This randomized phase III trial studies how well radiation therapy works compared with observation in treating patients with newly diagnosed grade II meningioma that has been completely removed by surgery. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors.
PRIMARY OBJECTIVE: I. To determine the extent of clinical benefit of the addition of adjuvant radiotherapy (RT) to gross total resection (GTR) for patients with newly diagnosed World Health Organization (WHO) grade II meningioma. SECONDARY OBJECTIVES: I. Overall survival (OS). II. Disease-specific survival (DSS). III. Toxicity (grade 3+, exclusive of expected alopecia). IV. Neurocognitive function (NCF). V. Patient reported outcomes (PRO) measurements. VI. Adherence to protocol-specific target and normal tissue parameters. VII. Concordance measurements of central versus parent-institution pathology. VIII. Assessment of pHH3 mitotic index and its correlation with progression-free survival (PFS) and OS. IX. Validation of the prognostic value of a 34-gene expression biomarker. X. Validation of the predictive value of a 34-gene expression biomarker in predicting the benefit of radiotherapy. XI. Tissue and specimen collection for future translational research. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo observation. Additionally, patients undergo magnetic resonance imaging (MRI) and blood collection throughout the study. ARM II: Patients undergo intensity-modulated radiation therapy (IMRT) or proton beam radiation therapy 5 days a week over 6.5-7 weeks for a total of 33 fractions in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo MRI and blood collection throughout the study. After completion of study treatment, patients are followed up at 3, 6, and 12 months, every 6 months for year 2 and 3, then yearly for 10 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
Undergo collection of blood samples
Undergo observation
Undergo IMRT
Progression free survival (PFS)
Kaplan-Meier method will be used to calculate the PFS rates for each of the two arms. Hazard ratio (HR) on the treatment effect will be calculated using the Cox proportional hazard model. A one-sided log-rank test will be used to test the difference in PFS between the two arms.
Time frame: From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed up to 10 years
PFS
Will be calculated based on the Kaplan-Meier curve. Cox proportional hazard model will be used to determine the adjusted treatment effect on PFS, with patient pretreatment characteristics as covariates.
Time frame: From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed at 3 years
PFS
Will be calculated based on the Kaplan-Meier curve. Cox proportional hazard model will be used to determine the adjusted treatment effect on PFS, with patient pretreatment characteristics as covariates.
Time frame: From randomization to the first documented disease progression, or death due to any cause, whichever comes first, assessed up to 5 years
Disease-specific survival (DSS)
Will be calculated using the cumulative incidence function for each arm. The HR for the treatment effect on DSS will be calculated using Gray's method under the competing risk approach, with death due to non-disease related cause treated as the competing risk. Multivariate analysis on DSS will be performed using the Fine-Gray model, with patient pretreatment characteristics as covariates.
Time frame: From randomization to disease-related death, assessed up to 10 years
DSS rates
Will be calculated using the cumulative incidence function for each arm. The HR for the treatment effect on DSS will be calculated using Gray's method under the competing risk approach, with death due to non-disease related cause treated as the competing risk. Multivariate analysis on DSS will be performed using the Fine-Gray model, with patient pretreatment characteristics as covariates.
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Correlative studies
Undergo MRI
Undergo proton beam radiation therapy
Ancillary studies
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
ACTIVE_NOT_RECRUITINGSaint Joseph's Hospital and Medical Center
Phoenix, Arizona, United States
SUSPENDEDMayo Clinic Hospital in Arizona
Phoenix, Arizona, United States
ACTIVE_NOT_RECRUITINGMayo Clinic in Arizona
Scottsdale, Arizona, United States
ACTIVE_NOT_RECRUITINGUniversity of Arizona Cancer Center-Orange Grove Campus
Tucson, Arizona, United States
SUSPENDEDBanner University Medical Center - Tucson
Tucson, Arizona, United States
SUSPENDEDUniversity of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
SUSPENDEDKaiser Permanente-Anaheim
Anaheim, California, United States
RECRUITINGSutter Cancer Centers Radiation Oncology Services-Auburn
Auburn, California, United States
RECRUITINGKaiser Permanente-Bellflower
Bellflower, California, United States
RECRUITING...and 205 more locations
Time frame: At 3 years
DSS rates
Will be calculated using the cumulative incidence function for each arm. The HR for the treatment effect on DSS will be calculated using Gray's method under the competing risk approach, with death due to non-disease related cause treated as the competing risk. Multivariate analysis on DSS will be performed using the Fine-Gray model, with patient pretreatment characteristics as covariates.
Time frame: At 5 years
Overall survival (OS)
Cox proportional hazard model will be used to determine the adjusted treatment effect on OS, with patient pretreatment characteristics as covariates.
Time frame: From randomization to death due to any cause, assessed up to 10 years
OS rates
Will be calculated based on the Kaplan-Meier curve. Cox proportional hazard model will be used to determine the adjusted treatment effect on OS, with patient pretreatment characteristics as covariates.
Time frame: At 5 years
Incidence of adverse events (exclusive of alopecia)
Will be measured by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4 (version 5 beginning April 5, 2018).
Time frame: Up to 3 years
Adherence rate to protocol-specific target and normal tissue parameters
Time frame: Up to 10 years
Concordance rate of central versus parent-institution pathology
Time frame: Up to 10 years
Prognostic value of 34-gene expression biomarker
Will generate Kaplan-Meier curves for different risk subgroups defined by the risk scores, separately for post-operative observation and post-operative radiotherapy arms. The log-rank test will be used to test the difference in clinical outcomes (PFS and OS) between molecular risk subgroups (separately for the post-operative observation arm and post-operative radiotherapy arm). Cox proportional hazard model will be used to estimate the prognostic effect of the gene expression defined risk groups on clinical outcomes adjusting for pre-treatment patient characteristics as well as treatment arm.
Time frame: Up to 5 years
Predictive value of 34-gene expression biomarker
Will be evaluated formally through the test of a statistical interaction between molecular risk group (low/intermediate versus high) and treatment (observation versus radiotherapy). The Kaplan-Meier curves of PFS and OS between treatment arms will be displayed separately among low/intermediate risk and high-risk groups. A Cox proportional hazards model will be built including treatment group, gene expression risk group, an interaction term between treatment and gene expression risk group, as well as other pre-treatment patient characteristics. The interaction test will be based on a two-sided 0.05 level Wald test in the Cox proportional hazards model. The treatment difference between radiation therapy and observation will also be tested within each gene expression risk subgroup in a multivariable Cox proportional hazards model, adjusting for other patient characteristics.
Time frame: Up to 5 years
Change in neurocognitive function (NCF) assessed by MD Anderson Symptom Inventory with Brain Tumor (MDASI-BT)
Will use a 2-sample t-test with a one-sided significance level of 0.05, with a Bonferroni adjustment to account for the neurocognitive function and symptom assessments resulting in an overall type I error of 0.1, there will be 72% statistical power to detect a medium effect size of 0.5 standard deviation (SD) for a comparison of the change from baseline to 6 months after randomization between the experimental and the control arm. Will compare NCF outcomes between IMRT to proton therapy.
Time frame: Baseline up to 60 months
Change in patient reported outcomes (PRO) as assessed by MDASI-BT
Will use a 2-sample t-test with a one-sided significance level of 0.05, with a Bonferroni adjustment to account for the neurocognitive function and symptom assessments resulting in an overall type I error of 0.1, there will be 72% statistical power to detect a medium effect size of 0.5 standard deviation for a comparison of the change from baseline to 6 months after randomization between the experimental and the control arm. Will compare PRO outcomes between IMRT to proton therapy.
Time frame: Baseline up to 60 months