Analysis of radiotherapy in patients with intermediate- and high-risk meningiomas

Jisang Kim; Jin-ho Song; So Jung Lee

doi:10.3857/roj.2025.00248

Radiation Oncology Journal > Volume 43(3); 2025 > Article

Kim, Song, and Lee: Analysis of radiotherapy in patients with intermediate- and high-risk meningiomas

Original Article

Radiation Oncology Journal 2025; 43(3): 135-143.

Published online: September 9, 2025

DOI: https://doi.org/10.3857/roj.2025.00248

Analysis of radiotherapy in patients with intermediate- and high-risk meningiomas

Jisang Kim¹, Jin-ho Song², So Jung Lee¹

¹Department of Radiation Oncology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

²Department of Radiation Oncology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea

Corresponding Author: So Jung Lee Department of Radiation Oncology, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea
Tel: +82-32-280-7390 E-mail: sj_lee@catholic.ac.kr

Received April 24, 2025 Revised June 19, 2025 Accepted July 1, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

This study aimed to investigate treatment outcomes in patients with intermediate- and high-risk meningioma who underwent radiotherapy (RT) and identify prognostic factors for progression-free survival (PFS). In addition, failure patterns after RT were analyzed.

Materials and Methods

We retrospectively reviewed 61 patients with intermediate- and high-risk meningiomas, categorized according to the NRG Oncology/Radiation Therapy Oncology Group 0539 trial, who underwent surgery followed by adjuvant or salvage RT.

Results

We included 12 and 49 patients with intermediate- and high-risk meningiomas, respectively. A total of 26 cases of tumor progression and 17 deaths after RT were identified. The 5-year PFS and overall survival of the entire cohort were 55.8% and 74.2%; intermediate-risk group, 80.2% and 100%; high-risk group, 48.7% and 67.1%, respectively. The World Health Organization (WHO) grade 3 (hazard ratio [HR], 16.7; 95% confidence interval [CI], 3.0 to 92.3; p = 0.001) and recurrent tumor (HR, 41.2; 95% CI, 3.6 to 473.6; p = 0.003) were identified as adverse prognostic factors for PFS in high-risk patients. Among the 15 patients who had recurrence after conventional fractionated radiotherapy (CFRT), 13 experienced local failure (LF) and two experienced distant failure.

Conclusion

RT with adjuvant or salvage intent showed favorable treatment outcomes in patients with intermediate- to high-risk meningioma. WHO grade 3 histology and recurrent tumors were identified as adverse prognostic factors for PFS in high-risk patients. LF was the dominant failure pattern after CFRT, accounting for 86.7% of all recurrences. These findings underscore the need for further studies on dose-escalated RT to enhance local control in patients with these adverse features.

Keywords: Meningioma, Radiotherapy, Treatment failure, Prognosis

Introduction

Meningiomas are the most common primary brain tumors, accounting for 36.1% of all central nervous system neoplasms [1]. Radiotherapy (RT) has been the mainstay of treatment, along with surgery [2,3]. Current guidelines from the European Association of Neuro-Oncology and National Comprehensive Cancer Network recommend postoperative RT for patients with World Health Organization (WHO) grade 2 meningioma following subtotal resection, and for patients with WHO grade 3 meningioma, as a therapeutic modality to reduce recurrence and improve survival [2,3]. A consensus has not been reached regarding the benefit of postoperative RT for patients with WHO grade 2 meningioma who have undergone complete resection [4-6]. Recently, two phase II prospective trials reported favorable progression-free survival (PFS) and overall survival (OS) outcomes following the introduction of postoperative RT in patients with meningioma [7,8]. The NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0539 trial reported favorable outcomes with postoperative RT, showing improvements compared to historical data in patients with intermediate- and high-risk meningioma [7,9]. In this trial, the “intermediate-risk” meningioma was defined as recurrent WHO grade 1 or newly diagnosed WHO grade 2 following gross total resection. “High-risk meningioma” included WHO grade 2 with subtotal resection, recurrent WHO grade 2, and all WHO grade 3 cases. The European Organisation for Research and Treatment of Cancer (EORTC) 22042-26042 trial introduced high-dose postoperative RT (60 Gy) in patients with WHO grade 2 after complete resection and reported superior PFS compared to previous historical data [8]. Both the NRG Oncology/RTOG 0539 and EORTC 22042-26042 trials demonstrated the potential benefits of postoperative RT in improving recurrence and survival outcomes in patients with WHO grade 2-3 meningioma and recurrent grade 1 meningioma. However, despite these findings, patients with high-risk meningioma continue to show relatively poor PFS after postoperative RT. Ongoing studies are investigating dose-escalation RT strategies to improve these outcomes [10,11]. In this study, we aimed to investigate the treatment outcomes of RT in patients with intermediate- and high-risk meningioma, as defined by the NRG Oncology/RTOG 0539 trial, in a real-world clinical setting. In addition, we sought to identify the prognostic factors for PFS and analyze recurrence patterns following RT to assist clinicians identify patients who may benefit from more intensive RT.

Materials and Methods

1. Patient selection

We retrospectively reviewed patients with intracranial meningiomas who underwent surgery followed by RT at two tertiary institutions between January 2000 and May 2024. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0–2, and were diagnosed with intracranial meningioma through surgical resection. All patients included in this study underwent surgical resection at the time of initial diagnosis, and their grade was assessed according to the 2007 WHO classification [12]. Through a retrospective review of patients with meningioma who underwent surgery followed by RT at two institutions, 61 patients with intermediate- and high-risk meningioma, as defined by the NRG Oncology/RTOG 0539 trial, were ultimately included in this study [7,9]. Intermediate-risk meningioma” was defined as recurrent WHO grade 1 or newly diagnosed WHO grade 2 meningioma following gross total resection. “High-risk meningioma” was defined as WHO grade 2 meningioma with subtotal resection, recurrent WHO grade 2, and all WHO grade 3 meningioma. Patients who had newly diagnosed WHO grade I meningioma, did not complete the planned RT, or lacked available follow-up radiologic imaging were excluded from the study. The extent of surgical resection was evaluated using Simpson’s classification, based on a review of the operative records [13]. Simpson grades I-III were considered gross total resection, while Simpson grades IV–V were categorized as subtotal resection. Recurrent meningioma was defined as the condition in which salvage treatment was conducted owing to the occurrence of a new enhancing lesion or a radiographic increase in the remnant tumor on contrast-enhanced T1-weighted brain magnetic resonance imaging (MRI).

2. Treatment delivery

All patients underwent surgical resection at the time of initial meningioma diagnosis. RT was delivered either as adjuvant treatment or as salvage treatment after tumor recurrence. RT was administered as either conventionally fractionated radiotherapy (CFRT), or stereotactic radiosurgery (SRS). During the RT simulation, patients were immobilized with either an individualized thermoplastic mask or a stereotactic frame, and contrast-enhanced computed tomography (CT) with 1.25–2.5 mm slice thickness was conducted. Contrast-enhanced T1-weighted MRI images obtained prior to RT simulation were fused with simulation CT scans for treatment planning. The gross tumor volume (GTV) included the enhancing lesion, thickened meninges, and/or surgical cavity. For grade 1 meningioma, a 0–3 mm isotropic margin was added to define the clinical target volume (CTV), while a 5–10 mm margin was added for grade 2–3 meningioma, respecting anatomic boundaries. The planning target volume was defined with a 3–5 mm margin from the CTV to account for geometric uncertainties and setup error. For SRS, the RT dose was prescribed to the GTV without a margin. SRS was implemented as a salvage treatment for recurrent tumors <2 cm in size and a single mass, and as an adjuvant therapy when there was a limited volume of residual tumor after surgery. In principle, SRS was applied to grade 1–2 meningiomas, with limited use for grade 3 meningiomas. CFRT was administered in 1.8–2.2 Gy single doses over 27–31 fractions. CFRT was delivered using three-dimensional conformal radiotherapy or intensity-modulated radiation therapy (IMRT). SRS was delivered at a median dose of 18 Gy (range, 12 to 22 Gy) using either the CyberKnife (Accuray Inc., Sunnyvale, CA, USA) or Novalis Tx system linear accelerator (Varian, Palo Alto, CA, USA) at the two institutions.

3. Follow-up and failure pattern analysis

Patients were monitored weekly during RT through clinical evaluation and complete blood count testing. Three months after completing RT, contrast-enhanced brain MRI was performed to evaluate post-treatment tumor response. Subsequently, patients with grade 1 meningioma underwent annual follow-up with enhanced MRI, while those with grade 2–3 meningioma were followed every 6 months for 5 years. Tumor progression was defined as the occurrence of a newly developed enhancing mass or any radiographic increase in the residual tumor compared to prior contrast-enhanced brain MRI, as confirmed by a neuroradiologist. In cases of tumor progression following RT, brain MRI scans at the time of progression and RT plans were comparatively analyzed to identify pattern of failure. T1-weighted contrast-enhanced brain MRI and RT plans were uploaded and fused using MIM software 7.0.8 (MIM Software Inc., Cleveland, OH, USA), and the recurrent mass was contoured by a radiation oncologist. Local failure (LF) was defined as any recurrence occurring within a 1 cm isotropic margin of the prescription volume. Any failure occurring outside this margin was classified as distant failure (DF). An example of the analysis of the failure pattern is shown in Fig. 1.

4. Statistical analysis

The primary and secondary endpoints of this study were PFS and OS, respectively. PFS and OS defined as the time between the initiation of RT to the date of tumor progression and to the date of death or last follow-up, respectively. The actuarial survival rate was estimated using the Kaplan-Meier method. The log-rank test was performed to analyze the significance of the prognostic factors for recurrence. Multivariate analysis was performed using the Cox proportional hazards model, including factors with a p ≤ 0.05 on a log-rank test or those deemed clinically significant [5]. Areas under the curve (AUC) were calculated to estimate the prognostic efficacy of the continuous variable on progression using a receiver operating characteristic curve. The optimal cut-off values of continuous variable for progression were determined using Youden’s index. Statistical significance was set at p < 0.05. All statistical analyses were conducted using the R software version 4.4.3 (R Development Core Team, Vienna, Austria).

Results

1. Patient and treatment characteristics

Data from 61 patients with histologically confirmed meningiomas who underwent RT were retrospectively investigated. The median follow-up duration was 47.2 months (range, 3.1 to 202.4). The median patient age was 61 years (range, 20 to 78), with a female predominance (39 patients, 63.9%). Twelve patients had intermediate-risk meningioma, and 49 patients had high-risk meningioma. WHO grade 2 tumors were the most common (47 patients, 77.0%), followed by grade 3 (9 patients, 14.8%) and grade 1 (5 patients, 8.2%). Meningiomas located at the skull base were observed in 37 patients (60.7%). Patient’s characteristics are summarized in Table 1. RT was delivered at initial diagnosis in 24 patients and at recurrence in 37 patients. For recurrent tumors, the median duration from the date of initial diagnosis to the date of occurrence of recurrence before RT was 27.9 months (range, 2.7 to 138.5). Among 37 patients with recurrent tumors, 15 underwent salvage surgery followed by adjuvant RT, while 22 received salvage RT alone. In the surgery immediately before RT, 31 patients (50.8%) underwent Simpson grade 1–3, and 30 underwent Simpson grade 4–5 resections. RT was delivered as adjuvant treatment in 39 patients and as salvage treatment in 22. CFRT was delivered using IMRT in 40 cases, while four received 3-dimensional conformal radiation therapy. CFRT was administered at a median dose of 55 Gy (range, 50.4 to 60) over 27–31 fractions. SRS was delivered at a median dose of 18 Gy (range 12 to 22). Treatment characteristics are detailed in Table 2.

2. Treatment outcomes and prognostic factors

At the time of analysis, 26 cases of tumor progression were identified: four in the intermediate-risk group and 22 in the high-risk group. Seventeen patients had died, including one in the intermediate-risk group and 16 in the high-risk group. The median PFS of the entire cohort was 103.8 months. The 3- and 5-year PFS rates were 72.9% and 55.8%, respectively. Median OS was not reached, with 3- and 5-year OS rates of 86.0% and 74.2%, respectively. For the intermediate-risk group, the 3-and 5-year PFS rates were 91.7% and 80.2%, and OS rates were 100% at both time points. Conversely, the high-risk group showed 3- and 5-year PFS rates of 67.6% and 48.7%, and OS rates of 82.2% and 67.1%, respectively. The high-risk group demonstrated a trend toward lower PFS (p = 0.074) and significantly lower OS (p = 0.009) compared to the intermediate-risk group (Fig. 2).

Owing to the small number of intermediate-risk patients (n = 12), the prognostic factor analysis was limited to the high-risk group to identify significant prognostic factors within the risk group. The cut-off value of the Ki-67 index for progression in the high-risk group was 6.8% (AUC, 0.609). In the univariate analysis of the high-risk group, WHO grade 3 tumors showed a distinctly lower PFS than WHO grade 2 tumors, but the difference was not statistically significant (5-year PFS, 25% vs. 53.6%; p = 0.256) (Fig. 3). The high Ki-67 group (>6.8%) showed a trend toward a lower PFS than the low Ki-67 group (5-year PFS, 41.2% vs. 78.7%; p = 0.050). Patients who received RT at recurrence had significantly lower PFS compared to those treated at initial diagnosis (5-year PFS, 36.3% vs. 92.9%; p = 0.002) (Fig. 3). No statistically significant differences in PFS were observed between CFRT and SRS (5-year PFS, 52.3% vs. 39.2%; p = 0.562). The results of the univariate analysis for PFS in high-risk group are summarized in Table 3. Multivariate analysis in high-risk group identified WHO grade 3 (hazard ratio [HR], 16.7; 95% confidence interval [CI], 3.0 to 92.3; p = 0.001) and recurrent tumor status (HR, 41.2; 95% CI, 3.6 to 473.6; p = 0.003) as significant adverse prognostic factors for PFS (Table 4).

3. Pattern of failure

Tumor progression was confirmed in 26 patients based on follow-up brain MRI after RT at the time of analysis. Among the 26 patients with recurrence, 10 received RT with SRS and 16 were treated with CFRT. In the SRS group, the number of patients eligible for failure pattern analysis was limited (3 of 10 patients) because of problems with the CyberKnife plan restoration; therefore, the analysis was performed only in the CFRT group. Failure pattern analysis was finally performed in 15 of the 16 patients who experienced recurrence after CFRT treatment. LF and DF occurred in 13 (of 15 cases, 86.7%) and 2 (of 15 cases, 13.3%) patients, respectively. Failure patterns were further analyzed according to the WHO grade (2/3), risk group (high-risk), and tumor status (initial/recurrent). In the WHO grade 3 group (n = 4), all initial recurrences were LF. In the high-risk group (n = 15), LF was the predominant pattern (86.7%), with two cases of DF. Among patients with recurrent tumors, LF was observed in 12 of 14 cases (85.7%) and DF was observed in two cases (14.3%). The recurrence patterns according to the subgroups are summarized in Table 5.

Discussion and Conclusion

This study investigated the PFS and OS of patients with intermediate- and high-risk meningiomas, as defined by the NRG Oncology/RTOG 0539 criteria. In our study, the 3-year PFS and OS for the intermediate-risk group were 91.7% and 100%, respectively, while for the high-risk group, these were 67.6% and 82.2%. These findings are consistent with the results reported in the NRG Oncology/RTOG 0539 and EORTC 22042-26042 trials, where 3-year PFS ranged from 88.7% to 93.8% and 3-year OS ranged from 96% to 98.2% in the intermediate-risk patients [7,8]. For high-risk meningioma, prior studies have reported 3-year PFS and OS ranging from 58.8% to 66.1% and 78.6% to 80.6%, respectively [9,14].

In our study, WHO grade 3 and recurrent tumors were identified as significant adverse prognostic factors for PFS in high-risk group. This aligns with the findings by Wang et al. [5], who reported that both WHO grade 3 and recurrent status were associated with poorer PFS among patients undergoing either adjuvant or salvage RT. WHO grade has been reported to be one of the most significant predictors of recurrence of meningioma [15,16]. Although WHO grade 3 accounts for only 1-3% of all meningiomas, it is characterized by aggressive malignant features and poor survival outcomes, with a 5-year PFS and OS of 37% and 65%–66% after treatment [17,18].

Recurrent meningiomas are also associated with worse outcomes compared to newly diagnosed cases [9,19]. Previous literature has reported that 6.3% to 41.4% of recurrent meningiomas undergo transformation to a higher WHO grade [20-22]. A subgroup analysis from the NRG Oncology/RTOG 0539 trial demonstrated that patients with recurrent WHO grade 2 meningioma had worse outcomes than those with newly diagnosed WHO grade 3 disease [9]. Talacchi et al. [19] observed that the recurrence-free interval becomes shorter with each recurrence and that marginal failure and DF become more frequent during the clinical course of recurrent atypical meningioma.

In this study, LF was the dominant failure pattern among the 15 patients who received CFRT. All patients evaluable for failure pattern analysis belonged to the high-risk group, and LF was the dominant pattern, accounting for 86.7% of the total failures. This is consistent with the results of previous studies that analyzed the recurrence pattern after RT in high-risk patients, in which LF ranged from 85.2% to 87.5% of the total recurrences [9,22]. In our study, all initial recurrences occurred as LF in the WHO grade 3 group. A study by Kuhn et al. [23], which analyzed recurrence patterns after SRS, reported that multifocal disease and high-grade histology (WHO grades 2 and 3) were associated with higher local recurrence. Owing to the rarity of the disease, studies analyzing recurrence patterns in patients exclusively with WHO grade 3 meningioma are scarce. In our study, WHO grade 3 was identified as an adverse prognostic factor for PFS, and LF was the principal failure pattern in these groups. In the recurrent tumor group, LF was the dominant pattern, while DF accounted for 14.3% of total recurrences. Talacchi et al. [19] reported that marginal and distant recurrences increased over the clinical course of patients with recurrent atypical meningiomas who underwent RT. The recurrence patterns and distinct clinical behaviors of recurrent meningiomas should be further clarified in future studies.

In this study, LF was identified as the predominant pattern of recurrence in patients with high-risk meningioma following RT in consistent with previous studies [9,22]. This finding suggests that dose-escalated RT may be a potential strategy to improve local control in these patients. Several previous studies have reported that dose-escalated RT (equivalent dose in 2 Gy fractions, 64 to 70 Gy) improves PFS in high-risk patients with meningioma, including those with grade 2–3 meningioma, those who underwent subtotal resection, and those with recurrent tumors (Table 6). In our study, no patients in the CFRT group underwent dose-escalated RT exceeding 60 Gy; therefore, a meaningful RT dose analysis could not be performed. Because this study had limitations in analyzing the RT dose owing to the characteristics of the cohort, the benefit of dose-escalated RT, and the optimal RT dose in patients with adverse features such as recurrent tumor or WHO grade 3 should be clarified in future studies involving a larger number of patients.

This study has several limitations. First, this study included a relatively small number of patients and failure pattern analysis was performed only in patients who underwent CFRT. Second, as this was a retrospective study involving two institutions, variations in treatment policies may have influenced the outcomes. In addition, owing to the long duration of the study, some heterogeneity may be inherent in the diagnostic and treatment methods used for patients with meningioma. Third, this study included patients who received RT with SRS or CFRT, which may have affected treatment outcomes. These points could be sources of bias in observational studies, and caution should be exercised when interpreting the results of this study. Fourth, owing to data limitations, the analysis of molecular factors known to affect the clinical behavior and prognosis of meningiomas was not performed. Despite these limitations, this study clarified the treatment outcomes of RT in intermediate- and high-risk meningiomas and identified prognostic factors for PFS in high-risk patients. The recurrence pattern after CFRT identified in this study may be supported when considering intensified RT in some patients with meningiomas.

In conclusion, RT with adjuvant or salvage intent showed favorable treatment outcomes in patients with intermediate-to high-risk meningiomas. WHO grade 3 histology and recurrent tumor status were identified as adverse prognostic factors for PFS in high-risk meningiomas. In addition, LF was the predominant recurrence pattern following CFRT, accounting for 86.7% of all recurrences. These findings underscore the need for further studies on dose-escalated RT to enhance local control in patients with these adverse features.

Statement of Ethics

This study was approved by the institutional review board of the Catholic Medical Center Ethics Committee (IRB No. XC25RIDI0024). The need for informed consent was waived owing to the retrospective nature of the study.

Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Funding

None.

Author Contributions

Conceptualization, SJL; Data curation, JK; Formal analysis, JK, SJL; Investigation, JK, methodology: JK, JHS, SJL; Visualization, JK; Writing of the original draft, JK; Writing of the review and editing, SJL, JHS.

Data Availability Statement

The data that support the finding of this study are available from the corresponding author upon reasonable request.

Fig. 1.

Illustrations of failure pattern analysis. Local failure pattern on axial (A) and sagittal (B) images of T1-weighted brain magnetic resonance imaging (MRI) at tumor recurrence. Distant failure pattern in the axial (C) and sagittal (D) image of T1-weighted brain MRI. The planning target volume is outlined in blue, and a 1 cm isotropic expansion of the planning target volume is delineated in green. The recurrent tumor is delineated in magenta.

Fig. 2.

Kaplan-Meier curves for progression-free survival and overall survival for the entire cohort and by risk group. (A) Progression-free survival of the entire cohort. (B) Progression-free survival according to risk group. (C) Overall survival of the entire cohort. (D) Overall survival according to risk group.

Fig. 3.

Kaplan-Meier curve for progression-free survival of high-risk patients stratified by World Health Organization (WHO) grade (A) and tumor status at introduction of radiotherapy (B).

Table 1.

Patient characteristics

Characteristic	Value (n = 61)
Age (year)	61 (20–78)
Sex
Male	22 (36.1)
Female	39 (63.9)
ECOG performance status
0–1	49 (80.3)
2–3	12 (19.7)
WHO grade
1	5 (8.2)
2	47 (77.0)
3	9 (14.8)
Risk group
Intermediate	12 (19.7)
High	49 (80.3)
Tumor location
Skull base	37 (60.7)
Non-skull base	24 (39.3)
Tumor size (cm)
<5	37 (60.7)
≥5	22 (36.0)
Unknown	2 (3.3)
Brain invasion
Yes	19 (31.1)
No	40 (65.6)
Unknown	2 (3.3)
Bone invasion
Yes	5 (8.2)
No	54 (88.5)
Unknown	2 (3.3)
Peritumoral edema
Yes	34 (55.7)
No	25 (41.0)
Unknown	2 (3.3)
Ki-67 index (%)
Median, 11% (range, <1 to 40)	54 (88.5)
Unknown	7 (11.5)
Tumor status at introduction of radiotherapy
Initial diagnosed	24 (39.3)
Recurrent	37 (60.7)

Values are presented as median (range) or number (%).

ECOG, Eastern Cooperative Oncology group; WHO, World Health Organization.

Table 2.

Treatment characteristics

Characteristic	Value (n = 61)
Simpson grade of surgical resection^a)
Grade 1–3	31 (50.8)
Grade 4–5	30 (49.2)
Aim of radiotherapy
Adjuvant	39 (63.9)
Salvage	22 (36.1)
Radiotherapy technique
IMRT	40 (65.6)
3D-CRT	4 (6.5)
SRS	17 (27.9)
Radiotherapy type
CFRT	44 (72.1)
PTV (cm³)	63.8 (3.7–398.2)
Dose (Gy)	55 (50.4–60)
50.4 Gy/28 fractions	1 (1.6)
52.7 Gy/27 fractions	1 (1.6)
54 Gy/30 fractions	16 (26.2)
55 Gy/25 fractions	6 (9.8)
55.8 Gy/31 fractions	7 (11.5)
60 Gy/30 fractions	13 (21.3)
SRS	17 (27.9)
PTV (cm³)	2.5 (0.6–14.6)
Dose (Gy)	18 (12–22)
Salvage treatment for recurrent tumor	37
Operation + adjuvant radiotherapy	15 (24.6)
Salvage radiotherapy alone	22 (36.1)

Values are presented as number (%) or median (range).

IMRT, intensity-modulated radiation therapy; 3D-CRT, three-dimensional conformal radiotherapy; SRS, stereotactic radiosurgery; CFRT, conventional fractionated radiotherapy; PTV, planning target volume.

^a)In cases of recurrent tumors, the Simpson grade was determined according to the most recent surgery conducted before radiotherapy.

Table 3.

Univariate analysis for PFS in high-risk group

Factor	No. (n = 49)	3-year PFS (%)	5-year PFS (%)	p-value
Age (year)
<50	14	65.8	26.3	0.294
≥50	35	68.5	54.1	0.294
Sex
Male	22	66.9	37.6	0.502
Female	27	68.2	61.4	0.502
ECOG performance status
0–1	38	64.9	42.2	0.419
2	11	77.1	77.1	0.419
WHO grade
2	40	71.7	53.6	0.256
3	9	50.0	25.0	0.256
Tumor location
Skull base	28	68.4	48.5	0.832
Non-skull base	21	64.8	48.6	0.832
Tumor size (cm)
<5	30	64.6	57.4	0.784
≥5	18	76.7	38.4	0.784
Peritumoral edema
Yes	28	71.6	49.1	0.629
No	20	66.0	52.8	0.629
Brain invasion
Yes	24	67.2	42.7	0.815
No	24	71.5	56.9	0.815
Bone invasion
Yes	5	100	-	0.652
No	43	67.2	49.9	0.652
Ki-67 index (%)
<6.8	15	78.7	78.7	0.050
>6.8	30	66.0	41.2
Simpson grade
Grade 1–3	23	69.3	60.6	0.347
Grade 4–5	26	65.3	37.3
Tumor status
Initial	17	92.9	92.9	0.002^a)
Recurrent	32	57.6	36.3
RT type
CFRT	36	68.4	52.3	0.562
SRS	13	52.3	39.2

PFS, progression-free survival; ECOG, Eastern Cooperative Oncology Group; WHO, World Health Organization; RT, radiotherapy; CFRT, conventional fractionated radiotherapy; SRS, stereotactic radiosurgery

^a)Statistically significant.

Table 4.

Multivariate analysis for progression-free survival in high-risk group

Factor	Progression-free survival
Factor	HR (95% CI)	p-value
WHO grade (grade 2/3)	16.7 (3.0–92.3)	0.001^a)
Tumor status (initial/recurrent)	41.2 (3.6–473.6)	0.003^a)
Ki-67 index (%) (<6.8/>6.8)	2.3 (0.7–7.7)	0.197

HR, hazard ratio; CI, confidence interval; WHO, World Health Organization.

^a)Statistically significant.

Table 5.

Analysis of failure patterns in the conventional fractionated radiotherapy group based on the WHO grade, risk group, and tumor status

Group	No. of patients^a)	Progression (available, total n = 15)
Group	No. of patients^a)	Local failure (n = 13)	Distant failure (n = 2)
WHO grade
Grade 1–2	11	9/11 (81.8)	2/11 (18.2)
Grade 3	4	4/4 (100)	0 (0)
Risk group
High	15	13/15 (86.7)	2/15 (13.3)
Tumor status
Initial	1	1/1 (100)	0 (0)
Progression/Recurrent	14	12/14 (85.7)	2/14 (14.3)

Values are presented as number (%).

WHO, World Health Organization.

^a)Number of patients in each group for whom failure pattern analysis was available.

Table 6.

Previous studies of dose-escalation RT for meningiomas

Studies	No.	Patients	RT	Dose	Outcome
Zeng et al. (2024) [10]	118	Grade 2–3 meningioma	CFRT	>66 Gy vs. <66 Gy (EQD2, α/β = 10)	3- and 5-year PFS, 78.9% and 64.6% vs. 57.2% and 40.8% (p = 0.03)
Deng et al. (2024) (MARCIE trial) [24]	33	Grade 2 with STR	CFRT-carbon boost	50 Gy/25 fxs followed by 18 Gy (RBE) in 6 fxs	3-year PFS and LC: 80.3% and 86.7%
Pontoriero et al. (2023) [25]	16	Grade 2 with STR or recurrent grade 2	CFRT-HFRT boost	46 Gy/23 fxs followed by boost RT (15 Gy/3 fxs)	3-year PFS, STR group, 100% recurrent tumor, 55.5%
Kim et al. (2023) [26]	158	Newly diagnosed grade 2 meningioma	CFRT	>57.42 Gy vs. ≤57.42 Gy (EQD2, α/β = 4)	5-year PFS, 87.4% vs. 72.0% (p = 0.049)
Sethi et al. (2015) [27]	101	Grade 1–3 meningioma	SRS	Grade 1: 10–18 Gy, Grade 2: 12–16 Gy, Grade 3: 15–20 Gy	LC, 1 Gy dose escalation, 42% relative reduction in local recurrence

RT, radiotherapy; CFRT, conventional fractionated radiotherapy; EQD2, equivalent dose in 2 Gy fractions; α/β, alpha/beta ratio; PFS, progression-free survival; STR, subtotal resection; fxs, fractions; RBE, relative biologic effectiveness; LC, local control; HFRT, hypofractionated radiotherapy; SRS, stereotactic radiotherapy.

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