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Comparing the Addition of Radiation Either Before or After Surgery for Patients With Brain Metastases

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ClinicalTrials.gov Identifier: NCT05438212
Recruitment Status : Recruiting
First Posted : June 29, 2022
Last Update Posted : September 21, 2023
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
NRG Oncology

Study Description
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Brief Summary:
This phase III trial compares the addition of stereotactic radiosurgery before or after surgery in treating patients with cancer that has spread to the brain (brain metastases). Stereotactic radiosurgery is a type of radiation therapy that delivers a high dose of radiation only to the small areas of cancer in the brain and avoids the surrounding normal brain tissue. Surgery and radiation may stop the tumor from growing for a few months or longer and may reduce symptoms of brain metastases.

Condition or disease Intervention/treatment Phase
Metastatic Malignant Neoplasm in the Brain Procedure: Brain Surgery Other: Quality-of-Life Assessment Other: Questionnaire Administration Radiation: Stereotactic Radiosurgery Phase 3

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 236 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Phase III Trial of Pre-Operative Compared to Post-Operative Stereotactic Radiosurgery in Patients With Resectable Brain Metastases
Actual Study Start Date : August 31, 2022
Estimated Primary Completion Date : March 16, 2027
Estimated Study Completion Date : March 16, 2032
Arms and Interventions
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Arm Intervention/treatment
Active Comparator: Arm I (surgery, stereotactic radiosurgery)
Patients undergo surgery per standard of care. Within 10-30 days after surgery, patients undergo stereotactic radiosurgery for 1 fraction.
 Procedure: Brain Surgery
Undergo surgery per standard of care

Other: Quality-of-Life Assessment
Ancillary studies

Other: Questionnaire Administration
Ancillary studies

Radiation: Stereotactic Radiosurgery
Undergo stereotactic radiosurgery
Experimental: Arm II (stereotactic radiosurgery, surgery)
Within 7 days before surgery, patients undergo stereotactic radiosurgery for 1 fraction. Patients undergo surgery per standard of care.
 Procedure: Brain Surgery
Undergo surgery per standard of care

Other: Quality-of-Life Assessment
Ancillary studies

Other: Questionnaire Administration
Ancillary studies

Radiation: Stereotactic Radiosurgery
Undergo stereotactic radiosurgery


Outcome Measures
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Primary Outcome Measures :
  1. Time to Composite Adverse Endpoint (CAE) [ Time Frame: Time from surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment) to local tumor progression (within the surgical bed), nodular meningeal disease, or radiation necrosis, whichever occurs first, assessed up to 4 years ]
    Analysis for this endpoint will consist of testing the cause-specific hazard ratio in a Cox proportional hazards model.


Secondary Outcome Measures :
  1. Overall Survival (OS) [ Time Frame: Time from randomization to death due to any cause, assessed up to 4 years ]
    Analysis for this endpoint will consist of estimation of the OS distribution of each treatment arm via the Kaplan-Meier method and a stratified log-rank test.

  2. Rate of local tumor progression [ Time Frame: Up to 4 years ]
    The time origin for these imaging-based endpoints will be time of surgery (with the post-operative magnetic resonance imaging [MRI] as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.

  3. Rate of radiation necrosis [ Time Frame: Up to 4 years ]
    The time origin for these imaging-based endpoints will be time of surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.

  4. Rate of nodular meningeal disease [ Time Frame: Up to 4 years ]
    The time origin for these imaging-based endpoints will be time of surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.

  5. Rate of distant brain failures [ Time Frame: Up to 4 years ]
    The time origin for these imaging-based endpoints will be time of surgery (with the post-operative MRI as the 'baseline' for purposes of disease assessment). These analyses will involve estimating the cumulative incidence function of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures in the presence of competing event of deaths. The Gray's test will be used to evaluate the difference in the distribution of local progression, radiation necrosis, nodular meningeal disease, and distant brain failures between treatment arms.

  6. Frequency of adverse events (AEs) [ Time Frame: Up to 4 years ]
    AEs will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Comprehensive summaries of all AEs by treatment arm will be generated and examined. Counts and frequencies of worst (highest score) AE per patient will be presented overall and by AE type category, separately by assigned treatment group. The proportion of patients with at least one grade 3 or higher AE will be compared between treatment arms. Any frequencies to be tested will be evaluated using the chi-square or exact test as appropriate, with two-sided significance level 0.05.

  7. Change in MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) [ Time Frame: Baseline up to 2 years after surgery ]
    Will implement mixed effects models for repeated measures to evaluate the MDASI-BT scores longitudinally.

  8. Change in cognitive function [ Time Frame: Baseline up to 2 years after surgery ]
    Measured by Montreal Cognitive Assessment (MoCA). Will implement mixed effects models for repeated measures to evaluate the MoCA scores longitudinally.


Other Outcome Measures:
  1. Type of surgical resection [ Time Frame: Up to 4 years ]
    Will compare if the type of surgical resection (piece-meal vs. en-bloc) may be associated with the rate of nodular meningeal disease. The competing risk approach by Gray (Gray 1988) will be used to compare the cumulative incidences of nMD by surgical type, where death prior to nMD will be treated as a competing risk event.


Eligibility Criteria
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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:

  • Radiographic confirmation of 1-4 brain metastases, one of which requires resection, as defined by magnetic resonance imaging (MRI) with contrast obtained within 14 days prior to registration

    • The maximum diameter of the lesion to be resected on the post-contrast MRI, as measured on any orthogonal plane (axial, sagittal, coronal), must measure > 2.0 cm and < 5.0 cm.
    • The maximum diameter of the lesions not to be resected must measure < 4.0 cm
  • Known active or history of invasive non-central nervous system (CNS) primary cancer based on documented pathologic diagnosis within the past 3 years
  • All brain metastases must be located > 5 mm from the optic chiasm and outside the brainstem
  • Patient is able to medically tolerate surgery and SRS
  • The lesion chosen for surgical therapy must be deemed an appropriate target for safe, gross total resection by the treating surgeon
  • History/physical examination within 14 days prior to registration
  • Age >= 18
  • Karnofsky performance status (KPS) >= 60 within 14 days prior to registration
  • A negative urine or serum pregnancy test (in persons of childbearing potential) within =< 14 days prior to registration. Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal for at least 12 consecutive months
  • Participants who are sexually active must agree to use medically acceptable forms of contraception during treatment on this study to prevent pregnancy
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information

Exclusion Criteria:

  • Prior cranial radiotherapy, including whole brain radiotherapy, or SRS to the resection site

    • Note: The index lesion to be resected cannot have been previously treated with SRS (i.e. repeat radiosurgery to the same location/lesion is not allowed on this protocol). Previous SRS to other lesions is allowed

  • Evidence of leptomeningeal disease (LMD)

    • Note: For the purposes of exclusion, LMD is a clinical diagnosis, defined as positive cerebrospinal fluid (CSF) cytology and/or unequivocal radiologic or clinical evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of leptomeningeal enhancement by imaging (MRI) would be considered to have LMD even in the absence of positive CSF cytology. In contrast, an asymptomatic or minimally symptomatic patient with mild or nonspecific leptomeningeal enhancement (MRI) would not be considered to have LMD. In that patient, CSF sampling is not required to formally exclude LMD, but can be performed at the investigator's discretion based on level of clinical suspicion
  • Any medical conditions which would make this protocol unreasonably hazardous, including, but not limited to: contraindications to general endotracheal anesthesia; intracranial surgery; and stereotactic radiosurgery
  • Primary histology of germ cell tumor, small cell carcinoma or lymphoma
  • More than one brain metastasis planned for resection
  • Inability to undergo MRI with contrast

  • Planned administration of cytotoxic chemotherapy or tyrosine/multi-kinase inhibitors within the 3 days prior to, the day of, or within 3 days after the completion of SRS

    • Note: chemotherapy and immunotherapy outside of this window are allowed
Contacts and Locations
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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): NCT05438212


Locations
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Sponsors and Collaborators
NRG Oncology
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Stuart H Burri NRG Oncology
More Information
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Responsible Party: NRG Oncology
ClinicalTrials.gov Identifier: NCT05438212    
Other Study ID Numbers: NRG-BN012
NCI-2022-04804 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-BN012 ( Other Identifier: NRG Oncology )
NRG-BN012 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
First Posted: June 29, 2022    Key Record Dates
Last Update Posted: September 21, 2023
Last Verified: September 2023

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Brain Neoplasms
Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
 Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases