<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/NCT03235427</url>
  </required_header>
  <id_info>
    <org_study_id>IIS-0046</org_study_id>
    <nct_id>NCT03235427</nct_id>
  </id_info>
  <brief_title>The CAROLE (CArdiac Related Oncologic Late Effects) Study</brief_title>
  <acronym>CAROLE</acronym>
  <official_title>The CAROLE (CArdiac Related Oncologic Late Effects) Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwell Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Northwell Health</source>
  <oversight_info>
    <has_dmc>No</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>
      CAROLE seeks to evaluate the relationship between chest Radiation Therapy and coronary artery&#xD;
      disease.&#xD;
&#xD;
      The purpose of CAROLE is to check the heart health of women who received breast cancer&#xD;
      treatments in the past and protect them from future heart disease.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Within the United States, there are an estimated 3.1 million women alive who have&#xD;
      been diagnosed with invasive breast cancer, and approximately 56% of them have received&#xD;
      radiation. Worldwide, there are 1.4 million diagnosed annually and, in 2012, it was the most&#xD;
      commonly diagnosed cancer in women. As patients continue to live longer, cardiac dose-related&#xD;
      toxicity has become an issue which impacts millions globally. Guidelines are sorely needed&#xD;
      for this large at-risk population of women.&#xD;
&#xD;
      Purpose: Radiation therapy to the chest has known cardiac late effects including coronary&#xD;
      artery disease, fibrosis, and valvular dysfunction. Unfortunately, there is no clear evidence&#xD;
      on which radiation doses to cardiac structures cause these late toxicities. As a result,&#xD;
      these effects are often under-recognized until after patients have become symptomatic. More&#xD;
      than half of breast cancer patients are treated with radiation, and many receive incidental&#xD;
      cardiac irradiation. Many of these women also receive systemic therapy which may pose&#xD;
      additional cardiac risks. The investigators data will help to establish baseline rates of&#xD;
      pre-clinical and clinical disease, which can be used to inform preventative guidelines that&#xD;
      are critically needed in this at-risk population. Additionally, the investigators data will&#xD;
      provide a better definition of the radiation dose-relationship associated with cardiac&#xD;
      toxicity so that it will be possible to predict more accurately who is at elevated risk for&#xD;
      iatrogenic cardiac disease.&#xD;
&#xD;
      Research Plan: This study will identify and evaluate 200 breast cancer patients treated at&#xD;
      the investigators institution (&gt;6 years prior) who are at risk for treatment-related cardiac&#xD;
      toxicity. All patients enrolled in the study will receive echocardiograms (echo),&#xD;
      electrocardiograms (EKGs), and coronary calcium (CAC) CT scans in order to comprehensively&#xD;
      evaluate for pre-clinical and clinical cardiac disease. Patients identified as having cardiac&#xD;
      disease during testing will be offered referral to a cardiologist. Patients who received&#xD;
      non-radiation treatments (chemotherapy, hormonal therapy, and/or surgery) will be compared to&#xD;
      radiated patients to establish baseline rates of preclinical and clinical disease. Patients&#xD;
      who received cardiotoxic systemic therapy (doxorubicin, trastuzumab, etc.) will also be&#xD;
      evaluated in subgroup analysis. Among radiation patients, this study proposes a novel method&#xD;
      of risk assessment, which is, to utilize a patient's stored treatment plan (from 2004-2011)&#xD;
      and fuse it with patients current cardiac imaging to delineate an accurate dose relationship&#xD;
      associated with clinical and pre-clinical disease. This is further described in the specific&#xD;
      aims below:&#xD;
&#xD;
      Specific Aim 1: Identify baseline levels of clinical and pre-clinical disease in breast&#xD;
      cancer patients.&#xD;
&#xD;
      Aim 1.1: Delineate the group of patients diagnosed and treated for breast cancer between&#xD;
      2004-2011, enroll health system patients with recent follow up (within 3 years).&#xD;
&#xD;
      Aim 1.2: Perform non-invasive cardiac testing (EKG, echo, CAC CT scans). Aim 1.3: Establish&#xD;
      rates of pre-clinical and clinical disease based on pre-determined criteria.&#xD;
&#xD;
      Specific Aim 2: Create an accurate dosimetric assessment of dose to cardiac structures.&#xD;
&#xD;
      Aim 1.1: Among study patients who received radiation treatment for breast cancer, obtain&#xD;
      stored planning CT simulation scans.&#xD;
&#xD;
      Aim 1.2: Upload CT simulation scans with dosimetric information and delineate cardiac&#xD;
      structures at risk in order to ensure accurate and reproducible target delineation.&#xD;
&#xD;
      Aim 1.3: Fuse the CAC CT scan with the CT simulation scan to accurately assess for dose&#xD;
      correlation between coronary calcium with the dose received.&#xD;
&#xD;
      Aim 1.4: Create a dose-relationship model for the heart and cardiac structures.&#xD;
&#xD;
      Specific Aim 3: Incorporate dosimetric cardiac risk information into the investigators&#xD;
      institution's clinical practice, publish data, and establish updated cardiac guidelines for&#xD;
      women who have received radiation for breast cancer.&#xD;
&#xD;
      The long-term goal of the project is to elucidate specific treatment and radiation&#xD;
      dose-related risks, which will then be used to inform follow-up recommendations and&#xD;
      guidelines. This project will impact the way investigators describe expected cardiac risk to&#xD;
      patients, the way the investigators recommend follow up care, and potentially, the way the&#xD;
      investigators prescribe treatment. At present, all patients receiving radiation for breast&#xD;
      cancer are informed that there is a risk of cardiac late effects, however, no specific&#xD;
      cardiac imaging or intervention is recommended other than routine medical follow up. There is&#xD;
      little distinction given to the side of the cancer, a patient's individual anatomy, or the&#xD;
      projected dose to the anterior heart and cardiac structures. This project will allow&#xD;
      physicians to provide a more accurate risk profile regarding future risk of cardiac&#xD;
      morbidity. If the study reveals a very high rate of pre-clinical atherosclerotic disease, it&#xD;
      also may prompt more routine CAC CT screening.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 27, 2017</start_date>
  <completion_date type="Actual">June 26, 2018</completion_date>
  <primary_completion_date type="Actual">June 26, 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Multimodality Cardiology Assessment- EKG</measure>
    <time_frame>1 Year</time_frame>
    <description>Assess whether radiation to the heart is associated with increased pre-clinical and clinical cardiac disease (as determined by a composite of multimodality cardiology assessments including EKG.&#xD;
Studies will be read using a standard, evidence based, set of criterion and documented using study templates) and compared to patients who did not receive radiation to the heart.&#xD;
All cardiac tests will be reviewed and reported as a composite with one the following; No evidence of disease/unrelated, preclinical disease, or clinical disease (non-numerically) based on the Cardiologists read of the study based on standard Pre-Specified criteria.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Multimodality Cardiology Assessment- Echocardiogram with Strain</measure>
    <time_frame>1 Year</time_frame>
    <description>Assess whether radiation to the heart is associated with increased pre-clinical and clinical cardiac disease (as determined by a composite of multimodality cardiology assessments including Echocardiogram with Strain.&#xD;
All cardiac tests will be reviewed and reported as a composite with one the following; No evidence of disease/unrelated, preclinical disease, or clinical disease (non-numerically) based on the Cardiologists read of the study based on standard Pre-Specified criteria.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Multimodality Cardiology Assessment- Coronary Artery Calcium (CAC) CT</measure>
    <time_frame>1 Year</time_frame>
    <description>Assess whether radiation to the heart is associated with increased pre-clinical and clinical cardiac disease (as determined by a composite of multimodality cardiology assessments including Coronary Artery Calcium (CAC) CT.&#xD;
All cardiac tests will be reviewed and reported as a composite with one the following; No evidence of disease/unrelated, preclinical disease, or clinical disease (non-numerically) based on the Cardiologists read of the study based on standard Pre-Specified criteria.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Agatston Score</measure>
    <time_frame>1 Year</time_frame>
    <description>Individual cardiac structures will be accessed using Agatston score. Agatston score is calculated using a CAC CT scan to measure for the presence of coronary artery disease based on the extent of coronary artery calcification. Specifically the left main, left anterior descending, left circumflex, and right coronary arteries are all read individually and the sum of these cardiac vessels scores is read as the overall Agatston score.&#xD;
Grading of coronary artery disease (based on total calcium score) measure is without units. Score categories are as follows: No evidence of disease/unrelated, preclinical disease, or clinical disease (non-numerically). Higher Agatston score correlates with more coronary artery disease.&#xD;
The assessment of calcium (Agatston score) on CAC CT will be compared to the dose received by the specified vessel as determined using deformable registration with prior radiation imaging (simulation CT scan).</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Composite Assessment of Cardiac Disease</measure>
    <time_frame>1 Year</time_frame>
    <description>Sub-analysis for association of specific oncologic treatment(s) with cardiac disease (as per previously described study templates) will also be performed on patients who received multimodality treatment (RT+ chemotherapy, RT + hormonal treatment, RT+ chemo and hormonal treatment, RT + individual cardio toxic chemotherapies [anthracycline, trastuzumab, etc.]) and on different surgical approaches (lumpectomy and mastectomy). Results will be reported as a single value for each arm/group.</description>
  </other_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">201</enrollment>
  <condition>Coronary Artery Disease</condition>
  <condition>Cardiac Disease</condition>
  <condition>Cardiac Toxicity</condition>
  <condition>Radiation</condition>
  <condition>Radiation Therapy</condition>
  <condition>Atherosclerotic Heart Disease</condition>
  <condition>Cardiotoxicity</condition>
  <condition>Breast Cancer</condition>
  <condition>Lung Cancer</condition>
  <condition>Lymphoma</condition>
  <condition>Cancer</condition>
  <condition>Carcinoma, Intraductal, Noninfiltrating</condition>
  <arm_group>
    <arm_group_label>Received Radiation Therapy(RT)</arm_group_label>
    <description>Patients who had received radiotherapy will be sub-stratified into those who received treatment to the left or right breast.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Did not receive Radiation Therapy (RT)</arm_group_label>
    <description>Patients who did not receive radiation treatment, but received chemotherapy, hormonal therapy, and/or surgery will be used as study controls to compare the prevalence and burden of cardiac disease as compared to radiation patients.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Women aged 18-65 at the time of breast cancer diagnosis, with a minimum of 6 years since&#xD;
        diagnosis, with no history of heart disease prior to participants breast cancer diagnosis.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  If you are a breast cancer survivor who was diagnosed between the ages of ≥ 18-65&#xD;
             years (now at age 26-78).&#xD;
&#xD;
          -  It has been at least 6 years since you were diagnosed.&#xD;
&#xD;
          -  If you did not have a diagnosis of heart disease before* having breast cancer.&#xD;
&#xD;
               -  (*women diagnosed with heart disease after breast cancer may still be eligible)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who are unable to care for themselves or who are unable to come in for&#xD;
             testing due to health conditions or incarceration will be rescheduled or removed in&#xD;
             the case of chronic ineligibility. No vulnerable patient populations will be used in&#xD;
             this study. Patients will be excluded if they have any pre-existing cardiac disease at&#xD;
             the time of diagnosis of their breast cancer (2004-2011).&#xD;
&#xD;
          -  Pregnant and nursing women are ineligible.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <minimum_age>26 Years</minimum_age>
    <maximum_age>78 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lucille Lee, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwell Health</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Lindsay L Puckett, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwell Health</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Northwell Health</name>
      <address>
        <city>Lake Success</city>
        <state>New York</state>
        <zip>11042</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Andersen R, Wethal T, Gunther A, Fossa A, Edvardsen T, Fossa SD, Kjekshus J. Relation of coronary artery calcium score to premature coronary artery disease in survivors &gt;15 years of Hodgkin's lymphoma. Am J Cardiol. 2010 Jan 15;105(2):149-52. doi: 10.1016/j.amjcard.2009.09.005. Epub 2009 Nov 14.</citation>
    <PMID>20102909</PMID>
  </reference>
  <reference>
    <citation>Correa CR, Litt HI, Hwang WT, Ferrari VA, Solin LJ, Harris EE. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol. 2007 Jul 20;25(21):3031-7. doi: 10.1200/JCO.2006.08.6595.</citation>
    <PMID>17634481</PMID>
  </reference>
  <reference>
    <citation>Chang M, Suh J, Kirtani V, Dobrescu A, Haas J, Zeldis S, Shayani S, Hindenburg AA. Coronary Calcium Scanning in Patients after Adjuvant Radiation for Early Breast Cancer and Ductal Carcinoma In situ. Front Oncol. 2013 Sep 25;3:253. doi: 10.3389/fonc.2013.00253. eCollection 2013.</citation>
    <PMID>24093087</PMID>
  </reference>
  <reference>
    <citation>Santoro F, Tarantino N, Pellegrino PL, Caivano M, Lopizzo A, Di Biase M, Brunetti ND. Cardiovascular sequelae of radiation therapy. Clin Res Cardiol. 2014 Dec;103(12):955-67. doi: 10.1007/s00392-014-0718-y. Epub 2014 May 7.</citation>
    <PMID>24803132</PMID>
  </reference>
  <reference>
    <citation>Tjessem KH, Bosse G, Fossa K, Reinertsen KV, Fossa SD, Johansen S, Fossa A. Coronary calcium score in 12-year breast cancer survivors after adjuvant radiotherapy with low to moderate heart exposure - Relationship to cardiac radiation dose and cardiovascular risk factors. Radiother Oncol. 2015 Mar;114(3):328-34. doi: 10.1016/j.radonc.2015.01.006. Epub 2015 Jan 16.</citation>
    <PMID>25600105</PMID>
  </reference>
  <reference>
    <citation>Ng AK. Review of the cardiac long-term effects of therapy for Hodgkin lymphoma. Br J Haematol. 2011 Jul;154(1):23-31. doi: 10.1111/j.1365-2141.2011.08713.x. Epub 2011 May 3.</citation>
    <PMID>21539537</PMID>
  </reference>
  <reference>
    <citation>Feng M, Moran JM, Koelling T, Chughtai A, Chan JL, Freedman L, Hayman JA, Jagsi R, Jolly S, Larouere J, Soriano J, Marsh R, Pierce LJ. Development and validation of a heart atlas to study cardiac exposure to radiation following treatment for breast cancer. Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):10-8. doi: 10.1016/j.ijrobp.2009.10.058. Epub 2010 Apr 24.</citation>
    <PMID>20421148</PMID>
  </reference>
  <reference>
    <citation>Rademaker J, Schoder H, Ariaratnam NS, Strauss HW, Yahalom J, Steingart R, Oeffinger KC. Coronary artery disease after radiation therapy for Hodgkin's lymphoma: coronary CT angiography findings and calcium scores in nine asymptomatic patients. AJR Am J Roentgenol. 2008 Jul;191(1):32-7. doi: 10.2214/AJR.07.3112.</citation>
    <PMID>18562721</PMID>
  </reference>
  <reference>
    <citation>Kim KP, Einstein AJ, Berrington de Gonzalez A. Coronary artery calcification screening: estimated radiation dose and cancer risk. Arch Intern Med. 2009 Jul 13;169(13):1188-94. doi: 10.1001/archinternmed.2009.162.</citation>
    <PMID>19597067</PMID>
  </reference>
  <reference>
    <citation>DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS, Jemal A. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014 Jul-Aug;64(4):252-71. doi: 10.3322/caac.21235. Epub 2014 Jun 1.</citation>
    <PMID>24890451</PMID>
  </reference>
  <reference>
    <citation>Youlden DR, Cramb SM, Dunn NA, Muller JM, Pyke CM, Baade PD. The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 2012 Jun;36(3):237-48. doi: 10.1016/j.canep.2012.02.007. Epub 2012 Mar 27.</citation>
    <PMID>22459198</PMID>
  </reference>
  <reference>
    <citation>Gyenes G, Rutqvist LE, Liedberg A, Fornander T. Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer. Radiother Oncol. 1998 Aug;48(2):185-90. doi: 10.1016/s0167-8140(98)00062-0.</citation>
    <PMID>9783890</PMID>
  </reference>
  <reference>
    <citation>Naghavi M, Falk E, Hecht HS, Jamieson MJ, Kaul S, Berman D, Fayad Z, Budoff MJ, Rumberger J, Naqvi TZ, Shaw LJ, Faergeman O, Cohn J, Bahr R, Koenig W, Demirovic J, Arking D, Herrera VL, Badimon J, Goldstein JA, Rudy Y, Airaksinen J, Schwartz RS, Riley WA, Mendes RA, Douglas P, Shah PK; SHAPE Task Force. From vulnerable plaque to vulnerable patient--Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report. Am J Cardiol. 2006 Jul 17;98(2A):2H-15H. doi: 10.1016/j.amjcard.2006.03.002. Epub 2006 Jun 12.</citation>
    <PMID>16843744</PMID>
  </reference>
  <reference>
    <citation>Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, Correa C, Cutter D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C, Hall P. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013 Mar 14;368(11):987-98. doi: 10.1056/NEJMoa1209825.</citation>
    <PMID>23484825</PMID>
  </reference>
  <reference>
    <citation>Carr ZA, Land CE, Kleinerman RA, Weinstock RW, Stovall M, Griem ML, Mabuchi K. Coronary heart disease after radiotherapy for peptic ulcer disease. Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):842-50. doi: 10.1016/j.ijrobp.2004.07.708.</citation>
    <PMID>15708264</PMID>
  </reference>
  <verification_date>May 2019</verification_date>
  <study_first_submitted>June 6, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <last_update_submitted>May 20, 2019</last_update_submitted>
  <last_update_submitted_qc>May 20, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">May 21, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Northwell Health</investigator_affiliation>
    <investigator_full_name>Lucille Lee</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Coronary</keyword>
  <keyword>Coronary Disease</keyword>
  <keyword>Coronary Arteriosclerosis</keyword>
  <keyword>Heart Disease</keyword>
  <keyword>Cardiotoxicity</keyword>
  <keyword>Breast Cancer</keyword>
  <keyword>Carcinoma</keyword>
  <keyword>Coronary Vessels</keyword>
  <keyword>Radiation</keyword>
  <keyword>Radiation Therapy</keyword>
  <keyword>Coronary Artery Disease</keyword>
  <keyword>CAD</keyword>
  <keyword>RT</keyword>
  <keyword>CT</keyword>
  <keyword>Cardiac toxicity</keyword>
  <keyword>Cardiac calcium score</keyword>
  <keyword>Chest RT</keyword>
  <keyword>Lung Cancer</keyword>
  <keyword>Lymphoma</keyword>
  <keyword>Cardiac CT Scan</keyword>
  <keyword>Coronary Artery</keyword>
  <keyword>Coronary arteries</keyword>
  <keyword>Cardiac Side Effect</keyword>
  <keyword>Cardiac tissue</keyword>
  <keyword>Cardiac</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Intraductal, Noninfiltrating</mesh_term>
    <mesh_term>Coronary Artery Disease</mesh_term>
    <mesh_term>Myocardial Ischemia</mesh_term>
    <mesh_term>Coronary Disease</mesh_term>
    <mesh_term>Heart Diseases</mesh_term>
    <mesh_term>Cardiotoxicity</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03235427
org study id: IIS-0046
nct id: NCT03235427
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
CAROLE seeks to evaluate the relationship between chest Radiation Therapy and coronary artery
      disease.

      The purpose of CAROLE is to check the heart health of women who received breast cancer
      treatments in the past and protect them from future heart disease.
Background: Within the United States, there are an estimated 3.1 million women alive who have
      been diagnosed with invasive breast cancer, and approximately 56% of them have received
      radiation. Worldwide, there are 1.4 million diagnosed annually and, in 2012, it was the most
      commonly diagnosed cancer in women. As patients continue to live longer, cardiac dose-related
      toxicity has become an issue which impacts millions globally. Guidelines are sorely needed
      for this large at-risk population of women.

      Purpose: Radiation therapy to the chest has known cardiac late effects including coronary
      artery disease, fibrosis, and valvular dysfunction. Unfortunately, there is no clear evidence
      on which radiation doses to cardiac structures cause these late toxicities. As a result,
      these effects are often under-recognized until after patients have become symptomatic. More
      than half of breast cancer patients are treated with radiation, and many receive incidental
      cardiac irradiation. Many of these women also receive systemic therapy which may pose
      additional cardiac risks. The investigators data will help to establish baseline rates of
      pre-clinical and clinical disease, which can be used to inform preventative guidelines that
      are critically needed in this at-risk population. Additionally, the investigators data will
      provide a better definition of the radiation dose-relationship associated with cardiac
      toxicity so that it will be possible to predict more accurately who is at elevated risk for
      iatrogenic cardiac disease.

      Research Plan: This study will identify and evaluate 200 breast cancer patients treated at
      the investigators institution (>6 years prior) who are at risk for treatment-related cardiac
      toxicity. All patients enrolled in the study will receive echocardiograms (echo),
      electrocardiograms (EKGs), and coronary calcium (CAC) CT scans in order to comprehensively
      evaluate for pre-clinical and clinical cardiac disease. Patients identified as having cardiac
      disease during testing will be offered referral to a cardiologist. Patients who received
      non-radiation treatments (chemotherapy, hormonal therapy, and/or surgery) will be compared to
      radiated patients to establish baseline rates of preclinical and clinical disease. Patients
      who received cardiotoxic systemic therapy (doxorubicin, trastuzumab, etc.) will also be
      evaluated in subgroup analysis. Among radiation patients, this study proposes a novel method
      of risk assessment, which is, to utilize a patient's stored treatment plan (from 2004-2011)
      and fuse it with patients current cardiac imaging to delineate an accurate dose relationship
      associated with clinical and pre-clinical disease. This is further described in the specific
      aims below:

      Specific Aim 1: Identify baseline levels of clinical and pre-clinical disease in breast
      cancer patients.

      Aim 1.1: Delineate the group of patients diagnosed and treated for breast cancer between
      2004-2011, enroll health system patients with recent follow up (within 3 years).

      Aim 1.2: Perform non-invasive cardiac testing (EKG, echo, CAC CT scans). Aim 1.3: Establish
      rates of pre-clinical and clinical disease based on pre-determined criteria.

      Specific Aim 2: Create an accurate dosimetric assessment of dose to cardiac structures.

      Aim 1.1: Among study patients who received radiation treatment for breast cancer, obtain
      stored planning CT simulation scans.

      Aim 1.2: Upload CT simulation scans with dosimetric information and delineate cardiac
      structures at risk in order to ensure accurate and reproducible target delineation.

      Aim 1.3: Fuse the CAC CT scan with the CT simulation scan to accurately assess for dose
      correlation between coronary calcium with the dose received.

      Aim 1.4: Create a dose-relationship model for the heart and cardiac structures.

      Specific Aim 3: Incorporate dosimetric cardiac risk information into the investigators
      institution's clinical practice, publish data, and establish updated cardiac guidelines for
      women who have received radiation for breast cancer.

      The long-term goal of the project is to elucidate specific treatment and radiation
      dose-related risks, which will then be used to inform follow-up recommendations and
      guidelines. This project will impact the way investigators describe expected cardiac risk to
      patients, the way the investigators recommend follow up care, and potentially, the way the
      investigators prescribe treatment. At present, all patients receiving radiation for breast
      cancer are informed that there is a risk of cardiac late effects, however, no specific
      cardiac imaging or intervention is recommended other than routine medical follow up. There is
      little distinction given to the side of the cancer, a patient's individual anatomy, or the
      projected dose to the anterior heart and cardiac structures. This project will allow
      physicians to provide a more accurate risk profile regarding future risk of cardiac
      morbidity. If the study reveals a very high rate of pre-clinical atherosclerotic disease, it
      also may prompt more routine CAC CT screening.
observational model: Case-Control
time perspective: Prospective
measure: Multimodality Cardiology Assessment- EKG
time frame: 1 Year
description: Assess whether radiation to the heart is associated with increased pre-clinical and clinical cardiac disease (as determined by a composite of multimodality cardiology assessments including EKG.
Studies will be read using a standard, evidence based, set of criterion and documented using study templates) and compared to patients who did not receive radiation to the heart.
All cardiac tests will be reviewed and reported as a composite with one the following; No evidence of disease/unrelated, preclinical disease, or clinical disease (non-numerically) based on the Cardiologists read of the study based on standard Pre-Specified criteria.
measure: Multimodality Cardiology Assessment- Echocardiogram with Strain
time frame: 1 Year
description: Assess whether radiation to the heart is associated with increased pre-clinical and clinical cardiac disease (as determined by a composite of multimodality cardiology assessments including Echocardiogram with Strain.
All cardiac tests will be reviewed and reported as a composite with one the following; No evidence of disease/unrelated, preclinical disease, or clinical disease (non-numerically) based on the Cardiologists read of the study based on standard Pre-Specified criteria.
measure: Multimodality Cardiology Assessment- Coronary Artery Calcium (CAC) CT
time frame: 1 Year
description: Assess whether radiation to the heart is associated with increased pre-clinical and clinical cardiac disease (as determined by a composite of multimodality cardiology assessments including Coronary Artery Calcium (CAC) CT.
All cardiac tests will be reviewed and reported as a composite with one the following; No evidence of disease/unrelated, preclinical disease, or clinical disease (non-numerically) based on the Cardiologists read of the study based on standard Pre-Specified criteria.
measure: Agatston Score
time frame: 1 Year
description: Individual cardiac structures will be accessed using Agatston score. Agatston score is calculated using a CAC CT scan to measure for the presence of coronary artery disease based on the extent of coronary artery calcification. Specifically the left main, left anterior descending, left circumflex, and right coronary arteries are all read individually and the sum of these cardiac vessels scores is read as the overall Agatston score.
Grading of coronary artery disease (based on total calcium score) measure is without units. Score categories are as follows: No evidence of disease/unrelated, preclinical disease, or clinical disease (non-numerically). Higher Agatston score correlates with more coronary artery disease.
The assessment of calcium (Agatston score) on CAC CT will be compared to the dose received by the specified vessel as determined using deformable registration with prior radiation imaging (simulation CT scan).
measure: Composite Assessment of Cardiac Disease
time frame: 1 Year
description: Sub-analysis for association of specific oncologic treatment(s) with cardiac disease (as per previously described study templates) will also be performed on patients who received multimodality treatment (RT+ chemotherapy, RT + hormonal treatment, RT+ chemo and hormonal treatment, RT + individual cardio toxic chemotherapies [anthracycline, trastuzumab, etc.]) and on different surgical approaches (lumpectomy and mastectomy). Results will be reported as a single value for each arm/group.
arm group label: Received Radiation Therapy(RT)
description: Patients who had received radiotherapy will be sub-stratified into those who received treatment to the left or right breast.
arm group label: Did not receive Radiation Therapy (RT)
description: Patients who did not receive radiation treatment, but received chemotherapy, hormonal therapy, and/or surgery will be used as study controls to compare the prevalence and burden of cardiac disease as compared to radiation patients.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
gender based: Yes
minimum age: 26 Years
maximum age: 78 Years
healthy volunteers: No
last name: Lucille Lee, MD
role: Principal Investigator
affiliation: Northwell Health
last name: Lindsay L Puckett, MD
role: Principal Investigator
affiliation: Northwell Health
facility: 
country: United States
citation: Andersen R, Wethal T, Gunther A, Fossa A, Edvardsen T, Fossa SD, Kjekshus J. Relation of coronary artery calcium score to premature coronary artery disease in survivors >15 years of Hodgkin's lymphoma. Am J Cardiol. 2010 Jan 15;105(2):149-52. doi: 10.1016/j.amjcard.2009.09.005. Epub 2009 Nov 14.
PMID: 20102909
citation: Correa CR, Litt HI, Hwang WT, Ferrari VA, Solin LJ, Harris EE. Coronary artery findings after left-sided compared with right-sided radiation treatment for early-stage breast cancer. J Clin Oncol. 2007 Jul 20;25(21):3031-7. doi: 10.1200/JCO.2006.08.6595.
PMID: 17634481
citation: Chang M, Suh J, Kirtani V, Dobrescu A, Haas J, Zeldis S, Shayani S, Hindenburg AA. Coronary Calcium Scanning in Patients after Adjuvant Radiation for Early Breast Cancer and Ductal Carcinoma In situ. Front Oncol. 2013 Sep 25;3:253. doi: 10.3389/fonc.2013.00253. eCollection 2013.
PMID: 24093087
citation: Santoro F, Tarantino N, Pellegrino PL, Caivano M, Lopizzo A, Di Biase M, Brunetti ND. Cardiovascular sequelae of radiation therapy. Clin Res Cardiol. 2014 Dec;103(12):955-67. doi: 10.1007/s00392-014-0718-y. Epub 2014 May 7.
PMID: 24803132
citation: Tjessem KH, Bosse G, Fossa K, Reinertsen KV, Fossa SD, Johansen S, Fossa A. Coronary calcium score in 12-year breast cancer survivors after adjuvant radiotherapy with low to moderate heart exposure - Relationship to cardiac radiation dose and cardiovascular risk factors. Radiother Oncol. 2015 Mar;114(3):328-34. doi: 10.1016/j.radonc.2015.01.006. Epub 2015 Jan 16.
PMID: 25600105
citation: Ng AK. Review of the cardiac long-term effects of therapy for Hodgkin lymphoma. Br J Haematol. 2011 Jul;154(1):23-31. doi: 10.1111/j.1365-2141.2011.08713.x. Epub 2011 May 3.
PMID: 21539537
citation: Feng M, Moran JM, Koelling T, Chughtai A, Chan JL, Freedman L, Hayman JA, Jagsi R, Jolly S, Larouere J, Soriano J, Marsh R, Pierce LJ. Development and validation of a heart atlas to study cardiac exposure to radiation following treatment for breast cancer. Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):10-8. doi: 10.1016/j.ijrobp.2009.10.058. Epub 2010 Apr 24.
PMID: 20421148
citation: Rademaker J, Schoder H, Ariaratnam NS, Strauss HW, Yahalom J, Steingart R, Oeffinger KC. Coronary artery disease after radiation therapy for Hodgkin's lymphoma: coronary CT angiography findings and calcium scores in nine asymptomatic patients. AJR Am J Roentgenol. 2008 Jul;191(1):32-7. doi: 10.2214/AJR.07.3112.
PMID: 18562721
citation: Kim KP, Einstein AJ, Berrington de Gonzalez A. Coronary artery calcification screening: estimated radiation dose and cancer risk. Arch Intern Med. 2009 Jul 13;169(13):1188-94. doi: 10.1001/archinternmed.2009.162.
PMID: 19597067
citation: DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS, Jemal A. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014 Jul-Aug;64(4):252-71. doi: 10.3322/caac.21235. Epub 2014 Jun 1.
PMID: 24890451
citation: Youlden DR, Cramb SM, Dunn NA, Muller JM, Pyke CM, Baade PD. The descriptive epidemiology of female breast cancer: an international comparison of screening, incidence, survival and mortality. Cancer Epidemiol. 2012 Jun;36(3):237-48. doi: 10.1016/j.canep.2012.02.007. Epub 2012 Mar 27.
PMID: 22459198
citation: Gyenes G, Rutqvist LE, Liedberg A, Fornander T. Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer. Radiother Oncol. 1998 Aug;48(2):185-90. doi: 10.1016/s0167-8140(98)00062-0.
PMID: 9783890
citation: Naghavi M, Falk E, Hecht HS, Jamieson MJ, Kaul S, Berman D, Fayad Z, Budoff MJ, Rumberger J, Naqvi TZ, Shaw LJ, Faergeman O, Cohn J, Bahr R, Koenig W, Demirovic J, Arking D, Herrera VL, Badimon J, Goldstein JA, Rudy Y, Airaksinen J, Schwartz RS, Riley WA, Mendes RA, Douglas P, Shah PK; SHAPE Task Force. From vulnerable plaque to vulnerable patient--Part III: Executive summary of the Screening for Heart Attack Prevention and Education (SHAPE) Task Force report. Am J Cardiol. 2006 Jul 17;98(2A):2H-15H. doi: 10.1016/j.amjcard.2006.03.002. Epub 2006 Jun 12.
PMID: 16843744
citation: Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Bronnum D, Correa C, Cutter D, Gagliardi G, Gigante B, Jensen MB, Nisbet A, Peto R, Rahimi K, Taylor C, Hall P. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013 Mar 14;368(11):987-98. doi: 10.1056/NEJMoa1209825.
PMID: 23484825
citation: Carr ZA, Land CE, Kleinerman RA, Weinstock RW, Stovall M, Griem ML, Mabuchi K. Coronary heart disease after radiotherapy for peptic ulcer disease. Int J Radiat Oncol Biol Phys. 2005 Mar 1;61(3):842-50. doi: 10.1016/j.ijrobp.2004.07.708.
PMID: 15708264
responsible party type: Principal Investigator
investigator affiliation: Northwell Health
investigator full name: Lucille Lee
investigator title: Principal Investigator
mesh term: Carcinoma, Intraductal, Noninfiltrating
mesh term: Coronary Artery Disease
mesh term: Myocardial Ischemia
mesh term: Coronary Disease
mesh term: Heart Diseases
mesh term: Cardiotoxicity
sharing ipd: Undecided