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Whole Brain Radiation Therapy Alone vs. Radiosurgery for SCLC Patients With 1-10 Brain Metastases (ENCEPHALON)

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ClinicalTrials.gov Identifier: NCT03297788
Recruitment Status : Recruiting
First Posted : September 29, 2017
Last Update Posted : January 9, 2020
Sponsor:
Collaborator:
Heidelberg University
Information provided by (Responsible Party):
Juergen Debus, University Hospital Heidelberg

Tracking Information
First Submitted Date  ICMJE September 19, 2017
First Posted Date  ICMJE September 29, 2017
Last Update Posted Date January 9, 2020
Actual Study Start Date  ICMJE December 1, 2017
Estimated Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 26, 2017)
Neurocognition [ Time Frame: 3 month after treatment ]
Drop of at least 5 Points from baseline in HVLT-R test (Hopkins Verbal Learning Test-Revised)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 2, 2017)
  • Intracranial progression [ Time Frame: up to 12 month after treatment ]
    number of new cerebral metastases
  • Intracranial progression [ Time Frame: up to 12 month after treatment ]
    Change in tumor size
  • Overall survival (OS) [ Time Frame: 12 month OS ]
    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.
  • Death due to brain metastases [ Time Frame: up to 12 month after treatment ]
    Death which directly connects to existing brain metastases
  • Locally progression-free survival [ Time Frame: up to 12 month after treatment ]
    12 month Progression-fee survival referring to local tumour progression
  • Progression-free survival (PFS) [ Time Frame: 12 month PFS ]
    12 month Progression-free survival
  • Changes in other cognitive performance measures [ Time Frame: up to 12 month after treatment ]
    HVLT_R
  • Quality of life [ Time Frame: up to 12 month after treatment ]
    BN20 QoL Questionaire
  • Quality of life [ Time Frame: up to 12 month after treatment ]
    EORTC QoL Questionaire PAL (palliative)
  • Changes in other cognitive performance measures [ Time Frame: up to 12 month after treatment ]
    CANTAB Test
Original Secondary Outcome Measures  ICMJE
 (submitted: September 26, 2017)
  • Intracranial progression [ Time Frame: up to 12 month after treatment ]
    number of new cerebral metastases
  • Intracranial progression [ Time Frame: up to 12 month after treatment ]
    Change in tumor size
  • Overall survival [ Time Frame: 12 month OS ]
    Duration of suvival 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.
  • Death due to brain metastases [ Time Frame: up to 12 month after treatment ]
    Death which directly connects to existing brain metastases
  • Locally progression-free survival [ Time Frame: up to 12 month after treatment ]
    12 month Progression-fee survival referring to local tumour progression
  • Progression-free survival [ Time Frame: 12 month PFS ]
    12 month Progression-free survival
  • Changes in other cognitive performance measures [ Time Frame: up to 12 month after treatment ]
    HVLT_R
  • Quality of life [ Time Frame: up to 12 month after treatment ]
    BN20 QOL
  • Quality of life [ Time Frame: up to 12 month after treatment ]
    EORTC QoL Questionaire PAL
  • Changes in other cognitive performance measures [ Time Frame: up to 12 month after treatment ]
    CANTAB Test
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Whole Brain Radiation Therapy Alone vs. Radiosurgery for SCLC Patients With 1-10 Brain Metastases
Official Title  ICMJE Whole Brain Radiation Therapy (WBRT) Alone Versus Radiosurgery (SRS) for Patients With 1-10 Brain Metastases From Small Cell Lung Cancer
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • SCLC
  • Brain Metastases
Intervention  ICMJE
  • Radiation: SRS

    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)
  • Radiation: WBRT
    WBRT will be applied in 10 fractions with single doses of 3 Gy to the whole brain.
Study Arms  ICMJE
  • Experimental: Arm A: SRS
    Patient receive stereotactic radiosurgery (SRS), dose prescription according to the size of radiated brain metastases
    Intervention: Radiation: SRS
  • Active Comparator: Arm B: WBRT
    Patients receive whole brain radiotherapy (WBRT)
    Intervention: Radiation: WBRT
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 26, 2017)
56
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2020
Estimated Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • histologically confirmed small cell lung cancer (SCLC)
  • Magentic resonance (MR)-imaging confirmed cerebral metastases (no resection, max. number of 10)
  • age ≥ 18 years of Age
  • For women with childbearing potential, (and men) adequate contraception.
  • Ability of subject to understand character and individual consequences of the clinical trial
  • Written informed consent (must be available before enrolment in the trial)

Exclusion Criteria:

refusal of the patients to take part in the study

  • previous radiotherapy of the brain
  • Patients who have not yet recovered from acute high-grade toxicities of prior therapies
  • Known carcinoma < 5 years ago (excluding Carcinoma in situ of the cervix, basal cell carcinoma, squamous cell carcinoma of the skin) requiring immediate treatment interfering with study therapy
  • Pregnant or lactating women
  • Participation in another competing clinical study or observation period of competing trials, respectively
  • MRI contraindication (i.e. cardiac pacemaker, implanted defibrillator, certain cardiac valve replacements, certain metal implants)
  • Karnofsky score (KPS) <60
  • Simultaneous cytotoxic chemotherapy
  • Last application of chemotherapy/immunotherapy/targeted therapy <1 week before cerebral radiotherapy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Stefan Rieken, PD. Dr. +49 6221 56 ext 8200 stefan.rieken@med.uni-heidelberg.de
Contact: Denise Bernhardt, Dr. +49 6221 56 ext 8200 denise.bernhardt@med.uni-heidelberg.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03297788
Other Study ID Numbers  ICMJE S-470/2017
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Juergen Debus, University Hospital Heidelberg
Study Sponsor  ICMJE Juergen Debus
Collaborators  ICMJE Heidelberg University
Investigators  ICMJE
Principal Investigator: Stefan Rieken, PD.Dr. chief senior physician in the department of Radiation Oncology
PRS Account University Hospital Heidelberg
Verification Date August 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP