In the challenging domain of neuro-oncology, the intersection of advanced age and aggressive brain tumors presents a critical hurdle to improving patient outcomes. A new retrospective study conducted by researchers at TUM University Hospital spanning two decades (2001-2021) shines a light on the complex influence of comorbidities on elderly patients diagnosed with high-grade gliomas (HGG), including glioblastoma (GBM), particularly focusing on their response to radiotherapy (RT) and concurrent chemoradiotherapy (CRT). Their findings have profound implications for treatment personalization and prognostication in this vulnerable population.
High-grade gliomas, notorious for their aggressive progression and poor prognosis, disproportionately affect the elderly, whose physiological resilience is often compromised by co-existing medical conditions. This study employs the age-adjusted Charlson Comorbidity Index (ACCI), a composite metric integrating patient age and existing comorbidities, to stratify elderly HGG patients on the basis of their overall health burden. The ACCI’s prognostic utility has been validated in multiple oncological settings, but its precise role in guiding therapy decisions and predicting outcomes in elderly glioma patients remained insufficiently explored until now.
Analyzing clinical data from 163 elderly HGG patients treated with either RT alone or CRT, the researchers sought to dissect survival outcomes linked to different comorbidity burdens. Patients were classified into two groups based on their ACCI scores: those with lower scores (≤5) representing a relatively lower comorbidity burden, and those with higher scores (≥6), indicative of more significant health challenges. Intriguingly, while patients with higher ACCI scores displayed a reduction in median overall survival (OS)—14.8 months compared to 22.6 months in the lower ACCI group—this difference did not achieve statistical significance, highlighting the nuanced role of comorbidity in survival prediction.
Delving deeper, the study uncovers that in patients with a lower comorbidity burden (ACCI ≤5), hypofractionated radiotherapy (hRT) alone was significantly associated with poorer OS compared to the standard Stupp protocol—a combination of radiotherapy with concomitant and adjuvant temozolomide chemotherapy—illustrated by a hazard ratio (HR) of 85.7. This stark contrast underscores the continued relevance of aggressive combinational treatment in healthier elderly patients. Conversely, for those with higher ACCI scores, no significant survival differences emerged between various treatment regimens, perhaps reflecting a ceiling effect imposed by frailty and existing comorbidities.
The protective role of hRT was particularly pronounced in progression-free survival (PFS) among patients with ACCI ≥6, suggesting that hypofractionation might better align with the physiological tolerances and comorbid profiles of these patients. Moreover, the molecular landscape remained an important determinant of outcomes. Methylation of the MGMT gene promoter, a well-established biomarker signaling enhanced chemo-sensitivity and better prognosis, emerged as a robust predictor of both OS and PFS across comorbidity groups, reaffirming the importance of molecular-based stratification.
Notably, the study highlights diabetes mellitus—specifically without complications—as a potent, independent predictor of worse survival outcomes. Patients bearing this diagnosis had nearly threefold higher risk of mortality and tumor progression. The interplay between diabetes and the ACCI score further complicated prognostic predictions, with a significant interaction indicating a more nuanced impact of diabetes across comorbidity strata. Such results hint at the metabolic and systemic inflammatory ramifications of diabetes that may exacerbate glioma pathophysiology and undermine treatment efficacy.
Employing advanced biostatistical techniques, including random survival forest (RSF) modeling and permutation importance measures, the investigators delineated age as the paramount factor influencing OS, while MGMT methylation status predominated in determining PFS. The ACCI, despite its comprehensiveness, exerted only a modest influence on survival predictions, casting doubt on its indispensability as a sole stratification tool in elderly HGG contexts.
The conclusions drawn from this extensive cohort call for a more circumspect utilization of the ACCI in clinical decision-making. Although the overall comorbidity burden undeniably influences outcomes, its predictive reliability appears limited and inconsistent. Diabetes emerges as a singularly significant comorbid condition warranting special attention, perhaps necessitating tailored metabolic control as part of comprehensive glioma management protocols in aged patients.
These findings underscore the urgent need for larger, prospective studies to unravel the complex web of interactions between comorbidities, aging, molecular tumor characteristics, and treatment modalities. Such investigations are vital to refine prognostic models and optimize therapeutic strategies balancing efficacy with tolerability in elderly glioma populations. Furthermore, personalized approaches integrating clinical, molecular, and systemic health parameters hold promise for transforming treatment landscapes.
In clinical practice, this study advocates for nuanced patient assessments that transcend aggregate comorbidity indices. A heightened vigilance toward diabetes management and molecular profiling could empower oncologists to better gauge therapeutic responses and survival trajectories. Radiotherapy fractionation choices should be judiciously aligned with individual patient health status, eschewing a one-size-fits-all mentality, especially in those vulnerable to treatment-related toxicities.
Beyond its immediate clinical relevance, the research enriches the scientific discourse on aging and cancer biology. The intersecting influences of systemic health and tumor aggressiveness render elderly patients a uniquely challenging demographic requiring interdisciplinary management encompassing oncology, endocrinology, geriatrics, and supportive care.
In summary, the investigation dismantles oversimplified assumptions regarding comorbidity indices as standalone prognostic tools in elderly HGG patients treated with RT and CRT. It spotlights diabetes as a pivotal clinical variable and reiterates the indispensability of molecular biomarkers, particularly MGMT methylation, in designing personalized treatment regimens. As the population ages globally, such integrative research is essential to enhancing survival and quality of life for elderly glioma patients.
This study’s insights pave the way for evolving clinical paradigms that prioritize individualized care frameworks sensitive to the heterogeneity inherent among elderly brain tumor patients. They signal a critical step towards optimizing balance between therapeutic aggressiveness and patient resilience — a balance pivotal to extending meaningful survival in this high-risk group.
Subject of Research: Prognostic impact of comorbidity burden measured by the age-adjusted Charlson Comorbidity Index on survival and treatment outcomes in elderly patients with high-grade gliomas undergoing radiotherapy or chemoradiotherapy.
Article Title: Comorbidity burden in elderly high-grade glioma patients: impact on radiotherapy outcomes
Article References: Leiss, S.M., Wiestler, B., Hou, H.X. et al. Comorbidity burden in elderly high-grade glioma patients: impact on radiotherapy outcomes. BMC Cancer 25, 1496 (2025). https://doi.org/10.1186/s12885-025-14957-5
Image Credits: Scienmag.com
DOI: https://doi.org/10.1186/s12885-025-14957-5
