Radiation Disease, Cognitive Impairment, Drug Effect
Conditions
Keywords
radiation induced brain injury, Memantine, Pioglitazone, cognitive function
Brief summary
This clinical trial aims to evaluate the efficacy of early intervention with Memantine and Pioglitazone in preventing Radiation-Induced Brain Injury (RIBI) in patients undergoing cranial radiotherapy. RIBI, a significant complication of radiation therapy for primary and metastatic brain tumors, as well as head and neck cancers, often presents with delayed and irreversible neurological damage, severely affecting patients' quality of life. Our previous studies have indicated that Memantine, an NMDAR antagonist, and Pioglitazone, a PPAR-γ agonist, play crucial roles in modulating the neuroprotective immune microenvironment by targeting key mechanisms of neuron-astrocyte fatty acid metabolism coupling. These findings suggest that early administration of these drugs could protect cognitive function and reduce neuroinflammation in patients post-radiation. This prospective phase II clinical trial will assess the combined efficacy of Memantine and Pioglitazone in improving cognitive outcomes and preventing RIBI without adversely impacting the anti-tumor efficacy of radiation therapy. The study will also explore the synergistic effects of these two FDA-approved drugs in early-stage RIBI prevention, providing a new therapeutic strategy for enhancing the quality of life in cancer patients receiving radiotherapy.
Interventions
Oral administration of Memantine Tablets (10mg/tablet): Week 1: 5mg in the morning. Week 2: 5mg twice daily. Week 3: 10mg in the morning, 5mg in the evening. Weeks 4-24: 10mg twice daily.
Simultaneous oral administration of Pioglitazone Tablets (15mg/tablet): Weeks 1-24: 30mg once daily.
RADIATIONHippocampal avoidance whole-brain radiotherapy (HA-WBRT)
Based on the RTOG 0933 protocol, hippocampal and perihippocampal regions are delineated, and hippocampal dose constraints are applied. The radiation dose to the perihippocampal region is determined based on the size, number, and volume of brain metastases (whole-brain radiation therapy: DT 30Gy/10F, weeks 1-2; with a simultaneous boost to the pathological local area if necessary, 10-20Gy).
Sponsors
Guangdong Provincial People's Hospital
Fujian Medical University Union Hospital
Southern Medical University, China
The Affiliated Panyu Center Hospital of Guangzhou Medical University
The Central Hospital of Shaoyang City
Affiliated Cancer Hospital & Institute of Guangzhou Medical University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Recursive Partitioning Analysis (RPA), Class I \ Class II * Karnofsky Performance Status of ≥70 * The primary tumor must be pathologically confirmed. For newly diagnosed brain metastases, the number of metastases is not limited, but the brain metastases could not have been within 5 mm of hippocampus. Additionally, there must be no hard or soft meningeal metastases. * No history of whole-brain radiation therapy; patients who are eligible for surgical resection of brain metastases prior to radiation therapy are allowed. * Bone marrow function: White blood cell count ≥ 4 × 10⁹/L, hemoglobin ≥ 90 g/L, and platelet count ≥ 100 × 10⁹/L. * Adequate hepatic function: Total bilirubin ≤ 1.5 × ULN (Upper Limit of Normal); ALT (alanine aminotransferase), AST (aspartate aminotransferase) ≤ 2.5 × ULN; ALP (alkaline phosphatase) ≤ 2.5 × ULN and total bilirubin ≤ ULN. * Adequate renal function: creatinine clearance rate ≥ 30 ml/min. * Patients or their legal guardians voluntarily participate and sign the informed consent form.
Exclusion criteria
* Radiographic evidence of hydrocephalus or other architectural distortion of the ventricular system, including placement of external ventricular drain or ventriculoperitoneal shunt. * Planned cytotoxic chemotherapy during the WBRT. * Pregnant or lactating women (Women of childbearing age must undergo a pregnancy test; effective contraception must be enforced during the treatment period). * Previous cranial radiation therapy (Except for patients with head and neck cancer where the disease site is outside the cranial radiation field). * Severe or active symptomatic cardiopulmonary diseases; clinically significant psychiatric disorders; Personality or psychiatric disease; Severe hepatic disease defined as a diagnosis of Child-Pugh class B or C hepatic disease; * Intolerant to or allergic to Memantine or pioglitazone. * Difficulty swallowing, chronic diarrhea, or bowel obstruction. * NYHA class III or IV heart failure or symptomatic peripheral edema (grade 2 or higher); those treated with insulin or oral hypoglycemic agents for steroid-induced hyperglycemia, or those currently using other NMDA antagonists.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| the cumulative incidence of cognitive failure | At weeks 4, 8, 16, 24, 36, and 48 after the completion of radiotherapy | the proportion of participants who experience cognitive impairments after radiation therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Score Decline | At weeks 4, 8, 16, 24, 36, and 48 after the completion of radiotherapy | based on the Reliable Change Index of at least one cognitive test |
| Progressive-free survival for Intracranial Tumors | At weeks 4, 8, 16, 24, 36, and 48 after the completion of radiotherapy | latencies to the first intracranial treatment failure or death from any cause |
| Overall Survival | At weeks 4, 8, 16, 24, 36, and 48 after the completion of radiotherapy | death due to any cause |
Outcome results
None listed