<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/NCT03297788</url>
  </required_header>
  <id_info>
    <org_study_id>ENCEPHALON</org_study_id>
    <nct_id>NCT03297788</nct_id>
  </id_info>
  <brief_title>Whole Brain Radiation Therapy Alone vs. Radiosurgery for SCLC Patients With 1-10 Brain Metastases</brief_title>
  <acronym>ENCEPHALON</acronym>
  <official_title>Whole Brain Radiation Therapy (WBRT) Alone Versus Radiosurgery (SRS) for Patients With 1-10 Brain Metastases From Small Cell Lung Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Juergen Debus</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Heidelberg University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University Hospital Heidelberg</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>
      Patients suffering from small cell lung cancer (SCLC) are at high risk for developing brain&#xD;
      metastases (BM). To prevent a clinical manifestation of preexisting microscopic brain&#xD;
      dissemination, prophylactic cranial irradiation (PCI) is offered to both limited and&#xD;
      extensive disease patients, if they respond to first line regime, thus being at risk or at&#xD;
      chance to develop clinical brain metastases. However, up to 10-15% of patients present with&#xD;
      BM at initial diagnosis. If MRI is used as a diagnostic tool for initial staging the number&#xD;
      even increases up to 15-20%. Additionally, between 40 - 50% of patients develop BM until time&#xD;
      of death and the risk of developing BM further increases with prolonged survival. Treatment&#xD;
      options are usually limited to WBRT and palliative chemotherapy but the actual effect of&#xD;
      therapeutic WBRT has mainly been studied in small retrospective and nonrandomized studies.&#xD;
      WBRT has been established as the treatment standard in patients with cerebral metastases from&#xD;
      SCLC, however, it has only modest efficacy. Results might be improved by additional dose&#xD;
      escalation. A SRS to cerebral metastases may be indicated in patients with intracranial&#xD;
      disease, and the current protocol is aimed at exploring the neurocognition and efficacy of&#xD;
      SCLC in patients with brain metastases treated with SRS or WBRT.&#xD;
&#xD;
      The present trial aims to exploratory investigate the treatment response to ´conventional&#xD;
      whole brain radiotherapy´ (WBRT) and ´stereotactic radiotherapy´(SRS) in SCLC patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Scientific Background: Patients suffering from BM from SCLC have a poor prognosis with a&#xD;
      median survival ranging between 2-14 months. Treatment options for BM in SCLC are usually&#xD;
      limited to WBRT, steroids or palliative chemotherapy. SCLC patients demonstrate an exception&#xD;
      in the treatment of BM, because treatment options for a limited number of BM from other solid&#xD;
      tumors commonly include surgery or SRS with or without WBRT. Even though SCLC is a&#xD;
      radiosensitive tumor, higher doses are commonly not applied. Locally ablative treatments like&#xD;
      SRS or surgery are less frequently used in patients with BM from SCLC as compared to other&#xD;
      types of cancer due to the high incidence of brain metastases in SCLC and the increased&#xD;
      likelihood of a diffuse failure pattern. It is of general belief that BM from SCLC are rarely&#xD;
      solitary and usually occur at multiple sites. The investigators could not confirm these&#xD;
      findings from this analysis as they found 1-5 BM in 39 % of their patients. WBRT, with a&#xD;
      treatment time of about two weeks, is commonly the technique of choice for SCLC patients with&#xD;
      any number of BM. In a recent Japanese trial, prophylactic cranial irradiation did not result&#xD;
      in longer overall survival compared with observation in patients with early disease (ED)&#xD;
      SCLC. PCI is therefore no longer recommended for patients with ED SCLC when patients receive&#xD;
      regularly MRI examinations during follow-up.&#xD;
&#xD;
      Though, the initial response to cranial irradiation is good, especially in the synchronous&#xD;
      setting, SCLC patients are at high risk of developing intracranial recurrence. In the&#xD;
      investigators´ retrospective analysis median Overall survival (OS) after re-WBRT was only 2&#xD;
      months and the median OS after SRS was 6 months. These results are similar as compared to&#xD;
      results for re-irradiation after PCI. In a recent analysis the investigators reported a&#xD;
      prolonged survival for patients treated with SRS in the recurrent setting after previous PCI&#xD;
      with a median survival of 5 months.&#xD;
&#xD;
      Therefore, the number of patients with oligometastatic cerebral disease might rise. Based on&#xD;
      recursive partitioning Analysis (RPA) classification, the investigators found a median&#xD;
      survival after WBRT of 17 months in RPA class I, 7 months in class II and 3 months in class&#xD;
      III (p&lt;0.0001), which is comparable to previous analyses using graded prognostic assessment&#xD;
      (GPA) scoring. This is further of special interest as patients in RPA class I had a&#xD;
      comparable or even better outcome than patients with non-cerebral disease treated with PCI.&#xD;
      On the other hand, patients with RPA class III should be carefully selected for WBRT and&#xD;
      treatment should be weighed against supportive therapy with steroids alone. This implicates&#xD;
      that patient selection is mandatory, even in SCLC, and that the general paradigm of WBRT&#xD;
      needs to be reevaluated.&#xD;
&#xD;
      Trial Objectives: The purpose of this trial is to explore the neurocognitive response in&#xD;
      patients with brain metastases from SCLC treated with WBRT or SRS. The investigators proposed&#xD;
      that patients treated with SRS would have inferior neurocognitive function based on the&#xD;
      Hopkins Verbal Learning Test-Revised (HVLT-R) compared with patients treated with SRS alone.&#xD;
&#xD;
      Patients Selection: Patients with a diagnosis of brain metastases from SCLC will be evaluated&#xD;
      and screened based on the protocol. All patients fulfilling the inclusion and exclusion&#xD;
      criteria will be informed about the possibility to participate in the study. Registration for&#xD;
      the study must be performed prior to beginning of RT. 56 patients will be enrolled in this&#xD;
      exploratory clinical trial.&#xD;
&#xD;
      Trial Design: This pilot trial will be conducted as a single-center prospective, randomized,&#xD;
      two-arm Phase II study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 1, 2017</start_date>
  <completion_date type="Anticipated">October 2024</completion_date>
  <primary_completion_date type="Anticipated">October 2023</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Neurocognition</measure>
    <time_frame>3 month after treatment</time_frame>
    <description>Drop of at least 5 Points from baseline in HVLT-R test (Hopkins Verbal Learning Test-Revised)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Intracranial progression</measure>
    <time_frame>up to 12 month after treatment</time_frame>
    <description>number of new cerebral metastases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intracranial progression</measure>
    <time_frame>up to 12 month after treatment</time_frame>
    <description>Change in tumor size</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>12 month OS</time_frame>
    <description>Duration of survival defined as the interval between the date of RT begin and the date of death or date of leaving the study e.g., lost to follow up) whatever occurs first.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death due to brain metastases</measure>
    <time_frame>up to 12 month after treatment</time_frame>
    <description>Death which directly connects to existing brain metastases</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Locally progression-free survival</measure>
    <time_frame>up to 12 month after treatment</time_frame>
    <description>12 month Progression-fee survival referring to local tumour progression</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>12 month PFS</time_frame>
    <description>12 month Progression-free survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in other cognitive performance measures</measure>
    <time_frame>up to 12 month after treatment</time_frame>
    <description>HVLT_R</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>up to 12 month after treatment</time_frame>
    <description>BN20 QoL Questionaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>up to 12 month after treatment</time_frame>
    <description>EORTC QoL Questionaire PAL (palliative)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in other cognitive performance measures</measure>
    <time_frame>up to 12 month after treatment</time_frame>
    <description>CANTAB Test</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">56</enrollment>
  <condition>SCLC</condition>
  <condition>Brain Metastases</condition>
  <arm_group>
    <arm_group_label>Arm A: SRS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patient receive stereotactic radiosurgery (SRS), dose prescription according to the size of radiated brain metastases</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B: WBRT</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients receive whole brain radiotherapy (WBRT)</description>
  </arm_group>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>SRS</intervention_name>
    <description>For SRS the dose prescription to the PTV will be as follows:&#xD;
20 Gy to the 70%-isodose (lesions &lt; 2 cm max. diameter)&#xD;
18 Gy to the 70%-isodose (lesions 2 - 3 cm max. diameter)&#xD;
6 x 5 Gy to the conformally surrounding isodose (lesions &gt; 3 cm max. diameter)</description>
    <arm_group_label>Arm A: SRS</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>WBRT</intervention_name>
    <description>WBRT will be applied in 10 fractions with single doses of 3 Gy to the whole brain.</description>
    <arm_group_label>Arm B: WBRT</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  histologically confirmed small cell lung cancer (SCLC)&#xD;
&#xD;
          -  Magentic resonance (MR)-imaging confirmed cerebral metastases (no resection, max.&#xD;
             number of 10)&#xD;
&#xD;
          -  age ≥ 18 years of Age&#xD;
&#xD;
          -  For women with childbearing potential, (and men) adequate contraception.&#xD;
&#xD;
          -  Ability of subject to understand character and individual consequences of the clinical&#xD;
             trial&#xD;
&#xD;
          -  Written informed consent (must be available before enrolment in the trial)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        refusal of the patients to take part in the study&#xD;
&#xD;
          -  previous radiotherapy of the brain&#xD;
&#xD;
          -  Patients who have not yet recovered from acute high-grade toxicities of prior&#xD;
             therapies&#xD;
&#xD;
          -  Known carcinoma &lt; 5 years ago (excluding Carcinoma in situ of the cervix, basal cell&#xD;
             carcinoma, squamous cell carcinoma of the skin) requiring immediate treatment&#xD;
             interfering with study therapy&#xD;
&#xD;
          -  Pregnant or lactating women&#xD;
&#xD;
          -  Participation in another competing clinical study or observation period of competing&#xD;
             trials, respectively&#xD;
&#xD;
          -  MRI contraindication (i.e. cardiac pacemaker, implanted defibrillator, certain cardiac&#xD;
             valve replacements, certain metal implants)&#xD;
&#xD;
          -  Karnofsky score (KPS) &lt;60&#xD;
&#xD;
          -  Simultaneous cytotoxic chemotherapy&#xD;
&#xD;
          -  Last application of chemotherapy/immunotherapy/targeted therapy &lt;1 week before&#xD;
             cerebral radiotherapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stefan Rieken, PD.Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>chief senior physician in the department of Radiation Oncology</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Stefan Rieken, PD. Dr.</last_name>
    <phone>+49 6221 56</phone>
    <phone_ext>8200</phone_ext>
    <email>stefan.rieken@med.uni-heidelberg.de</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Denise Bernhardt, Dr.</last_name>
    <phone>+49 6221 56</phone>
    <phone_ext>8200</phone_ext>
    <email>denise.bernhardt@med.uni-heidelberg.de</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University Hospital of Heidelberg, Department of Radiation Oncology</name>
      <address>
        <city>Heidelberg</city>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Juergen Debus, Prof. Dr.Dr.</last_name>
      <phone>+49 6221 56</phone>
      <phone_ext>8200</phone_ext>
      <email>juergen.debus@med.uni-heidelberg.de</email>
    </contact>
    <investigator>
      <last_name>Rami El Shafie, Dr.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
    <investigator>
      <last_name>Angela Paul, Dr.</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
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    <citation>Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, Postmus P, Collette L, Musat E, Senan S; EORTC Radiation Oncology Group and Lung Cancer Group. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-72. doi: 10.1056/NEJMoa071780.</citation>
    <PMID>17699816</PMID>
  </reference>
  <reference>
    <citation>Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Mueller RP, Tridello G, Collette L, Bottomley A. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol. 2013 Jan 1;31(1):65-72. doi: 10.1200/JCO.2011.41.0639. Epub 2012 Dec 3.</citation>
    <PMID>23213105</PMID>
  </reference>
  <reference>
    <citation>Son CH, Jimenez R, Niemierko A, Loeffler JS, Oh KS, Shih HA. Outcomes after whole brain reirradiation in patients with brain metastases. Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):e167-72. doi: 10.1016/j.ijrobp.2011.03.020. Epub 2011 May 27.</citation>
    <PMID>21620583</PMID>
  </reference>
  <reference>
    <citation>Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, Bhatt A, Jensen AW, Brown PD, Shih H, Kirkpatrick J, Schwer A, Gaspar LE, Fiveash JB, Chiang V, Knisely J, Sperduto CM, Mehta M. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):655-61. doi: 10.1016/j.ijrobp.2009.08.025. Epub 2009 Nov 26.</citation>
    <PMID>19942357</PMID>
  </reference>
  <reference>
    <citation>Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, Fiveash JB, Chiang V, Knisely JP, Sperduto CM, Lin N, Mehta M. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012 Feb 1;30(4):419-25. doi: 10.1200/JCO.2011.38.0527. Epub 2011 Dec 27.</citation>
    <PMID>22203767</PMID>
  </reference>
  <reference>
    <citation>Takahashi T, Yamanaka T, Seto T, Harada H, Nokihara H, Saka H, Nishio M, Kaneda H, Takayama K, Ishimoto O, Takeda K, Yoshioka H, Tachihara M, Sakai H, Goto K, Yamamoto N. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017 May;18(5):663-671. doi: 10.1016/S1470-2045(17)30230-9. Epub 2017 Mar 23.</citation>
    <PMID>28343976</PMID>
  </reference>
  <reference>
    <citation>Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, Xu W, Sahgal A. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012 Apr 18;2012(4):CD003869. doi: 10.1002/14651858.CD003869.pub3.</citation>
    <PMID>22513917</PMID>
  </reference>
  <reference>
    <citation>Welzel G, Fleckenstein K, Schaefer J, Hermann B, Kraus-Tiefenbacher U, Mai SK, Wenz F. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys. 2008 Dec 1;72(5):1311-8. doi: 10.1016/j.ijrobp.2008.03.009. Epub 2008 Apr 28.</citation>
    <PMID>18448270</PMID>
  </reference>
  <reference>
    <citation>Wong WW, Schild SE, Sawyer TE, Shaw EG. Analysis of outcome in patients reirradiated for brain metastases. Int J Radiat Oncol Biol Phys. 1996 Feb 1;34(3):585-90. doi: 10.1016/0360-3016(95)02156-6.</citation>
    <PMID>8621282</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>September 19, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 29, 2017</study_first_posted>
  <last_update_submitted>November 2, 2022</last_update_submitted>
  <last_update_submitted_qc>November 2, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 3, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University Hospital Heidelberg</investigator_affiliation>
    <investigator_full_name>Juergen Debus</investigator_full_name>
    <investigator_title>Director of the Department Radiation Oncology</investigator_title>
  </responsible_party>
  <keyword>SCLC</keyword>
  <keyword>Brain Metastases</keyword>
  <keyword>SRS (stereotactic radiosurgery)</keyword>
  <keyword>WBRT (whole brain radiotherapy)</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasm Metastasis</mesh_term>
    <mesh_term>Brain Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03297788
org study id: ENCEPHALON
nct id: NCT03297788
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Patients suffering from small cell lung cancer (SCLC) are at high risk for developing brain
      metastases (BM). To prevent a clinical manifestation of preexisting microscopic brain
      dissemination, prophylactic cranial irradiation (PCI) is offered to both limited and
      extensive disease patients, if they respond to first line regime, thus being at risk or at
      chance to develop clinical brain metastases. However, up to 10-15% of patients present with
      BM at initial diagnosis. If MRI is used as a diagnostic tool for initial staging the number
      even increases up to 15-20%. Additionally, between 40 - 50% of patients develop BM until time
      of death and the risk of developing BM further increases with prolonged survival. Treatment
      options are usually limited to WBRT and palliative chemotherapy but the actual effect of
      therapeutic WBRT has mainly been studied in small retrospective and nonrandomized studies.
      WBRT has been established as the treatment standard in patients with cerebral metastases from
      SCLC, however, it has only modest efficacy. Results might be improved by additional dose
      escalation. A SRS to cerebral metastases may be indicated in patients with intracranial
      disease, and the current protocol is aimed at exploring the neurocognition and efficacy of
      SCLC in patients with brain metastases treated with SRS or WBRT.

      The present trial aims to exploratory investigate the treatment response to ´conventional
      whole brain radiotherapy´ (WBRT) and ´stereotactic radiotherapy´(SRS) in SCLC patients.
Scientific Background: Patients suffering from BM from SCLC have a poor prognosis with a
      median survival ranging between 2-14 months. Treatment options for BM in SCLC are usually
      limited to WBRT, steroids or palliative chemotherapy. SCLC patients demonstrate an exception
      in the treatment of BM, because treatment options for a limited number of BM from other solid
      tumors commonly include surgery or SRS with or without WBRT. Even though SCLC is a
      radiosensitive tumor, higher doses are commonly not applied. Locally ablative treatments like
      SRS or surgery are less frequently used in patients with BM from SCLC as compared to other
      types of cancer due to the high incidence of brain metastases in SCLC and the increased
      likelihood of a diffuse failure pattern. It is of general belief that BM from SCLC are rarely
      solitary and usually occur at multiple sites. The investigators could not confirm these
      findings from this analysis as they found 1-5 BM in 39 % of their patients. WBRT, with a
      treatment time of about two weeks, is commonly the technique of choice for SCLC patients with
      any number of BM. In a recent Japanese trial, prophylactic cranial irradiation did not result
      in longer overall survival compared with observation in patients with early disease (ED)
      SCLC. PCI is therefore no longer recommended for patients with ED SCLC when patients receive
      regularly MRI examinations during follow-up.

      Though, the initial response to cranial irradiation is good, especially in the synchronous
      setting, SCLC patients are at high risk of developing intracranial recurrence. In the
      investigators´ retrospective analysis median Overall survival (OS) after re-WBRT was only 2
      months and the median OS after SRS was 6 months. These results are similar as compared to
      results for re-irradiation after PCI. In a recent analysis the investigators reported a
      prolonged survival for patients treated with SRS in the recurrent setting after previous PCI
      with a median survival of 5 months.

      Therefore, the number of patients with oligometastatic cerebral disease might rise. Based on
      recursive partitioning Analysis (RPA) classification, the investigators found a median
      survival after WBRT of 17 months in RPA class I, 7 months in class II and 3 months in class
      III (p<0.0001), which is comparable to previous analyses using graded prognostic assessment
      (GPA) scoring. This is further of special interest as patients in RPA class I had a
      comparable or even better outcome than patients with non-cerebral disease treated with PCI.
      On the other hand, patients with RPA class III should be carefully selected for WBRT and
      treatment should be weighed against supportive therapy with steroids alone. This implicates
      that patient selection is mandatory, even in SCLC, and that the general paradigm of WBRT
      needs to be reevaluated.

      Trial Objectives: The purpose of this trial is to explore the neurocognitive response in
      patients with brain metastases from SCLC treated with WBRT or SRS. The investigators proposed
      that patients treated with SRS would have inferior neurocognitive function based on the
      Hopkins Verbal Learning Test-Revised (HVLT-R) compared with patients treated with SRS alone.

      Patients Selection: Patients with a diagnosis of brain metastases from SCLC will be evaluated
      and screened based on the protocol. All patients fulfilling the inclusion and exclusion
      criteria will be informed about the possibility to participate in the study. Registration for
      the study must be performed prior to beginning of RT. 56 patients will be enrolled in this
      exploratory clinical trial.

      Trial Design: This pilot trial will be conducted as a single-center prospective, randomized,
      two-arm Phase II study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Neurocognition
time frame: 3 month after treatment
description: Drop of at least 5 Points from baseline in HVLT-R test (Hopkins Verbal Learning Test-Revised)
measure: Intracranial progression
time frame: up to 12 month after treatment
description: number of new cerebral metastases
measure: Intracranial progression
time frame: up to 12 month after treatment
description: Change in tumor size
measure: Overall survival (OS)
time frame: 12 month OS
description: Duration of survival defined as the interval between the date of RT begin and the date of death or date of leaving the study e.g., lost to follow up) whatever occurs first.
measure: Death due to brain metastases
time frame: up to 12 month after treatment
description: Death which directly connects to existing brain metastases
measure: Locally progression-free survival
time frame: up to 12 month after treatment
description: 12 month Progression-fee survival referring to local tumour progression
measure: Progression-free survival (PFS)
time frame: 12 month PFS
description: 12 month Progression-free survival
measure: Changes in other cognitive performance measures
time frame: up to 12 month after treatment
description: HVLT_R
measure: Quality of life
time frame: up to 12 month after treatment
description: BN20 QoL Questionaire
measure: Quality of life
time frame: up to 12 month after treatment
description: EORTC QoL Questionaire PAL (palliative)
measure: Changes in other cognitive performance measures
time frame: up to 12 month after treatment
description: CANTAB Test
arm group label: Arm A: SRS
arm group type: Experimental
description: Patient receive stereotactic radiosurgery (SRS), dose prescription according to the size of radiated brain metastases
arm group label: Arm B: WBRT
arm group type: Active Comparator
description: Patients receive whole brain radiotherapy (WBRT)
intervention type: Radiation
intervention name: SRS
description: For SRS the dose prescription to the PTV will be as follows:
20 Gy to the 70%-isodose (lesions < 2 cm max. diameter)
18 Gy to the 70%-isodose (lesions 2 - 3 cm max. diameter)
6 x 5 Gy to the conformally surrounding isodose (lesions > 3 cm max. diameter)
arm group label: Arm A: SRS
intervention type: Radiation
intervention name: WBRT
description: WBRT will be applied in 10 fractions with single doses of 3 Gy to the whole brain.
arm group label: Arm B: WBRT
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Stefan Rieken, PD.Dr.
role: Principal Investigator
affiliation: chief senior physician in the department of Radiation Oncology
last name: Stefan Rieken, PD. Dr.
phone: +49 6221 56
phone ext: 8200
email: stefan.rieken@med.uni-heidelberg.de
last name: Denise Bernhardt, Dr.
phone: +49 6221 56
phone ext: 8200
email: denise.bernhardt@med.uni-heidelberg.de
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: Germany
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PMID: 18495375
citation: Slotman B, Faivre-Finn C, Kramer G, Rankin E, Snee M, Hatton M, Postmus P, Collette L, Musat E, Senan S; EORTC Radiation Oncology Group and Lung Cancer Group. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-72. doi: 10.1056/NEJMoa071780.
PMID: 17699816
citation: Soffietti R, Kocher M, Abacioglu UM, Villa S, Fauchon F, Baumert BG, Fariselli L, Tzuk-Shina T, Kortmann RD, Carrie C, Ben Hassel M, Kouri M, Valeinis E, van den Berge D, Mueller RP, Tridello G, Collette L, Bottomley A. A European Organisation for Research and Treatment of Cancer phase III trial of adjuvant whole-brain radiotherapy versus observation in patients with one to three brain metastases from solid tumors after surgical resection or radiosurgery: quality-of-life results. J Clin Oncol. 2013 Jan 1;31(1):65-72. doi: 10.1200/JCO.2011.41.0639. Epub 2012 Dec 3.
PMID: 23213105
citation: Son CH, Jimenez R, Niemierko A, Loeffler JS, Oh KS, Shih HA. Outcomes after whole brain reirradiation in patients with brain metastases. Int J Radiat Oncol Biol Phys. 2012 Feb 1;82(2):e167-72. doi: 10.1016/j.ijrobp.2011.03.020. Epub 2011 May 27.
PMID: 21620583
citation: Sperduto PW, Chao ST, Sneed PK, Luo X, Suh J, Roberge D, Bhatt A, Jensen AW, Brown PD, Shih H, Kirkpatrick J, Schwer A, Gaspar LE, Fiveash JB, Chiang V, Knisely J, Sperduto CM, Mehta M. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):655-61. doi: 10.1016/j.ijrobp.2009.08.025. Epub 2009 Nov 26.
PMID: 19942357
citation: Sperduto PW, Kased N, Roberge D, Xu Z, Shanley R, Luo X, Sneed PK, Chao ST, Weil RJ, Suh J, Bhatt A, Jensen AW, Brown PD, Shih HA, Kirkpatrick J, Gaspar LE, Fiveash JB, Chiang V, Knisely JP, Sperduto CM, Lin N, Mehta M. Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol. 2012 Feb 1;30(4):419-25. doi: 10.1200/JCO.2011.38.0527. Epub 2011 Dec 27.
PMID: 22203767
citation: Takahashi T, Yamanaka T, Seto T, Harada H, Nokihara H, Saka H, Nishio M, Kaneda H, Takayama K, Ishimoto O, Takeda K, Yoshioka H, Tachihara M, Sakai H, Goto K, Yamamoto N. Prophylactic cranial irradiation versus observation in patients with extensive-disease small-cell lung cancer: a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2017 May;18(5):663-671. doi: 10.1016/S1470-2045(17)30230-9. Epub 2017 Mar 23.
PMID: 28343976
citation: Tsao MN, Lloyd N, Wong RK, Chow E, Rakovitch E, Laperriere N, Xu W, Sahgal A. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev. 2012 Apr 18;2012(4):CD003869. doi: 10.1002/14651858.CD003869.pub3.
PMID: 22513917
citation: Welzel G, Fleckenstein K, Schaefer J, Hermann B, Kraus-Tiefenbacher U, Mai SK, Wenz F. Memory function before and after whole brain radiotherapy in patients with and without brain metastases. Int J Radiat Oncol Biol Phys. 2008 Dec 1;72(5):1311-8. doi: 10.1016/j.ijrobp.2008.03.009. Epub 2008 Apr 28.
PMID: 18448270
citation: Wong WW, Schild SE, Sawyer TE, Shaw EG. Analysis of outcome in patients reirradiated for brain metastases. Int J Radiat Oncol Biol Phys. 1996 Feb 1;34(3):585-90. doi: 10.1016/0360-3016(95)02156-6.
PMID: 8621282
responsible party type: Sponsor-Investigator
investigator affiliation: University Hospital Heidelberg
investigator full name: Juergen Debus
investigator title: Director of the Department Radiation Oncology
mesh term: Neoplasm Metastasis
mesh term: Brain Neoplasms
sharing ipd: No