Local Treatment Strategies for Brain Metastases of Gastric and Esophageal Cancer: An International Observational Multicenter Retrospective Cohort Study (GASTROBRAIN)
Local Treatment Strategies for Brain Metastases of Gastric and Esophageal Cancer: An International Observational Multicenter Retrospective Cohort Study (GASTROBRAIN)
GASTROBRAIN trial is an international (2 countries) observational, multicenter (15 centers) retrospective cohort study designed to investigate local treatment strategies for brain metastases of gastric and esophageal cancer
Brain metastases (BM) arising from gastric cancer (GC) and esophageal cancer (EC) represent a rare but devastating complication of upper gastrointestinal malignancies. Historical estimates have placed the incidence of BM in this population at well below 1%, with some of the earliest large series reporting figures as low as 0.16% to 0.7%. This rarity, however, belies the clinical significance of the problem. Despite advances in systemic therapy, the prognosis for these patients has remained stubbornly poor, with median overall survival still measured in months.
The paucity of data directly resulting from this low incidence has created a critical knowledge gap. The current evidence base is fragmented, consisting predominantly of small, single-center case series. These studies are inherently limited by selection bias and lack the statistical power to draw definitive conclusions about the optimal sequencing and comparative effectiveness of various local treatment modalities.
This lack of high-level evidence has direct clinical consequences. Treatment decisions for patients with BM from GC and EC are frequently extrapolated from data on other solid tumors, such as lung or breast cancer, or are based on institutional preference and physician experience. This uncertainty underscores a profound unmet clinical need for large-scale, real-world data.
Investigators from a multi-institutional international consortium of cancer centers have therefore initiated a collaborative effort to create the largest and most comprehensive dataset of patients with gastric and esophageal cancer brain metastases described to date. Pooling clinical, pathological, molecular, and treatment-related data from patients diagnosed over the past quarter-century (2000-2025), this dataset will enable a robust analysis of modern local treatment patterns, long-term oncological outcomes, and prognostic factors - ultimately seeking to provide evidence-based insights to guide clinical decision-making for this rare and challenging patient population.
The primary objective of this study is to evaluate, in a large multi-institutional real-world cohort, the effectiveness of the following local treatment modalities for gastric and esophageal cancer brain metastases:
Neurosurgical resection (NRS):
Radiotherapy (RT):
Combined local treatment modalities:
No local treatment
Data to be collected for each patient will include:
Demographics and Baseline Characteristics
Primary Tumor Characteristics
TNM classification (8th edition: T, N, M categories with subcategories, including X when unknown)
Disease stage at initial diagnosis (I-II, III, IV, unknown)
History of primary tumor resection (yes/no/unknown)
Primary tumor location (Esophagus, Gastroesophageal Junction (GEJ), Stomach)
Histology (gastric adenocarcinoma, esophageal adenocarcinoma, esophageal squamous cell carcinoma, unknown)
Grade:
Lauren classification (applicable to gastric adenocarcinoma): intestinal, diffuse, mixed, unclassified, unknown
Extracranial Disease Burden:
At initial cancer diagnosis:
At the time of BM diagnosis:
Intracranial Tumor Characteristics
Clinical Presentation
Timing of BM diagnosis:
- Synchronous (within 60 days of primary tumor diagnosis or as initial presentation)
Neurological symptoms at BM diagnosis (symptomatic, asymptomatic, unknown)
Presence of neurological deficit at BM diagnosis (yes/no/unknown)
Neurological syndromes at BM diagnosis (global cerebral symptoms (headache, nausea, vomiting, dizziness), aphasic, dysarthric, pyramidal, sensory, extrapyramidal, cerebellar/vestibulo-ataxic, bulbar, pseudobulbar, paroxysmal, cognitive, brainstem, visual, meningeal, occlusive, behavioral, unknown)
Eastern Cooperative Oncology Group (ECOG) performance status at BM diagnosis (0-1, 2-3, unknown)
Molecular Profile (where available)
Primary tumor:
- HER2 status (positive/negative/unknown)
Brain metastases:
Treatment-Related Data
Systemic therapy prior to first local treatment (yes/no)
Lines of systemic therapy prior to BM diagnosis (number; categorized as 0, 1, 2, 3, 4, ≥ 5, unknown)
Systemic therapy after first local treatment (yes/no)
Lines of systemic therapy after first local treatment (number)
Number of local treatments per patient (median with range)
For radiotherapy:
- Radiation therapy device (Leksell Gamma Knife, Accuray CyberKnife, Varian TrueBeam/Novalis Tx, non-stereotactic linac, other)
- Biologically effective dose (BED) (Gy, median with range)
Institutional and Period Data
Institution type (federal center, reference center, regional center)
Treatment period (by year of primary cancer diagnosis):
Primary Endpoints:
Overall Survival (OS): Defined as the time from the date of brain metastasis (BM) diagnosis to the date of death from any cause or last follow-up (censored).
Time to Intracranial Progression (TTIP): Defined as the time from the date of initial gastric and esophageal cancer diagnosis to the date of first BM detection. Based on this interval, patients will be categorized into two groups:
- Synchronous BM: BM diagnosed either prior to or within 2 months (≤ 60 days) of the primary tumor diagnosis.
- Metachronous BM: BM diagnosed more than 2 months (> 60 days) after the primary tumor diagnosis.
Central Nervous System Progression-Free Survival (CNS-PFS): Defined as the time from the date of first local treatment for BM to the date of subsequent intracranial progression or last instrumental follow-up (censored). Subsequent intracranial progression includes:
Secondary Endpoints:
Statistical Analysis. All statistical analyses will be performed using IBM SPSS Statistics (version 29.0) and STATA (version 17.0, StataCorp LLC). A two-sided p-value < 0.05 will be considered statistically significant.
For analyses of cause-specific death, competing risks methodology will be employed to estimate the cumulative incidence of death from intracranial progression, extracranial progression, and other causes, with death from competing causes treated as a competing event.
- Univariable and Multivariable Analysis. Univariable analysis will be performed to identify potential prognostic factors associated with survival outcomes. For categorical variables, the log-rank test will be used. For continuous variables, univariable Cox proportional hazards regression will be performed.
Variables with p < 0.10 on univariable analysis, as well as clinically relevant factors regardless of significance, will be entered into multivariable Cox proportional hazards regression models to identify independent prognostic factors. The proportional hazards assumption will be tested. Results will be presented as hazard ratios (HR) with 95% CI.
- Preplanned subgroup analyses will be performed based on key variables such as local treatment modality, molecular profile, primary tumor location, timing of brain metastases (synchronous vs. metachronous), and presence of extracranial disease.
Specific Analyses:
Handling of Missing Data. The proportion of missing data will be reported for all variables. Patterns of missingness will be explored. Where appropriate and assuming data are missing at random, multiple imputation using chained equations (MICE) will be performed to impute missing values for key variables in multivariable models.
The results of this large-scale, international study aim to provide high-level evidence to guide clinical decision-making and pave the way for personalized treatment approaches for this rare but challenging patient population.
Inclusion Criteria:
Male and female patients aged 18 years or older;
Histologically confirmed epithelial malignancy of the stomach (gastric adenocarcinoma), esophagus (esophageal adenocarcinoma), or gastroesophageal junction (GEJ adenocarcinoma). Patients with squamous cell carcinoma of the esophagus are also eligible;
Radiologically ± histologically confirmed brain metastases, including:
Exclusion Criteria: