<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/NCT03783364</url>
  </required_header>
  <id_info>
    <org_study_id>EC /2018/0996</org_study_id>
    <nct_id>NCT03783364</nct_id>
  </id_info>
  <brief_title>Pre- or Postoperative Accelerated Radiotherapy</brief_title>
  <acronym>POP-ART</acronym>
  <official_title>Feasibility Study on Pre or Postoperative Accelerated Radiotherapy (POP-ART) in Breast Cancer Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Ghent</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Kom Op Tegen Kanker</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital, Ghent</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      20 non-metastasized breast cancer patients receiving neoadjuvant chemotherapy will be&#xD;
      randomized between preop or postop RT. Patients with clinically suspicious axillary lymph&#xD;
      nodes will receive a fine needle biopsy. Patients receiving postop RT will receive&#xD;
      neoadjuvant CT followed by surgery (21-28 days after CT) and adjuvant RT starting 28-35 days&#xD;
      after surgery. Patients receiving preop RT will receive RT first, followed by CT (5-8 days&#xD;
      after the end of RT) and surgery (21-28 days after CT). All patients will receive a clip to&#xD;
      locate the tumor before the start of any treatment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In early-stage breast cancer the cornerstone of treatment is surgery. There are 2&#xD;
      possibilities: either mastectomy (ME, the whole breast, including the tumour, is removed) or&#xD;
      breast-conserving surgery (BCS, only the tumour is removed, along with a part of the&#xD;
      surrounding healthy tissue). After surgery, most patients also receive some kind of adjuvant&#xD;
      systemic therapy like hormone therapy, chemotherapy (CT), targeted therapy or a combination&#xD;
      of these. After BCS, adjuvant radiotherapy (RT) has shown to improve locoregional control and&#xD;
      overall survival rates. After ME, a benefit of adjuvant RT was observed only in node positive&#xD;
      patients. In recent years, adjuvant or postoperative (postop) CT is more and more replaced by&#xD;
      preoperative (preop) or neo-adjuvant CT in patients with large tumours since the need for&#xD;
      mastectomy may then be significantly decreased. Several randomized controlled trials&#xD;
      demonstrated that there is no difference in overall survival whether CT is given pre- or&#xD;
      postoperatively.&#xD;
&#xD;
      The use of breast RT in the neo-adjuvant setting is far less common. It has been proposed for&#xD;
      patients with inoperable or inflammatory breast cancer and a recent retrospective study in&#xD;
      breast cancer patients showed preop RT might improve disease free survival compared to postop&#xD;
      RT. In another retrospective study comparing neoadjuvant versus adjuvant radio- and&#xD;
      chemotherapy a possible benefit of neoadjuvant treatment was suggested for tumours larger&#xD;
      than 2 cm. These benefits have also been observed in other cancer sites. There is evidence&#xD;
      from randomized trials that preop RT is more effective than postop RT in patients with rectal&#xD;
      carcinoma. For soft tissue sarcoma, better local control rates have been described with preop&#xD;
      than with postop RT. From a radiobiological point of view, the benefits of giving RT&#xD;
      preoperatively are not surprising. In contrast to the postop setting, the vasculature is&#xD;
      still intact and less radioresistant tumour clones are present, both possibly increasing&#xD;
      radiosensitivity. But there are other advantages of preop RT treatment. On the postop imaging&#xD;
      used for RT planning, the localisation of the initial tumor is challenging, even with the aid&#xD;
      of surgical clips. This is especially the case in patients receiving chemotherapy which is&#xD;
      typically given before RT, thus increasing the interval between surgery and radiotherapy to&#xD;
      about 6 months. In this 6-month period, tissue distortion and seroma, which are useful to&#xD;
      guide the radiation oncologist when delineating the target volume for boost irradiation, have&#xD;
      often disappeared. In the postop setting, larger volumes are delineated and interobserver&#xD;
      variability is larger than in the preop setting. Preop breast irradiation has the advantage&#xD;
      that the tumour is still in place and easy to locate. Zones of higher doses can be better&#xD;
      targeted. For the latter reason, less acute side effects and a better overall breast cosmesis&#xD;
      is expected. There is also a possibility of downsizing the tumour which might lead to a lower&#xD;
      need for mastectomy. While preop breast RT clearly has some advantages, there are some&#xD;
      obstacles that complicate its introduction into daily practice. One of these is the fear of&#xD;
      delaying surgery and/or chemotherapy for too long. At Ghent University, investigators have&#xD;
      experience with a 5-fraction RT schedule allowing preop RT delivery in a very short time&#xD;
      span. Large randomized trials confirm that moderate hypofractionation schemes in 15 or 16&#xD;
      fractions are at least equivalent in tumor control and toxicity although the total dose is&#xD;
      lower than the traditional 50 Gy in 25 fractions. Further acceleration to 5 fractions is&#xD;
      expected to have an even greater radiobiological advantage concerning tumor control. In the&#xD;
      UK FAST randomized trial, a schedule of 5 times 5.7 Gy, once a week, was compared to a&#xD;
      normofractionation schedule of 25 times 2 Gy. Tumor control and toxicity were comparable&#xD;
      after 3 years of follow-up. At Ghent University Hospital (UZ Gent) a feasibility trial was&#xD;
      started using the FAST scheme (5 x 5.7 Gy) over 12 days (instead of 5 weeks) in patients of&#xD;
      65 years or older. Additionally, patients requiring a boost received a simultaneously&#xD;
      integrated boost to the tumor bed of 5 x 6.5 Gy. The final analysis on 95 patients shows &lt;10%&#xD;
      grade 2-3 erythema, with only one case of moist desquamation, located at a skin fold(10).&#xD;
      With this RT schedule of 5 fractions in 12 days given preoperatively, the investigators&#xD;
      hypothesize that overall treatment time will not be increased.&#xD;
&#xD;
      The 3 main objectives of this project are: 1 - to prove the feasibility of preop breast RT in&#xD;
      5 fractions in patients also receiving neoadjuvant CT; 2 - to identify the involved cell&#xD;
      death mechanisms and the effect of preop breast RT on the in-situ immune micro-environment;&#xD;
      and 3 - to identify the markers that predict for response and toxicity.&#xD;
&#xD;
      Classically, radiotherapy is considered to mediate its effects via the direct killing of&#xD;
      cancer cells. It is now known that radiotherapy can induce systemic effects resulting in&#xD;
      tumour responses outside the irradiated regions. This phenomenon called the &quot;abscopal&quot;-effect&#xD;
      has been reported in breast and several kinds of malignancies and is nowadays considered to&#xD;
      be immune mediated. The hypothesis is that radiotherapy induces immunogenic cell death (ICD)&#xD;
      through the release of tumour-associated antigens and damage associated molecular patterns&#xD;
      (DAMPs), which leads to antigen uptake and dendritic cell maturation, resulting in the&#xD;
      priming and clonal expansion of cytotoxic T-lymphocytes (CTLs) in the lymph nodes. These CTLs&#xD;
      then travel back to the tumour, becoming tumour-infiltrating lymphocytes (TILs). Radiation&#xD;
      could increase these TILs in a clinical setting and, more importantly, a high level of&#xD;
      (post-therapy) TILs is associated with a good prognosis. Immunogenic cell death implicates&#xD;
      the release of DAMPs and tumoral antigens through a disintegrated cell plasma membrane. The&#xD;
      latter correlates with necrosis (regulated or secondary) instead of apoptosis, which was&#xD;
      considered to be the principal mechanism of radiation induced cell death for years. Distinct&#xD;
      cell death modalities may thus have a different (immunogenic) outcome. In this project the&#xD;
      investigators would like to determine the mode of cell death evoked by high-dose&#xD;
      pre-operative RT through measurement by immunohistochemistry (IHC) of cell death markers on&#xD;
      pre-treatment, post-RT (only in case of pre-operative RT) as well as tumorectomy tissue&#xD;
      samples. The investigators will correlate the results of the IHC stainings for cell death&#xD;
      markers with the presence (or increase) of tumour infiltrating lymphocytes (TILs) in the same&#xD;
      tissue samples and response to treatment. The number of TILs before and after radiotherapy&#xD;
      will be assessed according to international guidelines.&#xD;
&#xD;
      Extracellular vesicles (EVs), such as exosomes (50-150 nm) are composed of a lipid bilayer&#xD;
      that contains transmembrane proteins (such as receptors and adhesion molecules) derived from&#xD;
      the donor cell and encloses soluble hydrophilic components derived from the cytosol of the&#xD;
      donor cell such as signaling molecules, and nucleic acids (small RNAs such as miRNA).&#xD;
      Different cell types can release EVs, including immune cells (monocytes, neutrophils, etc.),&#xD;
      tumour cells, fibroblasts and adipocytes (fat cells). EVs are promising novel biomarkers&#xD;
      because: 1) their molecular content is a fingerprint of the releasing cells and their status&#xD;
      and consists of proteins, lipids, and nucleic acids, 2) they are released in easily&#xD;
      accessible body fluids including blood and 3) they are enriched for highly selected&#xD;
      biomarkers which otherwise would constitute only a very small proportion (less than 0.01%) of&#xD;
      the total molecular content of blood. Analysis of Glypican-1 positive EVs in circulation&#xD;
      distinguishes with absolute specificity and sensitivity healthy subjects and patients with a&#xD;
      benign pancreatic disease from patients with early- and late-stage pancreatic cancer. EV&#xD;
      transfer from stromal to breast cancer cells regulates therapy resistance pathways. miRNA&#xD;
      levels in circulating EVs identify remnant vital tumour tissue and are suitable to measure&#xD;
      therapy response and relapse monitoring. These pioneering studies suggest that quantification&#xD;
      and characterization of EVs can be implemented to predict therapy response.&#xD;
&#xD;
      20 non-metastasized female breast cancer patients receiving neoadjuvant chemotherapy (CT)&#xD;
      will be randomized between preop or postop RT. For each patient, a biopsy with tumor&#xD;
      histology, histological grade, ER/PR status, Her2/Neu status (amplification or not) and Ki67&#xD;
      status will be available. Menopausal status will be assessed before the start of treatment.&#xD;
      Patients with regular menses will be considered premenopausal. Patients &gt; 50 years old with &gt;&#xD;
      1 year of amenorrhea will be considered postmenopausal. In all other patients or patients&#xD;
      with an intrauterine device or hysterectomy, plasma levels of LH, FSH and estradiol will be&#xD;
      measured and documented.&#xD;
&#xD;
      Patients with clinically suspicious axillary lymph nodes will receive a fine needle biopsy.&#xD;
      If lymph node involvement is confirmed by fine needle biopsy, they will receive an axillary&#xD;
      clearance after neoadjuvant treatment and axillary RT will be performed (either preop or&#xD;
      postop). In clinically node negative patients with a tumour of ≤ 5 cm, a sentinel node biopsy&#xD;
      will be performed before the start of RT or CT. Patients with a tumour of &gt; 5 cm, clinically&#xD;
      node negative, will receive axillary clearance and axillary RT since a sentinel node biopsy&#xD;
      is unreliable in these large tumours. Patients receiving postop RT will receive neoadjuvant&#xD;
      CT followed by surgery (21-28 days after CT) and adjuvant RT starting 28-35 days after&#xD;
      surgery. Patients receiving preop RT will receive RT first, followed by CT (5-8 days after&#xD;
      the end of RT) and surgery (21-28 days after CT). All patients will receive a clip to locate&#xD;
      the tumor before the start of any treatment.&#xD;
&#xD;
      The feasibility of preop RT will be evaluated based on overall treatment time. From a&#xD;
      clinical point of view, it is not warranted that preop RT leads to an increase in the overall&#xD;
      treatment time, since this may compromise locoregional control and survival. However, it is&#xD;
      expected that preop RT will shorten the overall treatment time with about 14 days (SD 9 days)&#xD;
      since the interval between RT and CT is shortened considerably. A difference of less than 14&#xD;
      days is not considered clinically relevant. With 20 patients (10 patients in every treatment&#xD;
      arm), a 14 days' difference in overall treatment time can be detected with a power of &gt; 90%&#xD;
      (2-sided t-test, α = 0.05).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 17, 2018</start_date>
  <completion_date type="Actual">November 19, 2021</completion_date>
  <primary_completion_date type="Actual">November 19, 2021</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>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Feasibility of preop RT will be assessed in terms of overall treatment time</measure>
    <time_frame>4 years</time_frame>
    <description>Treatment time will be measured.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Breast symptoms: pain</measure>
    <time_frame>2 years</time_frame>
    <description>none, only on contact, not only on contact, but occasionally, not only on contact and regularly, need for pain medication</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Breast symptoms:Sense of heaviness</measure>
    <time_frame>2 years</time_frame>
    <description>yes, no</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Breast symptoms:Itching</measure>
    <time_frame>2 years</time_frame>
    <description>none, occasionally, regularly</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arm symptoms: pain</measure>
    <time_frame>2 years</time_frame>
    <description>none, occasionally, regularly</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arm symptoms: sense of heaviness</measure>
    <time_frame>2 years</time_frame>
    <description>yes or no</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Shoulder symptoms: pain</measure>
    <time_frame>2 years</time_frame>
    <description>none, occasionally, regularly</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Shoulder symptoms: Impaired mobility</measure>
    <time_frame>2 years</time_frame>
    <description>yes, no</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pain other than breast, shoulder or arm pain</measure>
    <time_frame>2 years</time_frame>
    <description>none, occasionally, regularly</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dysphagia according to the CTCAEE v. 4.03</measure>
    <time_frame>2 years</time_frame>
    <description>None; Symptomatic, able to eat regular diet; Symptomatic and altered eating/swallowing; Severely altered eating/swallowing; tube feeding or TPN or hospitalization indicated; Life-threatening consequences, urgent intervention indicated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dyspnea according to the CTCAE v. 4.03</measure>
    <time_frame>2 years</time_frame>
    <description>None; Shortness of breath with moderate exertion; Shortness of breath with minimal exertion; limiting instrumental ADL; Shortness of breath at rest; limiting self-care ADL; Life-threatening consequences, urgent intervention indicated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cough according to the CTCAE v. 4.03</measure>
    <time_frame>2 years</time_frame>
    <description>None, Mild symptoms, nonprescription intervention indicated, Moderate symptoms, medical intervention indicated; limiting instrumental ADL, Severe symptoms; limiting self-care ADL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fatigue according to the CTCAE v. 4.03</measure>
    <time_frame>2 years</time_frame>
    <description>None; Fatigue relieved by rest; Fatigue not relieved by rest, limiting instrumental ADL; Fatigue not relieved by rest, limiting self-care ADL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Breast edema</measure>
    <time_frame>2 years</time_frame>
    <description>none swelling or obscuration of anatomic architecture on close inspection Readily apparent obscuration of anatomic architecture, obliteration of skin folds; readily apparent deviation from normal anatomic contour, limiting instrumental ADL Gross deviation from normal anatomic contour, limiting self-care ADL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Dermatitis/desquamation according to the CTCAE v. 4.03</measure>
    <time_frame>2 years</time_frame>
    <description>none Faint erythema or dry desquamation Moderate to brisk erythema; moderate edema; patchy moist desquamation, mostly confined to skin folds and creases Moist desquamation in areas other than skin folds and creases; bleeding induced by minor trauma or abrasion2 Life-threatening consequences; skin necrosis or ulceration of full thickness dermis; spontaneous bleeding from involved site; skin graft indicated</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Desquamation</measure>
    <time_frame>2 years</time_frame>
    <description>none dry desquamation moist desquamation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Troponine T value</measure>
    <time_frame>2 years</time_frame>
    <description>in pg/ml</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>identify the involved cell death mechanisms and the effect of preop breast RT on the in-situ immune micro-environment</measure>
    <time_frame>3 years</time_frame>
    <description>Liquid biopsies will be taken at fixed time points to search for biomarkers of response and toxicity. Chromatographic approaches combined with density gradient centrifugation is required to enrich EVs from plasma with minimal remnants of Argonaute-2 protein-miRNA complexes and high-density lipoproteins. Standard operating procedures have been optimized to enrich plasma EVs, to extract proteins/RNA and to perform proteomics/small RNA sequencing. EVs will be isolated following SOPs, quantified by nanoparticle tracking analysis and analysed by label free mass spectrometry and RNA sequencing. Receiver Operating Characteristics illustrate the performance of a biomarker, the sensitivity versus specificity, and will allow the selection of possible optimal EV biomarkers.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>search for biomarkers of response and toxicity</measure>
    <time_frame>4 years</time_frame>
    <description>To determine the mode of cell death evoked by pre-operative RT and its effect on the in-situ immune micro-environment measurement (by immunohistochemistry (IHC)) of cell death markers and TILs will be performed on pre-treatment, post-RT (only in case of pre-operative RT) as well as tumorectomy tissue samples. The results of the IHC stainings for cell death markers will be correlated with the presence (or increase) of TILs in the same tissue samples and response to treatment.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Breast Cancer</condition>
  <condition>Radiation Toxicity</condition>
  <arm_group>
    <arm_group_label>preoperative</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>preoperative radiotherapy</description>
  </arm_group>
  <arm_group>
    <arm_group_label>postoperative</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>postoperative radiotherapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiotherapy</intervention_name>
    <description>Pre- or postoperative acellerated irradition in 5 fractions</description>
    <arm_group_label>postoperative</arm_group_label>
    <arm_group_label>preoperative</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        All of the following inclusion criteria must be met:&#xD;
&#xD;
          -  female patients with non-metastatic breast cancer,&#xD;
&#xD;
          -  biopsy proven,&#xD;
&#xD;
          -  age ≥ 18 years,&#xD;
&#xD;
          -  WHO performance status 0 or 1,&#xD;
&#xD;
          -  using contraceptives if in reproductive age category&#xD;
&#xD;
          -  eligible for neo-adjuvant CT after multidisciplinary decision,&#xD;
&#xD;
          -  informed consent obtained, signed and dated before specific protocol procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Any one or combination of the following:&#xD;
&#xD;
          -  distant metastases,&#xD;
&#xD;
          -  inflammatory breast cancer (mastitis carcinomatosa),&#xD;
&#xD;
          -  multifocal tumor,&#xD;
&#xD;
          -  lobular carcinoma,&#xD;
&#xD;
          -  bilateral breast cancer,&#xD;
&#xD;
          -  history of cancer, with the exception of non-melanoma skin cancer, in situ cervix&#xD;
             carcinoma&#xD;
&#xD;
          -  history of chemotherapy,&#xD;
&#xD;
          -  history of radiation treatment,&#xD;
&#xD;
          -  pregnant or breast feeding, or not using contraceptives if in reproductive age&#xD;
             category&#xD;
&#xD;
          -  exclusion criteria for chemotherapy:&#xD;
&#xD;
               -  leukocytes &lt; 2500&#xD;
&#xD;
               -  absolute neutrophil count &lt; 1000/µL&#xD;
&#xD;
               -  hemoglobine &lt; 8 g/dL (transfusion is allowed)&#xD;
&#xD;
               -  platelets &lt; 100 000/µl&#xD;
&#xD;
               -  total bilirubine &gt; 1.5 x maximal normal reference range&#xD;
&#xD;
               -  AST &gt; 2.5 x maximal normal reference range&#xD;
&#xD;
               -  ALT &gt; 2.5 x maximal normal reference range&#xD;
&#xD;
               -  creatinine &gt; 1.5 x maximal normal reference range&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) &lt; 55%&#xD;
&#xD;
          -  planned immediate reconstructive surgery,&#xD;
&#xD;
          -  conditions making toxicity evaluation difficult (e.g. skin disorders),&#xD;
&#xD;
          -  Amiodarone treatment in the last 6 months&#xD;
&#xD;
          -  patients unlikely to comply with the protocol (e.g. inability to return for follow-up&#xD;
             visits or unlikely to complete the study).&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Department of Radiotherapy, University Hospital Ghent</name>
      <address>
        <city>Ghent</city>
        <state>Oost-Vlaanderen</state>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University Hospital Ghent</name>
      <address>
        <city>Ghent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>January 2023</verification_date>
  <study_first_submitted>October 5, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 21, 2018</study_first_posted>
  <last_update_submitted>January 3, 2023</last_update_submitted>
  <last_update_submitted_qc>January 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 4, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <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/NCT03783364
org study id: EC /2018/0996
nct id: NCT03783364
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
20 non-metastasized breast cancer patients receiving neoadjuvant chemotherapy will be
      randomized between preop or postop RT. Patients with clinically suspicious axillary lymph
      nodes will receive a fine needle biopsy. Patients receiving postop RT will receive
      neoadjuvant CT followed by surgery (21-28 days after CT) and adjuvant RT starting 28-35 days
      after surgery. Patients receiving preop RT will receive RT first, followed by CT (5-8 days
      after the end of RT) and surgery (21-28 days after CT). All patients will receive a clip to
      locate the tumor before the start of any treatment.
In early-stage breast cancer the cornerstone of treatment is surgery. There are 2
      possibilities: either mastectomy (ME, the whole breast, including the tumour, is removed) or
      breast-conserving surgery (BCS, only the tumour is removed, along with a part of the
      surrounding healthy tissue). After surgery, most patients also receive some kind of adjuvant
      systemic therapy like hormone therapy, chemotherapy (CT), targeted therapy or a combination
      of these. After BCS, adjuvant radiotherapy (RT) has shown to improve locoregional control and
      overall survival rates. After ME, a benefit of adjuvant RT was observed only in node positive
      patients. In recent years, adjuvant or postoperative (postop) CT is more and more replaced by
      preoperative (preop) or neo-adjuvant CT in patients with large tumours since the need for
      mastectomy may then be significantly decreased. Several randomized controlled trials
      demonstrated that there is no difference in overall survival whether CT is given pre- or
      postoperatively.

      The use of breast RT in the neo-adjuvant setting is far less common. It has been proposed for
      patients with inoperable or inflammatory breast cancer and a recent retrospective study in
      breast cancer patients showed preop RT might improve disease free survival compared to postop
      RT. In another retrospective study comparing neoadjuvant versus adjuvant radio- and
      chemotherapy a possible benefit of neoadjuvant treatment was suggested for tumours larger
      than 2 cm. These benefits have also been observed in other cancer sites. There is evidence
      from randomized trials that preop RT is more effective than postop RT in patients with rectal
      carcinoma. For soft tissue sarcoma, better local control rates have been described with preop
      than with postop RT. From a radiobiological point of view, the benefits of giving RT
      preoperatively are not surprising. In contrast to the postop setting, the vasculature is
      still intact and less radioresistant tumour clones are present, both possibly increasing
      radiosensitivity. But there are other advantages of preop RT treatment. On the postop imaging
      used for RT planning, the localisation of the initial tumor is challenging, even with the aid
      of surgical clips. This is especially the case in patients receiving chemotherapy which is
      typically given before RT, thus increasing the interval between surgery and radiotherapy to
      about 6 months. In this 6-month period, tissue distortion and seroma, which are useful to
      guide the radiation oncologist when delineating the target volume for boost irradiation, have
      often disappeared. In the postop setting, larger volumes are delineated and interobserver
      variability is larger than in the preop setting. Preop breast irradiation has the advantage
      that the tumour is still in place and easy to locate. Zones of higher doses can be better
      targeted. For the latter reason, less acute side effects and a better overall breast cosmesis
      is expected. There is also a possibility of downsizing the tumour which might lead to a lower
      need for mastectomy. While preop breast RT clearly has some advantages, there are some
      obstacles that complicate its introduction into daily practice. One of these is the fear of
      delaying surgery and/or chemotherapy for too long. At Ghent University, investigators have
      experience with a 5-fraction RT schedule allowing preop RT delivery in a very short time
      span. Large randomized trials confirm that moderate hypofractionation schemes in 15 or 16
      fractions are at least equivalent in tumor control and toxicity although the total dose is
      lower than the traditional 50 Gy in 25 fractions. Further acceleration to 5 fractions is
      expected to have an even greater radiobiological advantage concerning tumor control. In the
      UK FAST randomized trial, a schedule of 5 times 5.7 Gy, once a week, was compared to a
      normofractionation schedule of 25 times 2 Gy. Tumor control and toxicity were comparable
      after 3 years of follow-up. At Ghent University Hospital (UZ Gent) a feasibility trial was
      started using the FAST scheme (5 x 5.7 Gy) over 12 days (instead of 5 weeks) in patients of
      65 years or older. Additionally, patients requiring a boost received a simultaneously
      integrated boost to the tumor bed of 5 x 6.5 Gy. The final analysis on 95 patients shows <10%
      grade 2-3 erythema, with only one case of moist desquamation, located at a skin fold(10).
      With this RT schedule of 5 fractions in 12 days given preoperatively, the investigators
      hypothesize that overall treatment time will not be increased.

      The 3 main objectives of this project are: 1 - to prove the feasibility of preop breast RT in
      5 fractions in patients also receiving neoadjuvant CT; 2 - to identify the involved cell
      death mechanisms and the effect of preop breast RT on the in-situ immune micro-environment;
      and 3 - to identify the markers that predict for response and toxicity.

      Classically, radiotherapy is considered to mediate its effects via the direct killing of
      cancer cells. It is now known that radiotherapy can induce systemic effects resulting in
      tumour responses outside the irradiated regions. This phenomenon called the "abscopal"-effect
      has been reported in breast and several kinds of malignancies and is nowadays considered to
      be immune mediated. The hypothesis is that radiotherapy induces immunogenic cell death (ICD)
      through the release of tumour-associated antigens and damage associated molecular patterns
      (DAMPs), which leads to antigen uptake and dendritic cell maturation, resulting in the
      priming and clonal expansion of cytotoxic T-lymphocytes (CTLs) in the lymph nodes. These CTLs
      then travel back to the tumour, becoming tumour-infiltrating lymphocytes (TILs). Radiation
      could increase these TILs in a clinical setting and, more importantly, a high level of
      (post-therapy) TILs is associated with a good prognosis. Immunogenic cell death implicates
      the release of DAMPs and tumoral antigens through a disintegrated cell plasma membrane. The
      latter correlates with necrosis (regulated or secondary) instead of apoptosis, which was
      considered to be the principal mechanism of radiation induced cell death for years. Distinct
      cell death modalities may thus have a different (immunogenic) outcome. In this project the
      investigators would like to determine the mode of cell death evoked by high-dose
      pre-operative RT through measurement by immunohistochemistry (IHC) of cell death markers on
      pre-treatment, post-RT (only in case of pre-operative RT) as well as tumorectomy tissue
      samples. The investigators will correlate the results of the IHC stainings for cell death
      markers with the presence (or increase) of tumour infiltrating lymphocytes (TILs) in the same
      tissue samples and response to treatment. The number of TILs before and after radiotherapy
      will be assessed according to international guidelines.

      Extracellular vesicles (EVs), such as exosomes (50-150 nm) are composed of a lipid bilayer
      that contains transmembrane proteins (such as receptors and adhesion molecules) derived from
      the donor cell and encloses soluble hydrophilic components derived from the cytosol of the
      donor cell such as signaling molecules, and nucleic acids (small RNAs such as miRNA).
      Different cell types can release EVs, including immune cells (monocytes, neutrophils, etc.),
      tumour cells, fibroblasts and adipocytes (fat cells). EVs are promising novel biomarkers
      because: 1) their molecular content is a fingerprint of the releasing cells and their status
      and consists of proteins, lipids, and nucleic acids, 2) they are released in easily
      accessible body fluids including blood and 3) they are enriched for highly selected
      biomarkers which otherwise would constitute only a very small proportion (less than 0.01%) of
      the total molecular content of blood. Analysis of Glypican-1 positive EVs in circulation
      distinguishes with absolute specificity and sensitivity healthy subjects and patients with a
      benign pancreatic disease from patients with early- and late-stage pancreatic cancer. EV
      transfer from stromal to breast cancer cells regulates therapy resistance pathways. miRNA
      levels in circulating EVs identify remnant vital tumour tissue and are suitable to measure
      therapy response and relapse monitoring. These pioneering studies suggest that quantification
      and characterization of EVs can be implemented to predict therapy response.

      20 non-metastasized female breast cancer patients receiving neoadjuvant chemotherapy (CT)
      will be randomized between preop or postop RT. For each patient, a biopsy with tumor
      histology, histological grade, ER/PR status, Her2/Neu status (amplification or not) and Ki67
      status will be available. Menopausal status will be assessed before the start of treatment.
      Patients with regular menses will be considered premenopausal. Patients > 50 years old with >
      1 year of amenorrhea will be considered postmenopausal. In all other patients or patients
      with an intrauterine device or hysterectomy, plasma levels of LH, FSH and estradiol will be
      measured and documented.

      Patients with clinically suspicious axillary lymph nodes will receive a fine needle biopsy.
      If lymph node involvement is confirmed by fine needle biopsy, they will receive an axillary
      clearance after neoadjuvant treatment and axillary RT will be performed (either preop or
      postop). In clinically node negative patients with a tumour of ≤ 5 cm, a sentinel node biopsy
      will be performed before the start of RT or CT. Patients with a tumour of > 5 cm, clinically
      node negative, will receive axillary clearance and axillary RT since a sentinel node biopsy
      is unreliable in these large tumours. Patients receiving postop RT will receive neoadjuvant
      CT followed by surgery (21-28 days after CT) and adjuvant RT starting 28-35 days after
      surgery. Patients receiving preop RT will receive RT first, followed by CT (5-8 days after
      the end of RT) and surgery (21-28 days after CT). All patients will receive a clip to locate
      the tumor before the start of any treatment.

      The feasibility of preop RT will be evaluated based on overall treatment time. From a
      clinical point of view, it is not warranted that preop RT leads to an increase in the overall
      treatment time, since this may compromise locoregional control and survival. However, it is
      expected that preop RT will shorten the overall treatment time with about 14 days (SD 9 days)
      since the interval between RT and CT is shortened considerably. A difference of less than 14
      days is not considered clinically relevant. With 20 patients (10 patients in every treatment
      arm), a 14 days' difference in overall treatment time can be detected with a power of > 90%
      (2-sided t-test, α = 0.05).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Feasibility of preop RT will be assessed in terms of overall treatment time
time frame: 4 years
description: Treatment time will be measured.
measure: Breast symptoms: pain
time frame: 2 years
description: none, only on contact, not only on contact, but occasionally, not only on contact and regularly, need for pain medication
measure: Breast symptoms:Sense of heaviness
time frame: 2 years
description: yes, no
measure: Breast symptoms:Itching
time frame: 2 years
description: none, occasionally, regularly
measure: Arm symptoms: pain
time frame: 2 years
description: none, occasionally, regularly
measure: Arm symptoms: sense of heaviness
time frame: 2 years
description: yes or no
measure: Shoulder symptoms: pain
time frame: 2 years
description: none, occasionally, regularly
measure: Shoulder symptoms: Impaired mobility
time frame: 2 years
description: yes, no
measure: Pain other than breast, shoulder or arm pain
time frame: 2 years
description: none, occasionally, regularly
measure: Dysphagia according to the CTCAEE v. 4.03
time frame: 2 years
description: None; Symptomatic, able to eat regular diet; Symptomatic and altered eating/swallowing; Severely altered eating/swallowing; tube feeding or TPN or hospitalization indicated; Life-threatening consequences, urgent intervention indicated
measure: Dyspnea according to the CTCAE v. 4.03
time frame: 2 years
description: None; Shortness of breath with moderate exertion; Shortness of breath with minimal exertion; limiting instrumental ADL; Shortness of breath at rest; limiting self-care ADL; Life-threatening consequences, urgent intervention indicated
measure: Cough according to the CTCAE v. 4.03
time frame: 2 years
description: None, Mild symptoms, nonprescription intervention indicated, Moderate symptoms, medical intervention indicated; limiting instrumental ADL, Severe symptoms; limiting self-care ADL
measure: Fatigue according to the CTCAE v. 4.03
time frame: 2 years
description: None; Fatigue relieved by rest; Fatigue not relieved by rest, limiting instrumental ADL; Fatigue not relieved by rest, limiting self-care ADL
measure: Breast edema
time frame: 2 years
description: none swelling or obscuration of anatomic architecture on close inspection Readily apparent obscuration of anatomic architecture, obliteration of skin folds; readily apparent deviation from normal anatomic contour, limiting instrumental ADL Gross deviation from normal anatomic contour, limiting self-care ADL
measure: Dermatitis/desquamation according to the CTCAE v. 4.03
time frame: 2 years
description: none Faint erythema or dry desquamation Moderate to brisk erythema; moderate edema; patchy moist desquamation, mostly confined to skin folds and creases Moist desquamation in areas other than skin folds and creases; bleeding induced by minor trauma or abrasion2 Life-threatening consequences; skin necrosis or ulceration of full thickness dermis; spontaneous bleeding from involved site; skin graft indicated
measure: Desquamation
time frame: 2 years
description: none dry desquamation moist desquamation
measure: Troponine T value
time frame: 2 years
description: in pg/ml
measure: identify the involved cell death mechanisms and the effect of preop breast RT on the in-situ immune micro-environment
time frame: 3 years
description: Liquid biopsies will be taken at fixed time points to search for biomarkers of response and toxicity. Chromatographic approaches combined with density gradient centrifugation is required to enrich EVs from plasma with minimal remnants of Argonaute-2 protein-miRNA complexes and high-density lipoproteins. Standard operating procedures have been optimized to enrich plasma EVs, to extract proteins/RNA and to perform proteomics/small RNA sequencing. EVs will be isolated following SOPs, quantified by nanoparticle tracking analysis and analysed by label free mass spectrometry and RNA sequencing. Receiver Operating Characteristics illustrate the performance of a biomarker, the sensitivity versus specificity, and will allow the selection of possible optimal EV biomarkers.
measure: search for biomarkers of response and toxicity
time frame: 4 years
description: To determine the mode of cell death evoked by pre-operative RT and its effect on the in-situ immune micro-environment measurement (by immunohistochemistry (IHC)) of cell death markers and TILs will be performed on pre-treatment, post-RT (only in case of pre-operative RT) as well as tumorectomy tissue samples. The results of the IHC stainings for cell death markers will be correlated with the presence (or increase) of TILs in the same tissue samples and response to treatment.
arm group label: preoperative
arm group type: Experimental
description: preoperative radiotherapy
arm group label: postoperative
arm group type: Active Comparator
description: postoperative radiotherapy
intervention type: Radiation
intervention name: Radiotherapy
description: Pre- or postoperative acellerated irradition in 5 fractions
arm group label: postoperative
arm group label: preoperative
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: Belgium
responsible party type: Sponsor
mesh term: Breast Neoplasms