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Stereotactic Radiotherapy of the Resection Cavity of Brain Metastases vs. Post-operative Whole-brain Radiotherapy (ESTRON)

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ClinicalTrials.gov Identifier: NCT03285932
Recruitment Status : Recruiting
First Posted : September 18, 2017
Last Update Posted : March 5, 2018
Sponsor:
Collaborator:
Heidelberg University
Information provided by (Responsible Party):
Juergen Debus, University Hospital Heidelberg

Tracking Information
First Submitted Date  ICMJE September 13, 2017
First Posted Date  ICMJE September 18, 2017
Last Update Posted Date March 5, 2018
Actual Study Start Date  ICMJE February 1, 2018
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 15, 2017)
neurological progression-free survival (PFS) [ Time Frame: 12 months PFS rate ]
Neurologic progression-free survival in follow-up imaging is the primary endpoint of the study. The duration is defined as the time interval between the date start of RT and the date of local and loco-regional progression or death, or the date of leaving the study without local and loco-regional progression (e.g., lost to follow up non-local progression) whatever occurs first. Patients not reported local and loco-regional progressive or dead, or lost to follow-up or non-local progressive will be censored at the date of the last follow-up examination where no signs of local and loco-regional progression were observed.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03285932 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 15, 2017)
  • Overall survival (OS) [ Time Frame: 12 months survival rate ]
    Time interval (days) 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. Patients not reported dead or lost to follow-up will be censored at the date of the last follow-up or the time when last seen alive.
  • Local PFS [ Time Frame: 12 months after treatment ]
    lenght of time (days) till local disease progression
  • Quality of life (QLQ-C30) [ Time Frame: up to 12 months after treatment ]
    Units on a Scale
  • Loco-regional recurrence [ Time Frame: up to 12 months after treatment ]
    Time to loco-regional recurrence
  • Quality of life (BN20) [ Time Frame: up to 12 months after treatment ]
    Units on a Scale
  • Local recurrence [ Time Frame: up to 12 months after treatment ]
    Time to local recurrence
  • Loco-regional PFS [ Time Frame: 12 months after treatment ]
    lenght of time (days) till loco-regional disease progression
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Stereotactic Radiotherapy of the Resection Cavity of Brain Metastases vs. Post-operative Whole-brain Radiotherapy
Official Title  ICMJE Evaluation of Stereotactic Radiotherapy of the Resection Cavity After Surgery of Brain Metastases Compared to Post-operative Whole-brain Radiotherapy
Brief Summary

In advanced cancer disease brain metastases are common, difficult to treat, and are associated with a poor prognosis. As new local and systemic therapies are eventually resulting in improved survival and quality of life for patients with brain metastases, negative neurocognitive effects of radiation therapy are becoming increasingly important as well as good loco-regional disease control of brain metastases.

Concerning treatment, brain metastases remain a major clinical problem and a multidisciplinary approach to management should be adopted. Neurosurgical resection with postoperative whole brain radiotherapy (WBRT) is one major treatment option in solitary or symptomatic brain metastases. Furthermore, WBRT is recommended for multiple brain metastases. For a limited number of brain metastases stereotactic radiosurgery (SRS) has been established as a highly effective treatment alternative.

Recently, a new treatment approach combing neurosurgery with postoperative stereotactic radiotherapy (SRT) of the resection cavity is emerging. Based on available evidence, postoperative SRT of the resection cavity improves local control following surgery, reduces the number of patients who require whole brain radiotherapy, and is well tolerated (1).

This protocol is aimed at primarily evaluating the safety and toxicity profile of SRT to the resection cavity following neurosurgical resection combined with SRT of potentially further unresected brain metastases, compared to postoperative whole-brain radiotherapy (WBRT). Secondary, the local effect of SRT in patients with brain metastases will be assessed by measuring time to local recurrence (LR), local and loco-regional progression-free survival (PFS).

Additional systemic treatment will be carried out according to the standards of the National Center for Tumor Therapy (NCT).

Detailed Description

Scientific Background: Brain metastases (BM) represent a significant healthcare problem. It is estimated that 20% to 40% of patients with cancer will develop metastatic cancer to the brain during the course of their illness 1. The most common primary sites are lung, melanoma, renal, breast and colorectal cancer 2. Options for patients with brain metastases had been limited to whole brain radiotherapy (WBRT) or supportive care alone, and systemic chemotherapy was often discontinued. Historically, the best possible supportive care or whole-brain radiotherapy (WBRT) were the standard of care 1 aiming at temporary symptom relief. For WBRT, efficacy in symptom relief but also in prolongation of the median survival time by 3-6 months is well documented. To date, microsurgical approaches and SRS, both proved to be safe and efficient, offer alternative treatment options that potentially meet these concerns 6,7. After proving its efficacy in achieving local tumor control in the treated volume, SRS was used as a stand-alone treatment option in patients with oligometastases (one to four metastases) in the brain. There is a rapidly expanding recent body of literature on outcomes of single-fraction SRS or hypofractionated SRS targeting the resection cavity after surgical resection of BM. Several retrospective series assessed the efficacy and safety of postoperative SRS to the resection cavity 9 aiming at an enhanced local tumor control but also at avoidance of the neurotoxic late effects of WBRT. WBRT followed by SRS of the tumor bed leads to 1-year local control rates of 70-93 %, which is comparable to results after surgery followed by WBRT. Median survival was 12-18 months with a 1-year incidence of new metastases in the brain of 45-60 %.

Trial Objectives: This protocol is primarily aimed at evaluating the safety and toxicity profile of SRS following neurosurgical resection and compares it to that of WBRT as the established standard of care. Secondary, the local effect of radiation therapy in patients with brain metastases will be assessed by measuring time to local and loco-regional recurrence, local and loco-regional PFS and overall survival at 12 months after treatment.

Patients´Selection: Patients with the diagnosis of brain metastases from solid tumors that have undergone neurosurgical resection of one brain metastasis will be evaluated and screened for the protocol. All patients fulfilling the inclusion and exclusion criteria will be informed about the study and included into the study if they declare informed consent. Registration for the study must be performed before the start of RT.

Trial Design: The trial will be performed as a single-center two-armed prospective randomized Phase II study. Patients will be randomized into an experimental arm and a control arm. All patients will receive post-operative contrast-enhanced cranial MRI imaging and imaging will be assessed by a radiologist. All available MRI sequences, including SPACE will be taken into consideration for the definition of treatment target lesions. Patients for whom the post-operative MRI reveals more than 10 suspect intracranial lesions (all sequences taken into account) will not be included in the trial.

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 Brain Metastases, Adult
Intervention  ICMJE
  • Radiation: post-operative stereotactic radiosurgery (SRS)

    For radiosurgery, patients will be immobilized. Treatment planning including the MRI and planning CT should be performed 1 -2 weeks before SRT and treatment finished at latest 3-4 weeks after surgery. Planning should be as close to SRT as possible.

    Organs at risk such as the brain stem, optic nerves, chiasm and spinal cord will be contoured. The Clinical Target Volume 1 (CTV1) will be defined as the resection cavity based on MRI and CT including T1 contrast enhanced changes around the resection cavity. The Clinical Target Volume 2 (CTV2) will be defined as a 3mm margin added to CTV1 by isotropic expansion and slightly adjusted as deemed appropriated by the experienced contouring physician. The Planning Target Volume (PTV) will be an additional margin of 1mm added to CTV2 by isotropic expansion.

    Treatment planning will be performed using Accuray's Multiplan or subsequent approved treatment planning systems for Cyberknife.

  • Radiation: Whole brain radiotherapy (WBRT)

    For WBRT, an individual head fixation mask is manufactured for each patient, and treatment planning is performed as virtual simulation or 3D-conformal RT planning based on CT-imaging. The portals include the whole brain with special focus as including the skull base areas and lamina cribrosa. For low infratentorial lesions, the treatment volume may include the whole brain down to the second cervical vertbra.

    RT will be applied with two portals (e.g. 87°and 273°) using a 6 MeV linear accelerator.

    For WBRT, a total dose of 30 Gy in 3 Gy fractions will be applied.

Study Arms  ICMJE
  • Experimental: Post-operative SRS of resection cavity

    High-resolution contrast-enhanced post-operative MRI imaging in preparation for Cyberknife SRS. Cyberknife SRS of the resection cavity and all potential additional metastases diagnosed in the treatment planning MRI (up to 10 lesions)

    Resection cavity:

    7 x 5 Gy @ 95%-isodose

    Potential additional brain metastases:

    20 Gy @ 70%-isodose (lesions < 2 cm max. diameter) 18 Gy @ 70%-isodose (lesions 2 - 3 cm max. diameter) 6 x 5 Gy @ 70%-isodose (lesions > 3 cm max. diameter)

    Intervention: Radiation: post-operative stereotactic radiosurgery (SRS)
  • Post-operative WBRT
    Post-operative WBRT will be performed according to the following dose regimen: 10 x 3 Gy
    Intervention: Radiation: Whole brain radiotherapy (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 15, 2017)
50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2021
Estimated Primary Completion Date November 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • histologically confirmed solid cancer
  • MRI confirmed cerebral metastases
  • Neurosurgical resection of one cerebral metastasis
  • age ≥ 18 years of age
  • Karnofsky Performance Score >60
  • for women with childbearing potential, (and men) adequate contraception.
  • ability 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 to the brain
  • > 10 unresected brain metastases in postoperative MRI
  • Patients who have not yet recovered from acute toxicities of prior therapies
  • known carcinoma < 2 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
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: Juergen Debus, Prof. Dr. Dr. +49 6221 56 ext 8200 juergen.debus@med.uni-heidelberg.de
Contact: Rami El Shafie, Dr. med. +49 6221 56 ext 8200 Rami.ElShafie@med.uni-heidelberg.de
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03285932
Other Study ID Numbers  ICMJE S-451/2017
Has Data Monitoring Committee Yes
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: Juergen Debus, Prof. Dr. Dr. Head of department Radiation Oncology
PRS Account University Hospital Heidelberg
Verification Date March 2018

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