This phase III trial compares the effectiveness of fractionated stereotactic radiosurgery (FSRS) to usual care stereotactic radiosurgery (SRS) in treating patients with cancer that has spread from where it first started to the brain. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. FSRS delivers a high dose of radiation to the tumor over 3 treatments. SRS is a type of external radiation therapy that uses special equipment to position the patient and precisely give a single large dose of radiation to a tumor. FSRS may be more effective compared to SRS in treating patients with cancer that has spread to the brain.
PRIMARY OBJECTIVE: I. To determine if the time to local failure is improved with FSRS compared to SRS in patients with intact (i.e., unresected) brain metastases. SECONDARY OBJECTIVES: I. To compare time to intracranial progression-free survival between FSRS and SRS. II. To compare overall survival between FSRS and SRS. III. To determine if the time to local failure is improved with FSRS compared to SRS, as evaluated by central review of imaging. IV. To evaluate if there is any difference in central nervous system (CNS) failure patterns (local versus \[vs.\] distant brain failure vs. both) in patients who receive FSRS compared to patients who receive SRS. V. To compare the rates of radiation necrosis in patients who receive FSRS vs. SRS. VI. To compare the time to salvage whole brain radiation therapy (WBRT) between patients who receive FSRS and those who receive SRS. VII. To compare the rates of post-treatment adverse events associated with FSRS and SRS. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo SRS over 30-90 minutes for 1 fraction on study. Additionally, patients undergo computed tomography (CT) and magnetic resonance imaging (MRI) on study. ARM II: Patients undergo FSRS over 30-90 minutes for 3 fractions on study. Additionally, patients undergo CT and MRI on study. After completion of study treatment, patients are followed up every 3 months for 1 year, every 4 months for 1 year then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
269
Undergo CT
Undergo FSRS
Undergo MRI
Undergo SRS
Banner University Medical Center - Tucson
Tucson, Arizona, United States
RECRUITINGUniversity of Arizona Cancer Center-North Campus
Tucson, Arizona, United States
RECRUITINGUniversity of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
RECRUITINGKaiser Permanente-Anaheim
Anaheim, California, United States
Time to local failure
The time to local failure will be evaluated at a per-patient level. The cause-specific hazard ratio will be estimated in a Cox proportional hazards (PH) model adjusting for patients and disease characteristics. The Cox PH model will be the principle approach. The cumulative incidence function estimator will also be used to estimate the rate of local failure in the presence of competing event of deaths in the two arms separately. A complementary analysis will involve Gray's test to evaluate the difference in the distribution of local failure between treatment arms. These results will be interpreted in light of the competing deaths.
Time frame: From randomization (with the treatment planning magnetic resonance imaging as the 'baseline' for purposes of disease assessment) to local tumor progression of any study lesion(s), assessed up to 5 years
Intracranial progression-free survival (IPFS)
IPFS will consist of estimation of its distribution for each treatment arm via the Kaplan-Meier method and a stratified log-rank test. Statistical power will depend on the total IPFS events accumulated at trial end.
Time frame: From the date of randomization until intracranial progression (local or distant intracranial) or death from any cause, whichever occurs first, assessed up to 5 years
Overall survival
Will consist of estimation of its distribution for each treatment arm via the Kaplan-Meier method and a stratified log-rank test. Reasons for death (e.g. due to neurological cause \[any central nervous system event such as an intracranial mass, hemorrhage, or hydrocephalus\] or non-neurological cause) will be recorded.
Time frame: From the date of randomization until death from any cause, assessed up to 5 years
Time to radiation necrosis (TTRN)
The rate of radiation necrosis will be compared in patients who receive fractionated stereotactic radiosurgery to patients who receive stereotactic radiosurgery. The primary comparison of treatment effect on TTRN will be based on testing the cause-specific hazard ratio (CHR) in a univariate Cox proportional hazards model. Additional supplementary analyses will include estimating the cause specific ratio in a Cox proportional hazards model adjusting for patients and disease characteristics (e.g. stratification randomization factors) and estimating the median TTRN via the cumulative incidence function estimator (Korn 1992). The Gray's test will also be used to evaluate the difference in the distribution of TTRN between treatment arms (Gray 1988).
Time frame: From randomization until radiation necrosis, assessed up to 5 years
Time to whole brain radiation therapy (WBRT)
Analysis of time to WBRT will consist of estimation of its distribution for each treatment arm via the Kaplan-Meier method and a stratified log-rank test. For patients who die prior to WBRT, time to WBRT will be censored at time of death.
Time frame: Up to 5 years
Incidence of adverse events (AEs)
AEs will be graded according to Common Terminology Criteria in Adverse Events version 5.0. Comprehensive summaries of all AEs by treatment arm will be generated and examined. Counts and frequencies of worst AE per patients 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 arms. Frequencies for specific potentially treatment related AEs where grade 3 or higher events are noted may be compared. Any frequencies to be tested will be evaluated using the chi-square or exact test as appropriate, with two-sided significance level of 0.05.
Time frame: Up to 2 years from start of radiation treatment
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Kaiser Permanente-Bellflower
Bellflower, California, United States
RECRUITINGCity of Hope Corona
Corona, California, United States
RECRUITINGCity of Hope Comprehensive Cancer Center
Duarte, California, United States
RECRUITINGUC San Diego Health System - Encinitas
Encinitas, California, United States
RECRUITINGUCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
Irvine, California, United States
RECRUITINGCity of Hope at Irvine Lennar
Irvine, California, United States
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