This is the only study examining outcomes in meningioma patients stratified by mFI-5. The results herein suggest that frail patients tend to have decreased PFS and a trend towards diminished OS. SRS in the setting of meningiomas has been established as an efficacious management strategy in a variety of grades and clinical settings. Appropriate patient selection and risk stratification can better inform the timing and ultimately the decision to proceed with therapy.
We have previously examined the influence of frailty, as measured by the mFI-5, in patients undergoing SRS for brain metastases. [12] Previously it was demonstrated that increasing frailty scores were associated with diminished OS and decreased intracranial PFS, which was further corroborated by this study.
It is rational to assume that there is a relationship between increasing frailty and a trend towards diminished OS. However, the direct influence of frailty on intracranial disease control is less clear. In the context of brain metastases, we have previously postulated that increasing frailty may be associated with poor tolerance to systemic chemotherapy, immunotherapy or targeted therapy and as a result earlier intracranial disease progression. [12]
The interplay between frailty and meningioma progression is not understood. In this study, frailty tended to be observed in patients with higher grade tumors and more aggressive prior treatment and thus we cannot exclude that frailty is a confounder here. Notably, however, there was no statistical difference in the incidence of high grade meningiomas in the frail and pre-frail cohorts. Furthermore, many patients without prior surgery were included in this analysis. Our study is underpowered for multivariate analysis and further work will be needed to refine these findings. Nevertheless, it has been previously recognized that increasing frailty is associated with aberrations in baseline levels of inflammation and dysregulation of the adaptive immune response [13]. Thus, there may be a biologic basis supporting increased frailty status and the association with earlier tumor progression.
The post-radiosurgical parenchyma releases a variety of cytokines to recruit monocyte/macrophage cell types to engage in wound healing, tissue debris trafficking, and neo-angiogenesis [14]. The earlier tumor progression seen in frailer patients may be a product of a less robust post-radiosurgical immune response enabling further tumor growth.
One question at hand is whether frailty can be modified to optimize surgical and possibly radiosurgical outcomes. The concept of pre-habilitation has been explored in surgical oncology and gynecologic oncology patients in particular. Patients enrolled in aggressive physical therapy and nutritional optimization prior to surgical intervention have improved surgical outcomes and decreased perioperative morbidity. [15, 16] Likewise, introducing an exercise regimen in patients with breast cancer led to an upregulation of several gene expression pathways involved in immunity and inflammation. [17] Whether a multimodal enhanced recovery pathway has any role in improving patient outcomes in the radiosurgical space is worth exploring, especially in patients who are frail or who have higher grade meningiomas.
Increased tumor volume in meningioma has been associated with higher Ki-67 index and is thought to harbor cell subsets with intrinsic radio resistance and proliferative properties [18]. Thus, it is not surprising that patients with larger tumors on initial presentation tend to undergo local failure with resultant recurrence. It has been demonstrated that tumor volume 4cm3 is associated with increased progression relative to volume below this threshold [19]. Our results corroborated the effect of time from diagnosis to SRS as a negative survival factor [20].
Overall, this study is a novel perspective examining frailty in the context of SRS. For patients with meningiomas, increasing frailty is associated with diminished PFS. As with any retrospective study, there are limitations of our study including the possibility of confounding and recall/selection bias. Very few patients met the criteria for “frail” therefore we combined the two “frail” and “severely frail” subgroups for analysis. As a result, a certain level of granularity may not have been captured while analyzing results across subgroups. We believe this work to be hypothesis generating and further studies will be needed to expand upon these results.