The 5-factor Modified Frailty Index as a Prognostic Factor for Stereotactic Radiosurgery in Meningioma Management

doi:10.21203/rs.3.rs-5130586/v1

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The 5-factor Modified Frailty Index as a Prognostic Factor for Stereotactic Radiosurgery in Meningioma Management

https://doi.org/10.21203/rs.3.rs-5130586/v1

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published 14 Nov, 2024

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Purpose

Meningiomas are the most frequent primary intracranial malignancy. While surgical resection can confer long term tumor control, stereotactic radiosurgery (SRS) is often used for small, asymptomatic tumors in the adjuvant setting. Frailty has been associated with increased rates of peri-operative morbidity but has yet to be defined in the setting of SRS for meningiomas. We therefore sought to examine the relationship between frailty and clinical/radiographic outcomes of patients with meningiomas who have undergone SRS.

Methods

A single-center, retrospective cohort study classified patients by their 5-factor modified frailty index (mFI-5) score into pre-frail (0–1) and frail (2–5) at the time of SRS treatment. Evaluations of overall survival (OS) and progression free survival (PFS) were performed using Kaplan-Meier analysis. Cox proportional hazards regression analysis was used to further define factors associated with OS/PFS.

Results

94 patients met inclusion criteria and underwent SRS for meningioma treatment from 2019–2023. Analyses compared prefrail (0–1) and frail (2–5) individuals. Kaplan-Meier analysis demonstrated an association between frailty and OS (24-month survival: 73.8%) in the frail group versus the pre-frail group (24-month survival: 90.6%, p = 0.053 HR = 3.68). There was a significant relationship between frailty and PFS (12-month PFS: 68.8%) in the frail group versus the pre-frail group (12-month PFS: 92.9%, p < 0.05 HR = 2.95). Univariable regression analysis demonstrated that frailty, prior surgical excision, and cumulative tumor volume predicted PFS.

Conclusion

Frailty, as assessed by the mFI-5, did not independently predict OS but did predict PFS in individuals with meningioma undergoing SRS.

frailty

stereotactic radiosurgery

meningioma

mFI-5

Meningiomas, with an incidence rate of 7.86 cases per 100,000 people per year, have been identified as the most common primary intracranial tumor [1]. They are further classified into WHO grades I, II, and III based on certain histological features, brain invasion and mitotic rate [2]. The CBTRUS Statistical Report from 2012–2016 reported the incidence of meningiomas WHO grades I, II, and III were 80.5%, 17.7%, and 1.7%, respectively [3]. The relative 10-year survival rates of patients with meningioma are 96.8% (WHO grade I), 90.2% (WHO grade II) and 30.4% (WHO grade III) [4].

Surgical excision is often employed for large, symptomatic tumors or higher grade meningiomas [5]. Radiotherapy, specifically stereotactic radiosurgery (SRS) has been increasingly used to treat small, asymptomatic meningiomas and is often utilized in the adjuvant setting, especially for high grade meningiomas [6].

Frailty has been identified as an independent risk factor for patients with central nervous system (CNS) malignancy demonstrating an associated increase in mortality and postoperative complications [7]. Two widely utilized metrics are the Charlson Comorbidity Index (CCI) and the 11-factor modified frailty index (mFI-11), which effectively have identified patients as frail, or at high risk, during surgical intervention. Although effective, these tools are not practical in the clinical setting [8, 19]. To provide a more practical tool a simplified 5-factor modified frailty index (mFI-5), as described in Table 1, was developed. An increase in mFI-5 has demonstrated an increased likelihood of postoperative mortality and complications in patients with brain metastases and gliomas [10, 11].

Frailty has not been adequately studied in patients undergoing SRS with meningiomas. As SRS is often utilized in patients with meningiomas who have undergone prior surgical excision or who are at increased risk for complications following craniotomy, understanding the impact of patient frailty on radiosurgical outcomes is imperative in this setting. As a result, we sought to study the relationship between frailty and tumor control, as well as overall survival, in patients with WHO grade I, II and III meningiomas undergoing SRS.

A single-center retrospective cohort study was performed. Patients with a diagnosis of meningioma receiving SRS between May 2019 and May 2023 were identified using an institutional database. Institutional review board approval was obtained.

Patients were treated with frame or mask-based SRS using the Gamma Knife Icon Unit (Elekta, Stockholm, Sweden), 1–5 fractions were utilized, and dose selection was determined by the treating neurosurgeon, radiation oncologist and radiation physicist.

A retrospective review of radiographic and clinical data obtained manually from patient electronic health records was then conducted. Baseline demographics including patient age, sex, meningioma location, WHO classification and cancer treatment history were assessed. mFI-5 score of 0–5 was determined by history of diabetes mellitus, hypertension, chronic obstructive pulmonary disease, congestive heart failure and need for assistance in activities of daily living (ADLs) as determined by a Karnofsky performance status (KPS) ≤ 60 prior to SRS treatment.

Given the power of our study we aggregated the results of frail patients (mFI-5 2–3) and severely frail (mFI-5 3+) and compared that group against pre-frail patients (mFI-5 0–1) for our final analysis. Quantitative variables were analyzed using the two-sample t-test or Wilcoxon rank sum test and are presented as mean ± standard deviation or median (interquartile range). Categorical variables were analyzed using Pearson’s chi-squared test or Fisher’s exact test and are reported as count (percentage). Overall survival (OS), progression-free survival (PFS), loss of local control and loss of global control were analyzed using a Kaplan-Meier survival analysis. Survival probabilities are reported with 95% confidence intervals (CIs).

Univariable Cox proportional-hazards regression was performed to determine whether frailty (based on mFI-5), age, sex, prior surgical excision, interval from surgery to radiosurgery and cumulative tumor volume were associated with OS and PFS. To obtain a potentially less-biased estimate for the association between frailty category and both OS and PFS, bivariable models with the covariates of frailty category and each variable that almost approached significance (P < 0.10) in the univariable model were fit to the data. Hazard ratios (HRs) are reported with 95% CIs.

A significance level α of 0.05 was used for all tests. All analyses were performed using R version 4.2.1.

Ninety-three patients met inclusion criteria and were evaluated in this retrospective review, with clinical and demographic characteristics presented in Table 1. The mean age of patients in the pre-frail group was 64.0 ± 12.3 with 57 (72%) being females and 22 (28%) being males. The mean age of patients in the frail group was 67.1 ± 10.2 with 10 (71%) being females and 4 (29%) being males. The median radiographic and clinical follow-up times of all patients were 13- and 16 months for frail and pre-frail patients respectively. Most patients were classified as prefrail (79, 84.9%) and the remainder classified as a group of frail/severely frail (14, 15.1%). No significant difference was observed between the two groups regarding age, sex, BMI or race.

Table 1

Baseline patient demographics of patients receiving SRS for Meningioma
	Variable	Pre-frail (n = 79)	Frail or Severely Frail (n = 14)	P
Frailty	mFI-5	0 (0–1)	2 (2–2)	N/A
Patient Characteristics	Age (years)	64.0 ± 12.3	67.1 ± 10.2	0.38
	Female Sex	57 (72.2%)	10 (71.0%)	0.99
	Body Mass Index (kg/m²)	30.6 ± 7.0	32.1 ± 7.0	0.44
	Race 1. White 2. Black 3. Asian	74 (93.7%) 3 (3.8%) 2 (2.5%)	12 (85.7%) 2 (14.3%) 0 (0.0%)	0.28
	Hispanic or Latino Ethnicity	1 (1.3%)	0 (0.0%)	0.99
	KPS > = 90	61 (77.2%)	8 (57.1%)	0.18
mFI-5 Components	Hypertension	32 (40.5%)	13 (92.9%)	0.0009*
	COPD	2 (2.5%)	2 (14.3%)	0.11
	Diabetes	2 (2.5%)	11 (78.6%)	< 0.0001*
	CHF	0 (0.0%)	2 (14.3%)	0.021*
	Need Assistance	0 (0.0%)	2 (14.3%)	0.021*
Prior Treatment	Surgical Excision	43 (54.4%)	10 (71.4%)	0.37
	Gamma Knife	3 (3.8%)	1 (7.1%)	0.49
	External Beam Radiation	10 (12.7%)	4 (28.6%)	0.21
	Medical Management	0 (0.0%)	0 (0.0%)	0.99
Follow-up	Clinical (months)	16 (10–27)	13 (10–24)	0.61
Follow-up	Radiographic (months)	15 (9–27)	11 (7–20)	0.30
Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; KPS, Karnofsky performance status; mFI-5, 5-factor modified frailty index Quantitative data presented as mean ± standard deviation or median (interquartile range). Categorical data presented as count (percentage). *P < 0.05 significant

As expected, patients in the frail cohort had increased rates of hypertension, diabetes, heart failure and the need for assistance with daily living (Table 1). The rates of COPD were similar in both cohorts.

Most patients in both groups had undergone surgical excision prior to SRS with a notably higher proportion in the frail/severely frail group (10, 74.1%) compared to the pre-frail group (43, 54.4%), although this was not found to be significant. The history of prior external beam whole brain radiation was less common but still more frequent in the frail/severely frail group (4, 28.6%) versus the pre-frail group (10, 12.7%), although this was also not found to be significant.

Table 2

Tumor and Radiosurgery Information
Variable	Pre-frail (n = 79)	Frail or Severely Frail (n = 14)	P
Tumor Location 1. Cavernous 2. Cerebellopontine Angle 3. Convexity 4. Intraventricular 5. Parafalcine 6. Parasaggital 7. Skull Base	3 (3.8%) 4 (5.1%) 15 (19.0%) 1 (1.3%) 17 (21.5%) 12 (15.2%) 27 (34.2%)	0 (0.0%) 0 (0.0%) 1 (7.1%) 0 (0.0%) 6 (42.9%) 1 (7.1%) 6 (42.9%)	0.61
Cumulative Tumor Volume (cm³)	6.3 ± 7.3	12.1 ± 13.5	0.021***
WHO Classification * 1. Grade 1 2. Grade 2 3. Grade 3	23/43 (53.5%) 20/43 (46.5%) 0/43 (0.0%)	3/9 (33.3%) 6/9 (66.7%) 0/9 (0.0%)	0.47
Interval between Prior Surgery and SRS (months)**	57.9 ± 71.9	32.4 ± 46.2	0.29
Tumor Resection Cavity Treatment Only	32 (43.2%)	8 (61.5%)	0.36
Number of Tumors Treated	1 (1–1)	1 (1–1)	0.88
Fractions of SRS	5 (3–5)	5 (3–5)	0.86
Margin Dose (Gy)	23.4 ± 5.6	25.0 ± 5.2	0.31
Maximal Dose (Gy)	46.6 ± 11.3	50.1 ± 10.5	0.28
Abbreviations: SRS, stereotactic radiosurgery; WHO, World Health Organization Quantitative data presented as mean ± standard deviation or median (interquartile range). Categorical data presented as count (percentage). * Of the 52 patients for whom histopathologic analysis was available Of the 52 patients who underwent surgical intervention *P < 0.05 significant

Within this cohort of patients, pathology was available for 52 patients (55.9%) and pathology revealed 26 patients with WHO grade I meningiomas and 26 with WHO grade II meningiomas (Table 2). Pre-frail patients had a smaller proportion of confirmed higher grade meningiomas with 23 patients (53.5%) having WHO grade I meningiomas and 20 patients (46.5%) having WHO grade II meningiomas. The frail group demonstrated a predilection towards higher grade meningiomas with 66.7% (n = 6) confirmed as WHO grade II and 33.3% (n = 3) confirmed WHO grade I, although this was not significant. The frail group also demonstrated a significantly (p = 0.021) greater tumor volume (12.1 ± 13.5) vs. the pre-frail group (6.3 ± 7.3). Radiosurgical variables were similar across both cohorts (Table 2).

Kaplan-Meier analysis demonstrated a significant association (P = 0.02) between frailty and PFS (Fig. 1). The probability of PFS at one year was 92.9% (87.1–99.2%) for pre-frail patients and 68.8% (47.4–99.8%) for frail patients. The two-year probability of PFS was 73.6% (61.0-88.9%) for pre-frail patients and 55.0% (31.0-97.8%) for frail patients.

Figure 1. (a) Kaplan-meier plot of overall survival for all patients at 36 months. (b) Kaplan-meier plot of progression free survival at 36 months. (c) Kaplan-meier plot of overall survival at 36 months stratified by frailty status (d) Kaplan-meier plot of progression free survival at 36 months stratified by frailty status.

On univariate analysis (Table 3) there was an association between frailty and progression free survival (PFS) (HR: 2.95 (1.09–7.59); P = 0.033). Prior surgical excision, interval between surgery and radiosurgery and cumulative tumor volume were all associated with earlier tumor progression. In a bivariable model adjusting for interval to radiosurgery, frailty maintained an association with PFS (HR for frailty: 3.45 (1.07–11.07); P = 0.038). Of note, prior surgical excision may represent a clinically significant risk factor of progression.

Table 3

Univariable Regression Analysis of overall survival and progression-free survival
Predictor	Hazard Ratio (95% CI)	P
Overall Survival
Frail Status (mFI-5 ≥ 2)	3.68 (0.88–15.45)	0.075*
Age (years)	1.06 (1.00-1.13)	0.060*
Female Sex	3.21 (0.39–26.10)	0.28
Prior Surgical Excision	2.38 (0.48–11.82)	0.28
Interval between Prior Surgery and Radiosurgery (months)	1.01 (1.00-1.02)	0.044*
Cumulative Tumor Volume (cm3)	1.03 (0.97–1.10)	0.30
WHO Classification 1. Grade 1 2. Grade 2	(Reference) 1.93 (0.46–8.21)	0.37
Progression Free Survival
Frail Status (mFI-5 ≥ 2)	2.95 (1.12–7.81)	0.029*
Age (years)	1.02 (0.97–1.06)	0.46
Female Sex	1.00 (0.38–2.63)	0.99
Prior Surgical Excision	3.27 (1.08–9.86)	0.035*
Interval between Prior Surgery and Radiosurgery (months)	1.01 (1.00-1.01)	0.049*
Cumulative Tumor Volume (cm³)	1.05 (1.01–1.08)	0.015*
WHO Classification 1. Grade 1 2. Grade 2	(Reference) 4.27 (1.71–10.64)	0.0018*
Abbreviations: CI, confidence interval; mFI-5, 5-factor modified frailty index; WHO, World Health Organization *P < 0.05 significant

There was a trend towards diminished OS with increasing frailty after SRS for meningiomas although this did not achieve statistical significance (p = 0.05). The one-year probability of OS was 95.5% (90.6–100.0%) for pre-frail patients and 92.3% (78.9–100.0%) for frail patients. While the probability of two-year survival demonstrated a larger drop for frail patients at 73.8% (46.4–100.0%) vs. 90.6% (82.8–99.2%) for pre-frail patients.

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.

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

The authors have no relevant financial or non-financial interests to disclose.

Author Contribution

SH and MS were responsible for study design, conceptualization and data collection planning. MS, RW, AY and SK contributed to IRB writing and submission. PV was responsible for statistical design and analysis. SH was responsible for data collection through chart review. PV and TK were responsible for figure preparation. All authors contributed to main manuscript writing, editing and formatting.

Data Availability

Data obtained from patient records and utilized for analysis and generation of results cannot be publicly shared in order to protect patient privacy.

Wiemels J, Wrensch M, Clause EB (2010) Epidemiology and etiology of meningioma. J Neurooncol 99:307–314. https://doi.org/10.1007/s11060-010-0386-3
Goldbrunner R et al (2021) EANO guideline on the diagnosis and management of meningiomas. Neuro Oncol 2311:1821–1834. https://doi.org/10.1093/neuonc/noab150
Ostrom QT et al (2019) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol 21.Supplement_5: v1-v100. https://doi.org/10.1093/neuonc/noz150
Holleczek B et al (2019) Incidence, mortality and outcome of meningiomas: a population-based study from Germany. Cancer Epidemiol 62:101562. https://doi.org/10.1016/j.canep.2019.07.001
Zhao L et al (2020) An Overview of Managements in Meningiomas. Front Oncol 10:1523. https://doi.org/10.3389/fonc.2020.01523
Shepard M et al (2021) Stereotactic Radiosurgery for Atypical (World Health Organization II) and Anaplastic (World Health Organization III) Meningiomas: Results From a Multicenter. Int Cohort Study Neurosurg 88(5):980–988. https://doi.org/10.1093/neuros/nyaa553
Zhu J et al (2023) Frailty as a predictor of neurosurgical outcomes in brain tumor patients: A systematic review and meta-analysis. Front Psychiatry 14:1126123. https://doi.org/10.3389/fpsyt.2023.1126123
Ening G, Osterheld F, Capper D, Schmieder K, Brenke C (2015) Charlson comorbidity index: an additional prognostic parameter for preoperative glioblastoma patient stratification. J Cancer Res Clin Oncol 141:1131–1137. https://doi.org/10.1007/s00432-014-1907-9
Youngerman BE et al (2018) The modified frailty index and 30-day adverse events in oncologic neurosurgery. J Neurooncol 136:197–206. https://doi.org/10.1007/s11060-017-2644-0
Khalafallah AM, Huq S, Jiminez AE, Brem H, Mukherjee D (2020) The 5-factor modified frailty index: an effective predictor of mortality in brain tumor patients. J Neurosurg 135:78–86. https://doi.org/10.3171/2020.5.JNS20766
Huq S et al (2020) Predicting Postoperative Outcomes in Brain Tumor Patients With a 5-Factor Modified Frailty Index. Neurosurgery 88:147–154. https://doi.org/10.1093/neuros/nyaa335
Lucido T et al (2023) The 5-factor modified frailty index as a prognostic factor of stereotactic radiosurgery for metastatic disease to the brain. Neurosurgery 140(4):929–937. https://doi.org/10.3171/2023.7.JNS231214
Yao X, Li H, Leng SX (2011) Inflammation and immune system alterations in frailty. Clin Geriatr Med 27(1):79–87. https://doi.org/10.1016/j.cger.2010.08.002
Russell JS, Brown JM The irradiated tumor microenvironment: role of tumor-associated macrophages in vascular recovery. Front Physiol 4:157. https:/doi.org/10.3389/fphys.2013.00157
Gillis C et al (2018) Effects of Nutritional Prehabilitation, With and Without Exercise, on Outcomes of Patients Who Undergo Colorectal Surgery: A Systematic Review and Meta-analysis. Gastroenterology 155(2):391–410e4. https://doi.org/10.1053/j.gastro.2018.05.012
Molenaar CJL, Papen-Botterhuis NE, Herrle F, Slooter GD (2019) Prehabilitation, making patients fit for surgery - a new frontier in perioperative care. Innov Surg Sci 4(4):132–138. https://doi.org/10.1515/iss-2019-0017
Ligibel JA et al (2019) Impact of a Pre-Operative Exercise Intervention on Breast Cancer Proliferation and Gene Expression: Results from the Pre-Operative Health and Body (PreHAB) Study. Clin Cancer Res 25(17):5398–5406. https://doi.org/10.1158/1078-0432.CCR-18-3143
Liu N, Song SY, Jiang JB, Wang TJ, Yan CX (2020) The prognostic role of Ki-67/MIB-1 in meningioma: A systematic review with meta-analysis. Med (Baltim) 99(9):e18644. https://doi.org/10.1097/MD.0000000000018644
Jensen RL (2009) Brain tumor hypoxia: tumorigenesis, angiogenesis, imaging, pseudoprogression, and as a therapeutic target. J Neurooncol 92:317–335. https://doi.org/10.1007/s11060-009-9827-2
Ferraro DJ et al (2014) A retrospective analysis of survival and prognostic factors after stereotactic radiosurgery for aggressive meningiomas. Radiat Oncol 9:38. https://doi.org/10.1186/1748-717X-9-38

No competing interests reported.

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You are reading this latest preprint version

The 5-factor Modified Frailty Index as a Prognostic Factor for Stereotactic Radiosurgery in Meningioma Management

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