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Cyberknife Radiosurgery for Patients With Brain Metastases Diagnosed With Either SPACE or MPRAGE Sequence (CYBER-SPACE)

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ClinicalTrials.gov Identifier: NCT03303365
Recruitment Status : Recruiting
First Posted : October 6, 2017
Last Update Posted : March 5, 2018
Sponsor:
Collaborator:
Heidelberg University
Information provided by (Responsible Party):
Juergen Debus, University Hospital Heidelberg

Brief Summary:

For patients with cerebral oligometastases who are in adequate clinical condition stereotactic radiosurgery (SRS) is the treatment of choice, being recommended by international guidelines for the treatment of one to four lesions. Newer findings have shown that for patients with more than four lesions SRS can be considered as a favorable alternative to whole-brain radiotherapy (WBRT), the currently established standard-of-care treatment. With modern techniques highly conformal SRS of multiple lesions has become feasible with comparable clinical effort and minimal toxicity as compared to WBRT. Developments in magnetic resonance imaging (MRI- imaging) have produced highly sensitive contrast-enhanced three-dimensional fast spin echo sequences such as SPACE that facilitate the detection of very small and early-stage lesions in a fashion superior to the established Magnetization Prepared Rapid Gradient Echo (MPRAGE) series.

Since it has been established that the response of brain metastases to SRS is better for smaller lesions and that WBRT can come at the price of significant neurotoxicity, the investigators hypothesize that 1) earlier detection of small brain metastases and 2) early and aggressive treatment of those by SRS will result in an overall clinical benefit by delaying the failure of repeated localized therapy and thus preserving quality of life and potentially prolonging overall survival. On the other hand however, overtreatment might be a valid concern with this approach since it has yet to be proved that a clinical benefit can be achieved.

The current study aims to stretch the boundaries of the term "cerebral oligometastases" by performing SRS for up to ten cerebral metastases, compared to the established clinical standard of four, given that existing data supports the non-inferiority of this approach and given that modern Cyberknife SRS facilitates the treatment of multiple lesions with minimal treatment-associated toxicity.


Condition or disease Intervention/treatment Phase
Brain Metastases Adult Solid Tumor Radiation: stereotactic radiosurgery (SRS) Phase 2

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Detailed Description:

Scientific Background: Brain metastases are the most common intracranial cancer manifestations, affecting up to one third of adult cancer patients with systemic spread. Prognosis is generally poor with overall survival ranging below 6 months on average. However, a more detailed inspection reveals a prognostic subgroup, for which improved overall survival and clinical symptom control can be achieved and that is most descriptively characterized by favorable clinical performance (KPI ≥ 70%) and extracranially controlled disease. Whereas for most patients with brain metastases whole-brain radiotherapy, steroids or best supportive care represent the palliation treatment of choice, the abovementioned subgroup is eligible to profit from a locally radical therapy concept and in those cases neurosurgical resection and stereotactic radiosurgery have both produced favorable results. In patients unsuitable for neurosurgical resection, single- or multifraction, SRS has several distinct advantages over WBRT, the most significant being short treatment time, less posttherapeutic neurocognitive impairment, better local tumor control and little to no hair loss. Furthermore, SRS can be repeated multiple times or performed before or after WBRT. Current clinical guidelines recommend SRS in cases of cerebral oligometastases, defined as one to four intracranial lesions with an extracranially controlled systemic disease status. However, recent data suggests that it may be a suitable treatment for patients with five to ten or even more than ten lesions, being non-inferior to the SRS of four or less lesions. There are several factors supporting this rationale: On the one hand technical improvements in the field of SRS have significantly facilitated the treatment of a higher number of target lesions with little to no increase in toxicity and comparable clinical effort. On the other hand, the ever improving sensitivity of medical imaging has caused an increase in the detection of oligometastatic constellations, enabling their treatment in an earlier stage. For a long time the contrast-based high-resolution cranial computer tomography (cCT) had been the gold standard of detecting cerebral metastases. This was significantly improved by the introduction of magnetic resonance imaging (MRI) with contrast-enhanced T1-weighted sequences. Sensitivity was further improved with the introduction of 3T MRI into clinical routine and the development of high-resolution three-dimensional gradient-echo sequences such as the contrast-based T1-weighted MPRAGE, featuring a slice thickness of 0.9 mm and multiplanar reconstruction, thus enabling the detection of very small sized lesions in the range of one to a few millimeters. However, the use of gradient-echo (GE) techniques to obtain three-dimensional high-spatial-resolution images comes at the cost of inferior contrast enhancement and higher susceptibility to artifacts than is the case with two-dimensional spin-echo (SE) techniques. Recent developments in MRI research have produced another sequence that might prove even superior to MPRAGE in the specific detection of very small and early brain metastases: Sampling perfection with application-optimized contrasts by using different flip angle evolutions (SPACE) is a three-dimensional fast SE sequence that combines high contrast enhancement superior to MPRAGE with a high spatial resolution and multiplanar reconstruction. Kato et al. have found this sequence to be significantly superior to MPRAGE in the detection of contrast enhanced parenchymal lesions, especially if those are < 5mm in size as is characteristic of small very-early-stage cerebral metastases.

Trial Objectives: It is the purpose of this study to evaluate treatment response and toxicity after SRS of up to ten simultaneous cerebral metastases, treating either all lesions visible in the highly sensitive SPACE MRI sequence or only those visible in the conventional contrast-based MPRAGE sequence. Treatment response is evaluated with respect to the ineligibility for further cerebral SRS at 12 months after initial SRS, defined by simultaneous new occurrence or progression of > 10 brain metastases (as a surrogate parameter for overall local control), furthermore overall survival and cognitive function and quality of life.

Patients´Selection: A total of n=200 patients will be enrolled into the trial (n=100 per treatment group). 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 pre-therapeutic MRI imaging as described in (Chapter 6) and imaging will be assessed by a radiologist. For patients in the experimental arm, all available MRI series, including SPACE will be taken into consideration for the definition of treatment target lesions. For patients in the control arm the assessing radiologist will be blinded with respect to the SPACE sequence and for the definition of treatment target lesions primarily contrast-based three-dimensional MPRAGE, complemented by all non-SPACE MRI sequences will be taken into consideration.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cyberknife Radiosurgery for Patients With Brain Metastases Diagnosed With Either SPACE or MPRAGE Sequence - A Prospective Randomized Evaluation of Response and Toxicity
Actual Study Start Date : February 1, 2018
Estimated Primary Completion Date : November 1, 2019
Estimated Study Completion Date : November 1, 2020

Arm Intervention/treatment
Experimental: Treatment based on SPACE MRI sequence
Cyberknife SRS of all suspect intracranial lesions visible in SPACE up to 10 simultaneous lesions
Radiation: stereotactic radiosurgery (SRS)

All patients will receive a pre-treatment cranial MRI for diagnostic and treatment planning purposes.

In Arm A, the contrast-based T1-weighted SPACE sequence is utilized for GTV definition. In Arm B, the contrast-based T1-weighted three-dimensional MPRAGE sequence is utilized for GTV definition. In both cases the GTV consists of all contrasted tissue associated with the target lesion and all additional tissue judged by an experienced physician to be part of the suspect target lesion. To the GTV a PTV margin of 1 mm is added by isotropic expansion that can be slightly modified if deemed necessary by the treating physician (e.g. intersection with adjoining OAR).

Dose prescription to the PTV for target lesions 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)

Active Comparator: Treatment based on MPRAGE
Cyberknife SRS of all suspect intracranial lesions visible in MPRAGE up to 10 simultaneous lesions
Radiation: stereotactic radiosurgery (SRS)

All patients will receive a pre-treatment cranial MRI for diagnostic and treatment planning purposes.

In Arm A, the contrast-based T1-weighted SPACE sequence is utilized for GTV definition. In Arm B, the contrast-based T1-weighted three-dimensional MPRAGE sequence is utilized for GTV definition. In both cases the GTV consists of all contrasted tissue associated with the target lesion and all additional tissue judged by an experienced physician to be part of the suspect target lesion. To the GTV a PTV margin of 1 mm is added by isotropic expansion that can be slightly modified if deemed necessary by the treating physician (e.g. intersection with adjoining OAR).

Dose prescription to the PTV for target lesions 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)




Primary Outcome Measures :
  1. Ineligibility for further cerebral SRS [ Time Frame: 12 months after initial SRS ]
    simultaneous new occurrence or progression of > 10 brain metastases


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: 12 months after initial SRS ]
    Time 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.

  2. cognitive function [ Time Frame: 6 months after initial SRS ]
    CANTAB Test (Cambridge Neuropsychological Test Automated Battery )

  3. quality of life [ Time Frame: 6 months after initial SRS ]
    EORTC QLQ-C30 questionnaire to assess the QoL of cancer patients, clinical assessment



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • radiologically confirmed metastases of the brain with an underlying history of a malignant illness
  • between one and ten suspect intracranial lesions, taking into consideration all available series of the pre-therapeutic MRI (performed at Heidelberg University Hospital and including SPACE sequence)
  • age ≥ 18 years of age
  • Karnofsky Performance Score (KPS) ≥ 70
  • 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 patient to take part in the study
  • Small-cell lung cancer (SCLC) as primary malignant illness
  • More than 10 suspect intracranial lesions in the initial pre-therapeutic MRI imaging (performed at Heidelberg University Hospital and including SPACE sequence)
  • metastasis so close to OAR that initial single-session SRS would be impossible due to lacking radiotolerance
  • known contraindications against the performing of cranial MRI
  • previous radiotherapy of the brain
  • Patients who have not yet recovered from acute toxicities of prior therapies
  • Pregnant or lactating women
  • Participation in another clinical study or observation period of competing trials, respectively

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03303365


Contacts
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Contact: Juergen Debus, Prof. Dr. Dr. +49 6221 56 ext 8200 juergen.debus@med.uni-heidelberg.de
Contact: Rami El Shafie, Dr. +49 6221 56 ext 8200 Rami.ElShafie@med.uni-heidelberg.de

Locations
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Germany
University Hospital of Heidelberg, Department of Radiation Oncology Recruiting
Heidelberg, Germany, 69120
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    Rami.ElShafie@med.uni-heidelberg.de   
Sub-Investigator: Stefan Rieken, PD         
Sub-Investigator: Angela Paul, Dr. med.         
Sub-Investigator: Kristin Lang, Dr. med.         
Sub-Investigator: Denise Bernhardt, Dr. med.         
Sponsors and Collaborators
Juergen Debus
Heidelberg University
Investigators
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Principal Investigator: Juergen Debus, Prof. Dr.Dr. Head of department Radiation Oncology

Publications:

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Responsible Party: Juergen Debus, Prof. Dr.Dr. Jürgen Debus, University Hospital Heidelberg
ClinicalTrials.gov Identifier: NCT03303365     History of Changes
Other Study ID Numbers: S-448/2017
First Posted: October 6, 2017    Key Record Dates
Last Update Posted: March 5, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Juergen Debus, University Hospital Heidelberg:
Brain Metastases
WBRT (whole brain radiotherapy)
SRS (stereotactic radiosurgery)
CYBER-Knife

Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplasms, Second Primary
Brain Neoplasms
Neoplastic Processes
Neoplasms
Pathologic Processes
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases