This randomized phase II clinical trial studies the side effects and how well proton beam or intensity-modulated radiation therapy works in preserving brain function in patients with IDH mutant grade II or III glioma. Proton beam radiation therapy uses tiny charged particles to deliver radiation directly to the tumor and may cause less damage to normal tissue. Intensity-modulated or photon beam radiation therapy uses high-energy x-ray beams shaped to treat the tumor and may also cause less damage to normal tissue. It is not yet known if proton beam radiation therapy is more effective than photon-based beam intensity-modulated radiation therapy in treating patients with glioma.
PRIMARY OBJECTIVES: I. To determine whether proton therapy, compared to intensity-modulated radiation therapy (IMRT), preserves cognitive outcomes over time as measured by the Clinical Trial Battery Composite (CTB COMP) score (calculated from the Hopkins Verbal Learning Test Revised \[HVLT-R\]) Total Recall, HVLT-R Delayed Recall, HVLT-R Delayed Recognition, Controlled Oral Word Association (COWA) test, Trail Making Test (TMT) part A and part B. SECONDARY OBJECTIVES: I. To assess whether treatment with proton therapy preserves neurocognitive function as measured separately by each test, HVLT-R, TMT parts A \& B, and COWA. II. To document and compare treatment related symptoms, overall symptom impact, and disease related factor groupings, utilizing the M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT), for both treatment arms. III. To assess whether treatment with proton therapy, compared to IMRT, results in superior quality of life as measured by the Linear Analog Scale Assessment (LASA) scale. IV. To compare local control patterns of failure and overall and progression-free survival between the two treatment arms. V. To assess adverse events. VI. To compare Illumnia MethylationEPIC beadchip array-derived IDH and 1p19q status determined centrally to that submitted by enrolling sites. TERTIARY OBJECTIVES: I. To assess the impact of chemotherapy use on cognitive outcomes, symptom outcomes and quality of life. II. To assess dose-response relationships between neuro-anatomic dosimetry and cognitive outcomes within and between treatment arms. III. To evaluate the association between tumor molecular status and cognition at baseline and within and between treatment arms over time. IV. To assess patterns of failure and pseudo progression as a function of radiation delivery type and dose received. V. To assess local control, overall survival and, progression free survival in IDH mutant grade II and III tumors. VI. To collect blood samples for future studies seeking to correlate changes in peripheral blood biomarkers (genes, micro ribonucleic acid \[RNA\], proteins, lymphocyte count, melatonin, etc) and the study endpoints. VII. To document and compare the impact of low to intermediate gliomas and therapy on patients' work and activity participation (The Work Productivity and Activity Impairment \[WPAI:GH\] Questionnaire: General Health version 2.0) as well as the relationship between changes in patients' work and activity participation and neurocognitive function and patient reported symptoms and interference. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients undergo photon-based IMRT once daily (QD), 5 days a week for 6 weeks for a total of 30 fractions. Beginning 28 days after completion of radiation therapy, patients receive standard of care temozolomide for 5 days. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression of unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) and collection of blood samples throughout the trial. ARM II: Patients undergo proton beam radiation therapy QD, 5 days a week for 6 weeks for a total of 30 fractions. Beginning 28 days after completion of radiation therapy, patients receive standard of care temozolomide for 5 days. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression of unacceptable toxicity. Patients undergo MRI and collection of blood samples throughout the trial. After completion of study treatment, patients are followed up at 6 and 12 months and then yearly for 10 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
NONE
Enrollment
120
Undergo collection of blood samples
Undergo IMRT
Correlative studies
Undergo MRI
Undergo proton beam radiation therapy
Ancillary studies
Ancillary studies
Drug
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Boca Raton Regional Hospital
Boca Raton, Florida, United States
Miami Cancer Institute
Miami, Florida, United States
Emory Proton Therapy Center
Atlanta, Georgia, United States
Emory University Hospital Midtown
Atlanta, Georgia, United States
Change in cognition as measured by the Clinical Trial Battery Composite (CTB COMP) score
Assessed with a general linear model with maximum likelihood estimation. Three models will be conducted. Baseline CTB COMP score, treatment arm, time, treatment by time interaction (if significant) and stratification factors will be included in the model for the primary endpoint. A second model will be built with these same variables and relevant covariates, such as total volume of intracranial disease, gross tumor volume (GTV) and clinical tumor volume (CTV) size, histology, anti-epileptic use, and disease response to therapy (as measured by Response Assessment in Neuro-Oncology \[RANO\] criteria). Other than baseline score CTB COMP, treatment arm, and time, only covariates with a p-value \< 0.10 will be retained in the model. A third model will be conducted at 10 years using the additional time points of neurocognitive assessments.
Time frame: Baseline to up to 10 years
Cognition as measured individually by Hopkins Verbal Learning Test Revised (HVLT-R), Trail Making Test (TMT) parts A and B, and Controlled Oral Word Association (COWA)
The HVLT-R, TMT parts A \& B, and COWA will be analyzed independently using a general linear model with maximum likelihood estimation. Standardized scores will be used.
Time frame: Up to 10 years
Change in symptoms as measured by M.D. Anderson Symptom Inventory Brain Tumor (MDASI-BT)
The change from baseline to each follow-up time point (calculated as baseline score subtracted from follow-up score) will be compared between treatment arms using a t-test, or Wilcoxon test if the data is not normally distributed. A reduced one-sided significance level will be used for the multiple comparisons in the MDASI-BT using the Bonferroni adjustment (alpha=0.017 for disease related factors and alpha=0.025 for treatment related symptoms and overall impact). A general linear model with maximum likelihood estimation will be used to assess symptom trends across time. Baseline score, treatment arm, time, treatment by time interaction (if significant), stratification factors, and relevant covariates, such as total volume of, GTV and CTV size, histology, anti-epileptic use, and disease response to therapy (as measured by RANO criteria) will be included as covariates in each model.
Time frame: Baseline to up to 10 years
Change in quality of life as measured by the Linear Analog Scale Assessment (LASA) scale
The change from baseline to each follow-up time point (calculated as baseline score subtracted from follow-up score) will be compared between treatment arms using a t-test, or Wilcoxon test if the data is not normally distributed. A one-sided alpha=0.05 will be used for the LASA. A general linear model with maximum likelihood estimation will be used to assess symptom and QOL trends across time. Baseline score, treatment arm, time, treatment by time interaction (if significant), stratification factors, and relevant covariates, such as total volume of, GTV and CTV size, histology, anti-epileptic use, and disease response to therapy (as measured by RANO criteria) will be included as covariates in each model. Other than baseline score, treatment arm, and time, only covariates with a p-value \< 0.10 will be retained in the model.
Time frame: Up to 10 years
Overall survival (OS)
OS will be estimated using the Kaplan-Meier method and compared between arms using the log rank test. Cox proportional hazards models will be used for OS adjusting for treatment arm and stratification factors.
Time frame: From randomization to the date of death, assessed up to 10 years
Local control as assessed by Response Assessment in Neuro-Oncology (RANO) criteria
Local control will be estimated using cumulative incidence, treating death prior to an event as a competing risk. Gray's test will be used to compare local control rates between arms. Cause-specific Cox proportional hazards models will be used for local control, adjusting for treatment arm and stratification factors. A two-sided significance level of 0.05 will be used for comparisons between arms.
Time frame: Up to 10 years
Progression-free survival (PFS)
A confidence interval will be used to determine if the PFS rate in the proton arm is greater than that in the photon at 1 year. PFS will be estimated using the Kaplan-Meier method and compared between arms using the log rank test. Cox proportional hazards models will be used for PFS adjusting for treatment arm and stratification factors.
Time frame: From date of randomization to date of progression or death, whichever occurs first, assessed up to 10 years
Incidence of adverse events (AEs) graded according to the National Cancer Institute's Common Terminology for Adverse Events version 5.0
Counts of all AEs by grade will be provided by treatment arm. Counts and frequencies will be provided for the worst grade AE experienced by the patient by treatment arm. Grade 3+ treatment related AEs will be compared between arms using a chi-square test, or Fisher's exact test if cell frequencies are \< 5, at the one-sided 0.05 significance level.
Time frame: Up to 10 years
IDH mutation as assessed by sequencing and 1p19q status as assessed by fluorescence in situ hybridization
A single test will be done for both IDH and 1p19q testing centrally while sites will perform a separate test for IDH and 1p19q. The results from the central and site testing will be compared using the kappa statistic. The asymptotic test of H0: k=0 will be performed using the Z-statistic to determine the strength of agreement. Concordance and discordance rates will be tabulated.
Time frame: Baseline
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Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, United States
Northwestern University
Chicago, Illinois, United States
Northwestern Medicine Cancer Center Delnor
Geneva, Illinois, United States
Northwestern Medicine Cancer Center Warrenville
Warrenville, Illinois, United States
University of Kansas Cancer Center
Kansas City, Kansas, United States
...and 24 more locations