Brief Summary
This phase III trial compares the usual treatment of surgery after stereotactic radiosurgery (SRS) to receiving SRS before 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 to target tumors and minimizes effect on normal surrounding brain tissue. The combination of surgery and radiation may stop the tumor from growing for a few months or longer and may reduce symptoms of brain metastases. This study investigates whether treating with SRS before surgery may be better than SRS after surgery in reducing the possibility of the tumor coming back, reducing or preventing the cancer from spreading to other areas of the brain and reducing the risk of scarring on the brain from radiation.
Brief Title
Comparing the Addition of Radiation Either Before or After Surgery for Patients With Brain Metastases
Detailed Description
PRIMARY OBJECTIVE:
I. To determine if the time to composite adverse endpoint (CAE) (defined as: 1) local tumor progression within the surgical bed; and/or 2) adverse radiation effect \[ARE\], the imaging correlate of post-stereotactic radiosurgery \[SRS\] radiation necrosis; and/or 3) nodular meningeal disease \[nMD\]) is improved in patients treated with pre-resection SRS to the intact lesion versus those treated with post-resection SRS.
SECONDARY OBJECTIVES:
I. To assess the trajectory of symptom burden in patients treated with pre-resection SRS to the intact lesion versus those treated to the post-resection surgical cavity as measured by MD Anderson Symptom Inventory for brain tumor (MDASI-BT).
II. To determine whether there is improved overall survival (OS) in patients with resected brain metastases who undergo pre-resection SRS compared to patients who receive post-resection SRS.
III. To compare rates of ARE, the imaging correlate of radiation necrosis, in patients who receive pre-resection SRS to patients who receive post-resection SRS.
IV. To determine whether there is increased time to whole brain radiotherapy (WBRT) in patients who receive pre-resection SRS compared to patients who receive post-resection SRS.
V. To assess the trajectory of neuro-cognitive function in patients treated with pre-resection SRS to the intact lesion versus those treated to the post-resection surgical cavity as measured by the Montreal Cognitive Assessment (MoCA).
VI. To compare rates of nodular meningeal disease in patients who receive pre-resection SRS to patients who receive post-resection SRS.
VII. To compare rates of local recurrence in the resection cavity for patients who receive pre-resection SRS to patients who receive post-resection SRS.
VIII. To compare rates of local recurrence of intact, non-index metastases treated with SRS.
IX. To compare rates of distant brain failure in patients who receive pre-resection SRS to patients who receive post-resection SRS.
X. To assess toxicity in the two treatment arms.
EXPLORATORY OBJECTIVE:
I. To explore if the type of surgical resection (piece-meal versus \[vs.\] en-bloc) may be associated with the rate of nodular meningeal disease.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo surgery per standard of care. Within 10-30 days after surgery, patients undergo stereotactic radiosurgery for 1 fraction.
ARM II: Within 7 days before surgery, patients undergo stereotactic radiosurgery for 1 fraction. Patients undergo surgery per standard of care.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for additional 2 years.
I. To determine if the time to composite adverse endpoint (CAE) (defined as: 1) local tumor progression within the surgical bed; and/or 2) adverse radiation effect \[ARE\], the imaging correlate of post-stereotactic radiosurgery \[SRS\] radiation necrosis; and/or 3) nodular meningeal disease \[nMD\]) is improved in patients treated with pre-resection SRS to the intact lesion versus those treated with post-resection SRS.
SECONDARY OBJECTIVES:
I. To assess the trajectory of symptom burden in patients treated with pre-resection SRS to the intact lesion versus those treated to the post-resection surgical cavity as measured by MD Anderson Symptom Inventory for brain tumor (MDASI-BT).
II. To determine whether there is improved overall survival (OS) in patients with resected brain metastases who undergo pre-resection SRS compared to patients who receive post-resection SRS.
III. To compare rates of ARE, the imaging correlate of radiation necrosis, in patients who receive pre-resection SRS to patients who receive post-resection SRS.
IV. To determine whether there is increased time to whole brain radiotherapy (WBRT) in patients who receive pre-resection SRS compared to patients who receive post-resection SRS.
V. To assess the trajectory of neuro-cognitive function in patients treated with pre-resection SRS to the intact lesion versus those treated to the post-resection surgical cavity as measured by the Montreal Cognitive Assessment (MoCA).
VI. To compare rates of nodular meningeal disease in patients who receive pre-resection SRS to patients who receive post-resection SRS.
VII. To compare rates of local recurrence in the resection cavity for patients who receive pre-resection SRS to patients who receive post-resection SRS.
VIII. To compare rates of local recurrence of intact, non-index metastases treated with SRS.
IX. To compare rates of distant brain failure in patients who receive pre-resection SRS to patients who receive post-resection SRS.
X. To assess toxicity in the two treatment arms.
EXPLORATORY OBJECTIVE:
I. To explore if the type of surgical resection (piece-meal versus \[vs.\] en-bloc) may be associated with the rate of nodular meningeal disease.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo surgery per standard of care. Within 10-30 days after surgery, patients undergo stereotactic radiosurgery for 1 fraction.
ARM II: Within 7 days before surgery, patients undergo stereotactic radiosurgery for 1 fraction. Patients undergo surgery per standard of care.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for additional 2 years.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Metastatic Malignant Neoplasm in the Brain
Eligibility 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 any lesions which will not be resected must be =\< 4.0 cm in maximum diameter
* 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
* Lesions chosen for surgical therapy must be deemed appropriate targets 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
* 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
* 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 any lesions which will not be resected must be =\< 4.0 cm in maximum diameter
* 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
* Lesions chosen for surgical therapy must be deemed appropriate targets 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
* 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
Inclusion 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 any lesions which will not be resected must be =\< 4.0 cm in maximum diameter
* 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
* Lesions chosen for surgical therapy must be deemed appropriate targets 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
* 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
* 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 any lesions which will not be resected must be =\< 4.0 cm in maximum diameter
* 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
* Lesions chosen for surgical therapy must be deemed appropriate targets 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
* 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
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Minimum Age
18 Years
NCT Id
NCT05438212
Org Class
Other
Org Full Name
NRG Oncology
Org Study Id
NRG-BN012
Overall Status
Recruiting
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Estimated
Official Title
A Randomized Phase III Trial of Pre-Operative Compared to Post-Operative Stereotactic Radiosurgery in Patients With Resectable Brain Metastases
Primary Outcomes
Outcome Description
Analysis for this endpoint will consist of testing the cause-specific hazard ratio in a Cox proportional hazards model.
Outcome Measure
Time to composite adverse endpoint (CAE)
Outcome 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
Secondary Ids
Secondary Id
NCI-2022-04804
Secondary Id
NRG-BN012
Secondary Id
NRG-BN012
Secondary Id
U10CA180868
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
Time from randomization to death due to any cause, assessed up to 4 years
Outcome Measure
Overall survival (OS)
Outcome Description
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 between treatment arms.
Outcome Time Frame
Up to 4 years
Outcome Measure
Rate of local tumor progression
Outcome Description
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 radiation necrosis between treatment arms.
Outcome Time Frame
Up to 4 years
Outcome Measure
Rate of radiation necrosis
Outcome Description
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 nodular meningeal disease between treatment arms.
Outcome Time Frame
Up to 4 years
Outcome Measure
Rate of nodular meningeal disease
Outcome Description
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 distant brain failures between treatment arms.
Outcome Time Frame
Up to 4 years
Outcome Measure
Rate of distant brain failures
Outcome Description
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.
Outcome Time Frame
Up to 4 years
Outcome Measure
Frequency of adverse events (AEs)
Outcome Description
Will implement mixed effects models for repeated measures to evaluate the MDASI-BT scores longitudinally.
Outcome Time Frame
Baseline up to 2 years after surgery
Outcome Measure
Change in MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT)
Outcome Description
Measured by Montreal Cognitive Assessment (MoCA). Will implement mixed effects models for repeated measures to evaluate the MoCA scores longitudinally.
Outcome Time Frame
Baseline up to 2 years after surgery
Outcome Measure
Change in cognitive function
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
999
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Justin Tang
Investigator Email
jtang@montefiore.org