death other&#xD;
      than from breast cancer will be considered as censored in evaluation of PFI and RFI. Survival&#xD;
      curves will be calculated according to the Kaplan-Meier method. The log-rank test will be&#xD;
      used to evaluate differences in survival between groups with intervention and&#xD;
      no-intervention. A multivariate analysis will be performed by Cox regression and the&#xD;
      following variables will be included: age, DFI, performance status (PS), liver metastasis,&#xD;
      pulmonary metastasis, presence of other metastasis, hormone receptor status, HER2 status,&#xD;
      Ki-67 status, intrinsic subtype, administration of local therapy, and chemotherapy regimens.&#xD;
      Statistical significance will be defined as a p value &lt;0.05. All p values will be calculated&#xD;
      for two-sided analyses. For observed survival, all deaths will be considered as events&#xD;
      including patients who died from secondary causes without recurrence. Statistical analyses&#xD;
      will be performed using SPSS 22.0 (SPSS, Chicago, IL) software.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>June 2014</start_date>
  <completion_date type="Anticipated">June 2022</completion_date>
  <primary_completion_date type="Anticipated">June 2020</primary_completion_date>
  <study_type>Observational [Patient Registry]</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <target_duration>5 Years</target_duration>
  <primary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>3 years</time_frame>
    <description>Time interval between diagnosis and death</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression free survival (PFS)</measure>
    <time_frame>3 years</time_frame>
    <description>Time interval between diagnosis and first date of progression of disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Morbidity due to treatment modality</measure>
    <time_frame>6 months</time_frame>
    <description>Morbidity due to treatment modality</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">300</enrollment>
  <condition>Breast Cancer</condition>
  <condition>Metastasis</condition>
  <arm_group>
    <arm_group_label>lung and/or hepatic metastasis</arm_group_label>
    <description>intervention to metastasis (resection and/or radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), cyberKnife stereotactic radio surgery) vs no intervention (only systemic treatment)</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>intervention</intervention_name>
    <description>hepatic and/or pulmonary resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization, CyberKnife stereotactic radiosurgery</description>
    <arm_group_label>lung and/or hepatic metastasis</arm_group_label>
    <other_name>Surgery, Chemotherapy,stereotactic radiosurgery</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>systemic treatment</intervention_name>
    <description>Systemic therapy</description>
    <arm_group_label>lung and/or hepatic metastasis</arm_group_label>
    <other_name>no intervention</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Breast cancer patients: 1) who present primary tumor with lung and/or hepatic metastases;&#xD;
        2) those with residual lung and/or hepatic metastases after systemic therapy; and 3) those&#xD;
        with relapsed lung and/or hepatic metastases after curative locoregional therapy.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Metastatic breast cancer (lung and/or hepatic metastasis) 18 years and older Antineoplastic&#xD;
        treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        No lung and/or hepatic metastasis Below 18 years No antineoplastic treatment&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lutfi Dogan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ankara Oncology Research and Training Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Beyza Ozcinar, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Istanbul University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Hasan Karanlik, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Istanbul University Institute of Oncology Capa Istanbul</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Atilla Soran</last_name>
    <role>Study Director</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Serdar Ozbas, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Ankara Guven Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Lutfi Dogan, MD</last_name>
    <phone>+905057134549</phone>
    <email>lutfidogan1@yahoo.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Beyza Ozcinar, MD</last_name>
    <email>drbeyza@hotmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Istanbul University Istanbul Medical Faculty</name>
      <address>
        <city>Istanbul</city>
        <country>Turkey</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vahit Ozmen, MD</last_name>
    </contact>
    <investigator>
      <last_name>Neslihan Cabioglu, MD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Turkey</country>
  </location_countries>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>September 25, 2014</study_first_submitted>
  <study_first_submitted_qc>September 25, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 29, 2014</study_first_posted>
  <last_update_submitted>February 19, 2020</last_update_submitted>
  <last_update_submitted_qc>February 19, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 21, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Federation of Breast Diseases Societies</investigator_affiliation>
    <investigator_full_name>Hasan Karanlık</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>breast cancer, intervention to metastasis</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
    <mesh_term>Neoplasm Metastasis</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/NCT02251353
org study id: IMET
nct id: NCT02251353
lead sponsor: 
has dmc: Yes
The number of intervention performed for metastatic breast cancer has dramatically increased
      over the past 2 decades. Hepatectomy and pulmonary resection for stage IV colorectal cancer
      is now considered the standard of care for resectable patients with isolated hepatic and/or
      pulmonary disease and acceptable performance status. However, the indications for resection /
      intervention of breast cancer origin metastases are not as clearly defined. The aim of this
      study to focus on emerging data for the intervention (resection and/or radiofrequency
      ablation (RFA), transcatheter arterial chemoembolization (TACE), cyberKnife stereotactic
      radiosurgery) of breast cancer metastatic disease to the lung and liver, with a focus on
      indications for resection / intervention.
Purpose Despite breast cancer being the most common cancer in women in the developed world,
      only a minority of patients (< 10%) has stage IV disease at diagnosis (1). In addition,
      20-30% of patients with early breast cancer will experience distant metastatic relapse (2).
      Due to advances in available multimodality therapies and a better understanding of tumor
      biology, survival of stage IV patients is constantly improving (3-5).

      Clinically, oligometastatic breast cancer is characterized by solitary/few detectable
      lesions, usually limited to single organs, in which local therapy with curative intent could
      impact survival. This population of 'potentially curable' stage IV disease is estimated to be
      1-10% of newly diagnosed patients with metastatic breast cancer (5). A multimodal approach is
      endorsed for these selected patients (5,6). The identification of patients with truly
      oligometastatic disease is challenging. Most published series refer to an era before modern
      imaging (i.e. positron emission tomography-computed tomography), and thus many patients were
      probably understaged, potentially leading to underestimation of the global effect of an
      aggressive local management.

      Patients with oligometastatic disease can be divided into 3 cohorts (7,8): 1) patients who
      present with oligometastases; 2) patients with residual oligometastases after systemic
      therapy; and 3) those with relapsed oligometastases after curative locoregional therapy.
      These different groups have possibly distinct prognoses, and may need differential
      approaches.

      Several series have reported on lung and liver metastases resection in oligometastatic breast
      cancer and most data are from small series of patients collected over many years. The largest
      dataset comes from the International Registry of Lung Metastases and presents results of lung
      metastasectomy in 467 breast cancer patients (9). Complete resection was possible in 84% of
      patients and led to a median survival of 37 months (5-year OS = 38%, 10-year OS = 22%).
      Identified prognostic factors for lung resection include disease-free interval and number of
      metastases (disease-free interval >36 months and solitary metastases being the most
      favorable), ER status, size of metastases, completeness of resection, and use of anatomical
      resection (as opposite to wedge resection) (9-19). Obviously, the reported data refer to a
      subset of patients who were selected for favorable prognostic factors, and any comparison
      with surgically untreated patients is threatened by serious biases.

      Pulmonary resection in metastatic breast cancer patients, apart from its potential
      therapeutic value, is also an important diagnostic tool, especially in patients with a
      suspected first recurrence, allowing for differential diagnosis with second primary lung
      cancers and benign lesions (19,20). The proportion of lesions proved not to be breast cancer
      metastases in various series ranges from 7% to 66% (9,14,18,21). As the morbidity and
      mortality of pulmonary resection has decreased substantially over the last decades, this
      potentially beneficial procedure can be discussed in a selected group of patients (9,19,21).

      Surgery to remove liver metastases is an accepted treatment modality in patients with
      colorectal cancer (22). Its role in breast cancer is, however, much less recognized. Liver is
      a common metastatic breast cancer site, but only 5% of patients have isolated liver
      involvement. In various series of hepatic resection for breast cancer metastases, the
      reported median survival ranged from 14.5 to 63 months and the 5-year survival from 14% to
      61%, in general, comparing well with nonsurgically treated patients. Most of the reported
      series, however, describe extremely selected patients, constituting 1% or less of metastatic
      breast cancer patients treated over the respective periods of time (22-26). As an example, in
      the one of the important series, all patients were asymptomatic and identified through
      intensive surveillance programs (27). Patients with isolated liver metastasis can potentially
      be managed with local treatments (surgery, radiofrequency ablation (RFA), transcatheter
      arterial chemoembolization (TACE), cyberKnife stereotactic radiosurgery). In contrast to
      liver colorectal metastases, local treatment for breast cancer liver metastasis is not
      considered a therapeutic option due to common involvement of additional organs; nevertheless,
      in some selected patients, local approaches have been associated with long-term survival
      (10,29,30).

      Because patients who are potentially eligible for this therapeutic strategy represent only
      1%-3% of the total metastatic breast cancer population, a large global collaboration is
      needed to confirm its impact on long-term survival or cure and to ensure adequate statistical
      power and strength of the results. Enrolled patients must have comparable clinical and
      biological characteristics, extent of staging, and frequency of monitoring to avoid selection
      biases and stage migration, which can substantially affect the outcome.

      The number of intervention performed for metastatic breast cancer has dramatically increased
      over the past 2 decades. Hepatectomy and pulmonary resection for stage IV colorectal cancer
      is now considered the standard of care for resectable patients with isolated hepatic and/or
      pulmonary disease and acceptable performance status. However, the indications for resection /
      intervention of breast cancer origin metastases are not as clearly defined. The aim of this
      study to focus on emerging data for the intervention (resection and/or radiofrequency
      ablation (RFA), transcatheter arterial chemoembolization (TACE), cyberKnife stereotactic
      radiosurgery) of breast cancer metastatic disease to the lung and liver, with a focus on
      indications for resection / intervention.

      Patient acquisition and data collection All patient should be female. All following
      demographic, clinical and tumour specific data will be collected: patient age, performance
      status according to the WHO classification at the time of first presentation to the hospital,
      stage, type and receptor status (ER, PR, HER-2) of the primary tumour, tumor load in the lung
      and/or liver (uni-or bilateral affection, number of metastases, diameter of the largest
      tumour size), chronology of the metastases (metachronous or synchronous), presence of further
      metastatic (synchronous metastases) or recurrent (metachronous) extrahepatic tumour growth
      and lymph node involvement in the mediastinal region or hepatoduodenal ligament. In addition,
      treatment-related and follow-up data will be documented: Intervention method (surgical
      resection, cryosurgery, laser-induced thermotherapy, radio-frequency ablation, ethanol
      injection, cyber-knife), median follow-up, incidence of tumour recurrence, time to
      recurrence, overall survival, and the administration of chemotherapy. Survival will be
      calculated from the date of diagnosis of the lung and/or liver metastases.

      Definitions Lung and/or liver metastases will be defined as metachronous if the interval
      between resection of the primary tumour and first diagnosis of metastases is longer than 3
      months. General physical condition of study patients will be measured by the performance
      status according to the WHO classification.

      Prior and during the treatment, all patients will be undergone evaluation with complete
      medical history, physical examination, baseline blood tests, and imaging evaluations
      (positron emission tomography (PET-CT) and/or radiography, bone scintigraphy, computed
      tomography scan, magnetic resonance imaging, ultrasonography). Effects of the treatment will
      be monitoring by imaging analyses at every 3 months for lesions detected at diagnosis of lung
      and/or hepatic metastasis or every 6 months without detectable lesions before the treatment.

      R0 resection is a complete resection with no microscopic residual tumor, while R1 resection
      means a complete resection with no grossly visual tumor as defined by surgeon, but
      microscopic cancer may be left behind. R2 resection indicates a partial resection with
      grossly visible tumor left behind.

      Effects of the treatment were assessed by analyses of maximum response, according to either
      the criteria of the World Health Organization (WHO) (30) or the Response Evaluation Criteria
      in Solid Tumors (RECIST) version 1.0 (31) since its announcement in 2004. Responses in bone
      metastases were evaluated using the methods reported by MD Anderson Cancer Center (32,33),
      with CR as clear evidence of complete bone recalcification with attainment of near-normal
      bone architecture or normalization of scan, and partial response as radio- logical evidence
      of sclerosis in lytic lesions or marked improvement of bone scan. In recent years, MRI was
      performed when available, and the imaging information was taken into account in evaluation of
      bone metastases. Responses in pleural fluids were determined as: CR for radiological
      demonstration of complete disappearance of pleural fluid, and PR for 50% or more decrease.
      For study inclusion, pathological diagnosis of the primary lesions had to be obtained,
      whereas tissue or cellular pathology of the metastatic lesions was preferred but not
      mandatory. In patients who performed surgical resection, a complete histopathological
      response will be defined as the absence of vital tumour cells. Detection of tumour necrosis
      or scar formation within the tumour tissue will be regarded as a partial pathohistological
      response.

      Ethics committee approval in Istanbul University Istanbul Medical Faculty can be obtained to
      participate for this study.

      Statistical analysis The characteristics of the patients with assessable data will be
      compared with X2 test or Wilcoxon rank-sum tests. Overall survival (OS) will be defined as
      duration from diagnosis of the metastasis to last visit or death. Progression free interval
      (PFI) will be defined as duration from diagnosis of the metastasis to the point when disease
      progression will be detected. Complete response (CR) will be achieved by a systemic therapy
      or no evidence of clinical disease (NED) after a local therapy considered relapse-free, and
      the duration between induction of relapse free status and the point of relapse detection will
      be defined as the relapse free interval (RFI); survival time after induction of relapse-free
      status without relapse will be defined as relapse free survival (RFS). Unrelated death other
      than from breast cancer will be considered as censored in evaluation of PFI and RFI. Survival
      curves will be calculated according to the Kaplan-Meier method. The log-rank test will be
      used to evaluate differences in survival between groups with intervention and
      no-intervention. A multivariate analysis will be performed by Cox regression and the
      following variables will be included: age, DFI, performance status (PS), liver metastasis,
      pulmonary metastasis, presence of other metastasis, hormone receptor status, HER2 status,
      Ki-67 status, intrinsic subtype, administration of local therapy, and chemotherapy regimens.
      Statistical significance will be defined as a p value <0.05. All p values will be calculated
      for two-sided analyses. For observed survival, all deaths will be considered as events
      including patients who died from secondary causes without recurrence. Statistical analyses
      will be performed using SPSS 22.0 (SPSS, Chicago, IL) software.
observational model: Cohort
time perspective: Prospective
measure: Overall survival (OS)
time frame: 3 years
description: Time interval between diagnosis and death
measure: Progression free survival (PFS)
time frame: 3 years
description: Time interval between diagnosis and first date of progression of disease
measure: Morbidity due to treatment modality
time frame: 6 months
description: Morbidity due to treatment modality
arm group label: lung and/or hepatic metastasis
description: intervention to metastasis (resection and/or radiofrequency ablation (RFA), transcatheter arterial chemoembolization (TACE), cyberKnife stereotactic radio surgery) vs no intervention (only systemic treatment)
intervention type: Procedure
intervention name: intervention
description: hepatic and/or pulmonary resection, radiofrequency ablation (RFA), transcatheter arterial chemoembolization, CyberKnife stereotactic radiosurgery
arm group label: lung and/or hepatic metastasis
other name: Surgery, Chemotherapy,stereotactic radiosurgery
intervention type: Drug
intervention name: systemic treatment
description: Systemic therapy
arm group label: lung and/or hepatic metastasis
other name: no intervention
study pop: 
sampling method: Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lutfi Dogan, MD
role: Principal Investigator
affiliation: Ankara Oncology Research and Training Hospital
last name: Beyza Ozcinar, MD
role: Principal Investigator
affiliation: Istanbul University
last name: Hasan Karanlik, MD
role: Study Chair
affiliation: Istanbul University Institute of Oncology Capa Istanbul
last name: Atilla Soran
role: Study Director
affiliation: University of Pittsburgh
last name: Serdar Ozbas, MD
role: Study Chair
affiliation: Ankara Guven Hospital
last name: Lutfi Dogan, MD
phone: +905057134549
email: lutfidogan1@yahoo.com
last name: Beyza Ozcinar, MD
email: drbeyza@hotmail.com
facility: 
status: Recruiting
contact: 
investigator: 
country: Turkey
responsible party type: Principal Investigator
investigator affiliation: Federation of Breast Diseases Societies
investigator full name: Hasan Karanlık
investigator title: Professor
mesh term: Breast Neoplasms
mesh term: Neoplasm Metastasis
sharing ipd: No