Age-stratified comorbid and pharmacologic analysis of patients with glioblastoma

Abstract

Background: Increased age is a strong and unfavorable prognostic factor for patients with glioblastoma (GBM). However, the relationships between stratified patient age, comorbidities, and medications have yet to be explored in GBM patient survival analyses.

Objective: To evaluate co-morbid conditions, tumor-related symptoms, medication prescriptions, and subject age for patients with GBM and to establish potential targets for prospective studies.

Methods: Electronic health records for 565 patients with IDHwt GBM were evaluated at a single center between January 1, 2000 and August 9, 2021 were retrospectively assessed. Data were stratified by MGMT promoter methylation status when available and were used to construct multivariable time-dependent cox models and intra-cohort hazards.

Results: Younger (<65 years of age) but not older (≥65 years) GBM patients demonstrated a worse prognosis with movement related disabilities (P < 0.0001), gait/balance difficulty (P = 0.04) and weakness (P = 0.007), as well as psychiatric conditions, mental health disorders (P = 0.002) and anxiety (P = 0.001). In contrast, older but not younger GBM patients demonstrated a worse prognosis with epilepsy (P = 0.039). Both groups had worse survival with confusion/altered mental status (P = 0.023 vs < 0.000) and an improved survival with a Temozolomide prescription. Older but not younger GBM patients experienced an improved hazard with a prescription of ace-inhibitor medications (P = 0.048).

Conclusion: Age-dependent novel associations between clinical symptoms and medications prescribed for co-morbid conditions were demonstrated in patients with GBM. The results of the current work support future mechanistic studies that investigate the negative relationship(s) between increased age, comorbidities, and drug therapies for differential clinical decision-making across the lifespan of patients with GBM.

Keywords: Confusion; Delirium; Dementia; Elderly; Glioma.

Fig. 1

Inclusion and exclusion criteria for the analysis of human subjects diagnosed with glioblastoma. All patients were pathologically diagnosed in the Northwestern Medicine system.

Fig. 2

Comparison of frequency for different age groups among the Surveillance, Epidemiology, and End Results (SEER) database and the Northwestern Medicine Enterprise Data Warehouse (NMEDW) database for patients with a diagnosis of glioblastoma (GBM). Human subjects aged 18–39 years old (purple), 40–64 years old (blue), 65–74 (green), and 75+ (yellow) are represented as different fractions of a total population.

Fig. 3

Age-stratified survival of pathologically diagnosed patients with glioblastoma based on data in the Northwestern Medicine Enterprise Data Warehouse. Patients shown as Kaplan-Meier curves are 18–34 years old (blue), 35–44 years old (orange), 45–55 years old (yellow), 55–64 years old (green), 65–74 years old (purple), 75+ years old (red), and the total population (black). mOS: Mean Overall Survival. ns: not significant. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Fig. 4

Kaplan-Meier survival analysis of glioblastoma patients for MGMT methylation status, biopsy vs resection status, and pre-operative KPS stratified by age. (A) 18–64 years of age and (B) 65+ years of age for glioblastoma patients with MGMT methylated (blue) or unmethylated (red) tumor. (C) 18–64 years of age and (D) 65+ years of age for glioblastoma patients that received a tumor resection (blue) vs biopsy (red). (E) 18–64 years of age and (F) 65+ years of age for glioblastoma patients with a pre-operative KPS of 80–100 (blue) and 10–70 (red). mOS: Mean Overall Survival.

Fig. 5

Results of Cox proportional hazard analysis of glioblastoma patient co-morbidities that were stratified by age. Co-morbid hazard ratios were analyzed for younger 18–64 years of age and older 65+ years of age patients with glioblastoma. GI: Gastrointestinal, HTN: Hypertension, AMS: Altered Mental Status. Red bars indicate significant increases in the hazard ratio. *P < 0.05, **P < 0.01, ***P < 0.001.

Fig. 6

Results of Cox proportional hazard analysis of glioblastoma patient tumor survival for related symptoms that were stratified by age. Co-morbid hazard ratios were analyzed for younger 18–64 years of age and older 65+ years of age patients with glioblastoma. DVT: Deep Venous Thrombosis, PE: Pulmonary Embolism. Red bars indicate significant increases in the hazard ratio. *P < 0.05, **P < 0.01.

Fig. 7

Results of Cox proportional hazard analysis of glioblastoma patient tumor survival for medication prescription that were stratified by age. Co-morbid hazard ratios were analyzed for younger 18–64 years of age and older 65+ years of age patients with glioblastoma. SSRI: Selective Serotonin Reuptake Inhibitors, SNRIs: Serotonin and Norepinephrine Reuptake Inhibitors, TCAs: Tricyclic Antidepressants, GAD: Generalized Anxiety Disorder medications, ACE: Angiotensin-Converting Enzyme, ARBs, Angiotensin II Receptor Blockers, TMZ: Temozolomide. Blue bars indicate significant decreases in hazard ratio. Red bars indicate significant increases in the hazard ratio. *P < 0.05, **P < 0.01, ****P < 0.0001.

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