RE-TREAT: Re-TREAT: Re-irradiation for Relapsed Brain Metastases

Sponsor
Rigshospitalet, Denmark (Other)
Overall Status
Recruiting
CT.gov ID
NCT05126875
Collaborator
(none)
44
Enrollment
1
Location
1
Arm
25.6
Anticipated Duration (Months)
1.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The Re-TREAT study is a prospective clinical, phase 2, interventional, single-arm, multicenter trial for patients with local relapse of one or more brain metastases. Patients with recurrence of one or more brain metastases that have previously been treated with stereotactic radiosurgey (SRS) are treated with repeated SRS. The aim is to evaluate the efficacy and toxicity of salvage SRS. The primary outcome is local control of the relapsed tumor and the secondary endpoints include toxicity as evaluated by the investigator and quality of life measured as a patient reported outcome. As an exploratory endpoint, the value of advanced MRI (magnetic resonance imaging) and PET (positron emission tomography) imaging as a biomarker for prediction of response to treatment or toxicity will be studied.

Condition or DiseaseIntervention/TreatmentPhase
  • Radiation: Repeated stereotactic radiosurgery
N/A

Detailed Description

Background It is estimated that 10-20 % of patients with cancer develop brain metastases (BM) and the number is increasing due to prolonged patient survival as a result of improvements in surgery and systemic treatment. With few exceptions however, chemotherapy is not effective in treating disease within the central nervous system and therefore BM are often treated as a separate compartment independently from the rest of the disease throughout the body. Treatment modalities include surgical resection, stereotactic radiosurgery (SRS) and whole brain irradiation (WBI) or a combination.

SRS is a technique where a high dose of radiation is delivered through multiple fields, often as rotational intensity modulated radiation therapy (IMRT), where the beam is aimed at the tumor from everchanging angles, in order to minimize the dose to the surrounding tissue. In contrast to other radiation modalities, where a margin is added to the target in order to eradicate tumor cells that are not visible on imaging, SRS employs very small margins because brain metastases tend to be localized with sharp boundaries to surrounding tissue. The relative low dose absorbed by the surrounding tissue allows for delivery of the whole radiation dose to the tumor in one to three treatment sessions ('fractions'), as opposed to conventionally fractionated radiotherapy which is delivered in multiple fractions for the protection of surrounding healthy tissue.

As a whole, SRS results in high rates of local tumor control (65-90%) and low rates of toxicity (10-15%), which is usually mild. The most significant adverse event following SRS is radionecrosis, which is estimated to occur in 5-25% of patients. This is a condition which is poorly defined but is commonly used to describe a situation where the contrast enhancing area in the irradiated volume increases, often accompanied by increasing edema in the surrounding tissue. The condition may or may not cause symptoms. In cases of symptomatic, progressive radionecrosis, oral corticosteroids such as prednisolone may be needed for longer periods of time. Differentiation between relapsed metastasis and radionecrosis is notoriously difficult and represents one of the major diagnostic challenges in all of neuro-oncology. Advanced imaging techniques such as dynamic MRI (e.g. perfusion weighted images) or PET (positron emission tomography) have been used to aid in differentiation in experimental studies, but this currently remains an area of research. The development of the brain lesion over time and use of close follow-up using MRI will most often aid in interpretation of the images by the multidisciplinary team conference consisting of a radiologist, a radiation oncologist and a neurosurgeon.

There is no standard treatment in case of local tumor relapse following SRS. Patients who have not previously received WBI may be offered this, but the possible detrimental effects on neurocognition and quality of life are well documented4 and many clinicians as well as patients prefer to avoid this for as long as possible. Few patients in this category are recommended surgical resection.

Salvage SRS (repeated SRS to the same area at time of relapse) is commonly practiced at some institutions, Rigshospitalet being one of them, but the evidence to support routine use is sparse. The treatment has been evaluated only in retrospective studies. These have found high rates of local control (70-90%), but as adverse events and side effects cannot be evaluated from retrospective studies without risk of critical bias, the safety of this treatment remains to be established.

Aim of the study The Re-TREAT study is a prospective clinical, phase 2, interventional, single-arm, multicenter trial with patients with local relapse of one or more brain metastases. In the trial, they are treated with salvage SRS. The aim is to evaluate the efficacy and toxicity of salvage SRS. The primary outcome is local control of the relapsed tumor and the secondary endpoints include toxicity as evaluated by the investigator and quality of life measured as a patient reported outcome. As an exploratory endpoint, the value of advanced MRI and PET-imaging as a biomarker for prediction of response to treatment or toxicity will be studied.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
44 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Re-TREAT: A Phase 2 Study of Stereotactic Re-irradiation of Relapsed Brain Metastases
Actual Study Start Date :
Jul 1, 2021
Anticipated Primary Completion Date :
Aug 20, 2023
Anticipated Study Completion Date :
Aug 20, 2023

Arms and Interventions

ArmIntervention/Treatment
Experimental: Treatment arm

Treatment with stereotactic radiosurgery

Radiation: Repeated stereotactic radiosurgery
Repeated stereotactic radiosurgery to recurring brain metastases
Other Names:
  • SRS
  • Outcome Measures

    Primary Outcome Measures

    1. Freedom from progression of treated metastasis [3 months post treatment]

      Freedom from progression of lesion size defined as stable or decreasing unidimensional measurement (longest diameter) on T1-weighted contrast enhanced magnetic resonance imaging (MRI)

    Secondary Outcome Measures

    1. Adverse events [12 months]

      Adverse events graded using National Cancer Institute (NCI) Common Toxicity Criteria (CTC) Adverse Events (AE) version 5.0

    2. Overall response [3 months]

      Overall radiographic response of all treated lesions

    3. Neurological status [6 months]

      Neurological status assessed by NANO (neurologic assessment in neuro-oncology) scale

    4. Time to intracranial relapse [From date of treatment until the day of radiologically documented relapse in the brain assessed up to 12 months]

      Time to recurrence of treated lesion or occurrence of new lesion(s)

    5. Overall survival [From date of treatment until date of death from any cause assessed up to 12 months]

      Overall survival from entry into study

    6. Patient reported outcomes [6 months]

      Health related quality of life measured by the FACT-Br (Functional Assessment of Cancer Therapy - Brain) questionnaire

    Other Outcome Measures

    1. Positron emission tomography using fluoro-ethyl tyrosine (FET) tracer before and after treatment [3 months]

      Exploratory endpoint. The measured change in biological tumor volume (BTV) and Tmax/brain (maximal tumor activity) as compared to baseline values.

    2. Dynamic MRI using DCE (dynamic contrast enhancement) perfusion measurement before and after treatment [3 months]

      Exploratory endpoint. The measured change in tumor blood volume measurement, tumor perfusion and tumor permability (Ki) as compared to baseline values.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Brain metastases of solid tumor (carcinoma of unknown origin may be included but histological verification in case of BM alone is required)

    • Progression of previously treated lesion as decided by the multidisciplinary team conference

    • Previous single fraction SRS in area in question and dose plans must be available electronically

    • Previous single fraction SRS given > 3 months previously

    • ECOG (Eastern Cooperative Oncology Group) performance status ≤2

    • Life expectancy >3 months

    • Signed written consent.

    • Patients may have more than one recurring lesion and may also have new, untreated metastases which may be treated with standard SRS (up to a total of 4 metastases in accordance with Danish national guidelines).

    Exclusion Criteria:
    • Two previous courses of radiotherapy for the same metastasis (e.g. SRS and WBRT)

    • Target lesions located in- or in proximity to eloquent brain areas that require reduction of radiotherapy dose

    • Target lesion gross tumor volume (GTV) for radiotherapy greater than 14,1 cm3 (equivalent to a sphere with a diameter of 3 cm)

    • Current or planned concomitant medical treatment that is likely to be active against brain metastases (e.g. tyrosine kinase inhibitors for EGFR-positive (epidermal growth factor receptor) non-small cell lung cancer) or that may influence interpretation of images (e.g. bevacizumab, a monoclonal antibody directed towards VEGF (vascular endothelial growth factor)) in the opinion of the investigators

    • Contraindication to magnetic resonance imaging using Gadolinium contrast enhancement (e.g. pacemaker, metallic implant or impaired renal function)

    • Rapid extracranial disease progression that in the opinion of the investigators confer a high risk of drop out from the study without evaluation scan at 3 months

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Rigshospitalet, University of CopenhagenCopenhagenDenmark2100

    Sponsors and Collaborators

    • Rigshospitalet, Denmark

    Investigators

    • Principal Investigator: Søren Møller, MD, PhD, Rigshospitalet, Denmark

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Søren Møller, MD, Consultant, Rigshospitalet, Denmark
    ClinicalTrials.gov Identifier:
    NCT05126875
    Other Study ID Numbers:
    • RE-TREAT
    First Posted:
    Nov 19, 2021
    Last Update Posted:
    Nov 19, 2021
    Last Verified:
    Nov 1, 2021
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Nov 19, 2021