A Phase II Study of Hippocampal-Avoidance Using Proton Therapy in Low-Grade Glioma
Status:
Not yet recruiting
Trial end date:
2028-05-01
Target enrollment:
Participant gender:
Summary
Low-grade gliomas (LGGs) are the most common brain tumors in children, and a subset of these
tumors are treated definitively with focal radiation therapy (RT). These patients often
survive for many years after receiving RT and experience late deficits in memory. Verbal
recall is an important measure of memory and is associated with other important functional
outcomes, such as problem-solving, independence of every-day functioning, and quality of
life. Decline in memory, as measured by verbal recall, is associated with RT dose to the
hippocampi. Therefore, this phase II study investigates the feasibility of reducing RT doses
to the hippocampi (i.e., hippocampal avoidance [HA]) by using proton therapy for midline or
suprasellar LGGs.
Primary Objective:
- To determine the feasibility of HA with proton therapy in suprasellar or midline LGGs.
Feasibility will be established if 70% of plans meet the first or second dose
constraints shown below.
1. First priority RT dose constraints for bilateral hippocampi: volume receiving 40
CGE (V40CGE) ≤ 25%, dose to 100% of Hippocampus (D100%) ≤ 5CGE.
2. Second priority RT dose constraints for bilateral hippocampi: V40CGE ≤ 35%, D100% ≤
10 CGE.
Secondary Objectives:
- To estimate the 3-year event-free-survival (EFS) for LGGs treated with HA.
- To estimate the change in California Verbal Learning Test short-term delay (CVLT-SD)
from baseline to 3 years and from baseline to 5 years
- To compare CVLT-SD and Cogstate neurocognitive scores in patients with proton therapy
plans that: (1) meet first priority RT dose constraints, (2) meet second priority RT
dose constraints but not first priority RT dose constraints, and (3) that did not meet
either first or second RT priority dose constrains (i.e. HA was not feasible).
- To investigate the effect of BRAF alteration, tumor histology and tumor location on
progression-free survival (PFS) and overall survival (OS) in a prospective cohort of
patients treated in a homogenous manner.
- To investigate whether the methylation profiles of LGGs differ across tumor locations
(thalamic/midbrain vs. hypothalamic/optic pathway vs. others) and histologies (pilocytic
astrocytoma vs. diffuse astrocytoma vs. others), which, in conjunction with specific
genetic alterations, may stratify patients into different subgroups and highlight
different therapeutic targets.
- To record longitudinal measures of circulating tumor DNA (ctDNA) in plasma and correlate
these measures with radiographic evidence of disease progression.
- To bank formalin-fixed, paraffin-embedded (FFPE)/frozen tumors and whole blood from
subjects for subsequent biology studies not currently defined in this protocol.
- To quantify and characterize tumor infiltrating lymphocytes (TILs) and to characterize
the epigenetics of T cells and the T cell receptor repertoire within the tumor
microenvironment.
- To estimate the cumulative incidence of endocrine deficiencies, vision loss, hearing
loss and vasculopathy after proton therapy and compare these data to those after photon
therapy.
Exploratory Objectives:
- To describe the change in overall cognitive performance from baseline to 3 years and
from baseline to 5 years with an age appropriate battery, including gold standard
measures shown in the published studies to be sensitive to attention, memory processing
speed and executive function that will afford comparison to historical controls.
- To characterize longitudinal changes in connection strength within brain networks in the
first 3 years after proton therapy and to investigate associations between these changes
and neurocognitive performance with focus on the hippocampi.
- To correlate the distribution and change in L-methyl-11C-methionine positron emission
tomography (MET-PET) uptake to tumor progression and from baseline to 3 years and to
investigate whether cases of pseudoprogression exhibit a differential pattern of uptake
and distribution than do cases of true progression after controlling for histology.
- To investigate the effect of BRAF alteration, tumor histology and tumor location on PFS
and OS in a prospective cohort of patients treated in a homogenous manner.
- To record longitudinal measures of circulating tumor DNA (ctDNA) in plasma and correlate
these measures with radiographic evidence of disease progression.
- To bank formalin-fixed, paraffin-embedded (FFPE)/frozen tumors and whole blood from
subjects for subsequent biology studies not currently defined in this protocol.
- To quantify and characterize tumor infiltrating lymphocytes (TILs) and to characterize
the epigenetics of T cells and the T cell receptor repertoire within the tumor
microenvironment.
- To estimate the cumulative incidence of endocrine deficiencies, vision loss, hearing
loss and vasculopathy after proton therapy and compare these data to those after photon
therapy.