Temporally-Modulated Pulsed Radiation Therapy for Large-Volume Reirradiation of Recurrent Meningioma

Abstract

Purpose

Patients with recurrent meningiomas treated with prior radiation therapy have limited treatment options. This study aims to evaluate the efficacy and tolerability of reirradiation with temporally-modulated pulsed radiation therapy (TMPRT) in a cohort of patients with recurrent meningioma.

Methods and Materials

We retrospectively identified 26 patients with recurrent meningioma treated with TMPRT from 2003 to 2025 at a single institution. All patients had radiographic or pathologic evidence of progression, were not candidates for radiosurgery or surgery, had previously received conventionally fractioned radiation therapy, and were retreated with temporally-modulated pulsed radiation therapy. Radiographic progression was assessed using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Acute and late toxicities were graded based on Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Overall survival and progression-free survival (PFS) were estimated using the Kaplan–Meier method.

Results

Median follow-up was 61.9 months. Median TMPRT dose was 54 Gy in 2 Gy fractions. Median planning treatment volume was 193 cm³. PFS at 6 months was 77% (95% CI, 56%-89%) and median PFS was 27.2 months (95% CI, 7.5-46.5 months). Median overall survival was 27.2 months (95% CI, 16.4-73.9 months). Three patients (12%) experienced grade ≥3 acute toxicity, 3 patients (12%) experienced grade ≥3 late toxicity.

Conclusions

TMPRT was effective and generally well-tolerated in a cohort of patients with recurrent meningioma previously treated with radiation therapy. This represents the largest-volume reported reirradiation meningioma cohort, and suggests that TMPRT may safely expand the role of photon reirradiation to a patient population with limited local treatment options.

Introduction

Meningiomas are the most common primary brain tumors in adults.¹ According to the Central Brain Tumor Registry of the United States, meningiomas accounted for 41.7% of all central nervous system (CNS) tumors and 56.8% of all benign CNS tumors diagnosed in the United States between 2017 and 2021.² The incidence of nonmalignant meningioma is estimated to be 9.7 per 100,000 people in the United States and is expected to increase as the population ages.²

Initial management of meningioma is guided by symptomatology, tumor size, and World Health Organization (WHO) grade, with treatment strategies ranging from routine surveillance to maximal surgical resection and radiation therapy (RT).³ For tumors requiring intervention, favorable local control is often achieved with surgical resection ± adjuvant radiation therapy. However, recurrence remains a significant clinical challenge, particularly in higher-grade and subtotally resected tumors. Even after gross total resection, up to 8% to 18% of WHO grade I, 15% to 30% of grade II, and 62% to 88% of grade III meningiomas recur within 5 years.⁴

Unfortunately, for patients with recurrent meningioma previously treated with RT, therapeutic options are limited. Surgical reresection is often limited by anatomic constraints, prior scarring, and patient performance status. Systemic therapy has historically shown minimal efficacy, with 6-month PFS (PFS-6) rates of 15% to 50% and with stabilization of disease at best.5, 6, 7, 8, 9, 10, 11 More recently, mTOR pathway inhibitors, bevacizumab, and newer peptide receptor radionuclide therapy (PRRT) with Lutetium-DOTATATE have shown promising phase II PFS-6 rates of 50% to 90%.12, 13, 14, 15, 16, 17, 18 Randomized trials are ongoing in this space.^19,20

Although reirradiation with conventional RT is regularly performed, its use is limited by cumulative dose constraints and concern for toxicity to organs-at-risk. This has driven interest in particle therapy, stereotactic radiosurgery and temporally-modulated pulsed RT (TMPRT) in reirradiation settings.21, 22, 23, 24 TMPRT is a low-dose rate technique that divides each individual fraction of radiation into a number of subfractions in order to minimize normal tissue toxicity and allow for maximal intrafraction repair.²⁵ Low-dose (0.2 Gy) pulses are delivered at the beginning of sequential 3-minute intervals to create an apparent dose rate of 0.0667 Gy/minute, theoretically taking advantage of sublethal damage repair in normal tissue, low-dose hyper-radiosensitivity, and cell cycle redistribution to increase the therapeutic ratio.²⁵ This strategy has been explored in other CNS tumors, particularly gliomas, where reirradiation with TMPRT for recurrent disease has demonstrated favorable toxicity and disease outcomes.26, 27, 28, 29 TMPRT is now being investigated in NRG-CC017 for high-grade glioma.

Although TMPRT has shown promise in high-grade glioma, its role in recurrent meningioma remains insufficiently characterized. To address this knowledge gap, we performed a retrospective, single-center analysis evaluating long-term survival and toxicity outcomes in patients with recurrent meningioma reirradiated with TMPRT.

Methods and Materials

Patient identification and characteristics

From 2003 to 2025, 26 patients previously treated with conventional radiation therapy were treated with TMPRT for recurrent meningioma. At time of recurrence, patients were treated according to institutional practice involving reoperation when feasible. TMPRT was generally recommended for patients previously treated with conventionally fractionated RT who had evidence of radiographic in-field recurrences who were not candidates for radiosurgery (due to tumor volume) or further surgery. For this study, the relevant patients were identified, and their charts were retrospectively reviewed within the electronic health record of a single institutional database. An attempt was made to reclassify the patient cohort to the WHO 2021 system; however, due to a majority of the pathology dating over 10 years old, molecular data were largely unavailable.

Ethics. Data collection and analysis were conducted in accordance with an institutional review board-approved retrospective review process.

TMPRT delivery method

TMPRT was typically delivered 5 days per week with daily fractions of 1.8 to 2 Gy using 0.2-Gy pulses every 3 minutes (with the first 3-minute break occurring after the first pulse) to create an apparent dose rate of 0.0667 Gy/minute. Treatment was delivered with 6-MV photons. Most commonly, intensity modulated RT (IMRT) was used, encompassing gross disease with a 0.5 to 1.0 cm, anatomically constrained clinical target volume margin. IMRT was most commonly delivered with static IMRT with 3 to 5 fields. For 4 patients (15%), 3-dimensional conformal therapy was used, encompassing gross disease with a 0.5 to 1.0 cm, anatomically constrained clinical target volume margin. Planning target volume (PTV) margin was generally 0.3 cm. Dose homogeneity on a beam level was prioritized to avoid focal high dose-rate and low-dose-rate regions. The homogeneity index (HI = D2%-D98%/D_mean) was calculated for each beam and for the composite plan when these data were available.

Customized aquaplast head and neck masks (Aquaplast) were used to provide optimal immobilization and reproducibility between sessions. Target volumes were determined with magnetic resonance imaging (MRI) findings, and DOTATATE-PET in patients treated after 2022.

The dose constraints were determined from the TMPRT plan only, irrespective of the isodose distributions of the initial RT plan. The lens and cervical spine were always shielded from the direct beam. Attempts were made to limit the retreatment dose to the optic chiasm to 54 Gy, the retina of at least 1 eye to 50 Gy, and the brainstem to 54 Gy. No limitations were placed on the cumulative dose, including the initial treatment dose. PTVs were obtained from the original plans in MIM (MIM Software Inc).

Follow-up and statistical analysis

After completion of therapy, MRI scans were obtained according to routine follow-up parameters or upon clinical progression. Patients were routinely seen for short interval follow-up 3 to 6 weeks following completion of TMPRT, then in 2.5- to 3-month intervals with MRI or as clinically indicated. Follow-up visits included MRI with contrast and a thorough neurologic examination. Recurrence was defined via progression on follow-up MRI imaging using RECIST criteria. Toxicity related to radiation was evaluated using the Common Terminology Criteria for Adverse Events v5.0, where acute toxicity was defined within 90 days of the completion of RT and late toxicity defined as any time thereafter.

Statistical analysis was aimed to ascertain survival estimates over time and to identify factors independently influencing local recurrence and survival outcomes. The timeframe for overall survival (OS) was computed from initial diagnosis until the date of last follow-up or recorded date of mortality. In the event no date of mortality was found in the chart, OS was augmented using publicly available death certificates for patients lost to follow-up. Similarly, TMPRT survival was calculated from the TMPRT initiation date. Survival functions were estimated using the Kaplan–Meier method, and median follow-up was calculated using the reverse Kaplan–Meier method. Cumulative incidence with the Fine–Gray method with death as a competing risk was used to analyze local recurrence (LR). Associations of variables with LR were evaluated using Fine–Gray competing-risks regression. Associations of variables with grade ≥3 toxicity were evaluated using Wilcoxon rank-sum tests for continuous variables and Fisher exact tests for categorical variables. Statistical assessment and graphical analysis were performed in R.

Results

Patient demographics, tumor characteristics, and treatments rendered

Twenty-six patients were retrospectively identified, with a median follow-up of 61.9 months (IQR, 31.8-112.0). Patient and tumor characteristics including sex, race, tumor location, age, KPS, tumor grade, RT interval, and tumor size are outlined in Table 1. Treatments rendered are summarized in Table 1, including number of prior surgeries and RT courses, TMPRT dose, and TMPRT technique. All patients retreated with TMPRT had been previously treated with RT using a standard dose rate to a median dose of 54 Gy (range, 45-60 Gy). Seventeen patients (65%) underwent surgery as initial treatment at progression, whereas 9 patients (35%) underwent TMPRT. Median reirradiation dose with TMPRT was 54 Gy (range, 37.5-60 Gy). Twenty-four patients received planned TMPRT dose, and 2 patients received TMPRT at lower median total dose (46 and 48 Gy of intended 54 Gy) due to hospitalization limiting ability to complete treatment, 1 of which was an acute toxicity of TMPRT.

Table 1.

Patient, tumor, and treatment characteristics

Characteristic	N = 26*
Age, y	67.5 (50.0-75.0)
Sex
Female	11 (42%)
Male	15 (58%)
Race
Asian	1 (3.8%)
White	25 (96%)
Karnofsky performance status
50	1 (3.8%)
70	3 (12%)
80	6 (23%)
90	11 (42%)
100	5 (19%)
Tumor location
Cavernous sinus	8 (30.8%)
Convexity	6 (23.1%)
Lateral ventricle	1 (3.8%)
Middle cranial fossa	1 (3.8%)
Parafalcine/Parasagittal	6 (23.1%)
Sphenoid wing	5 (19.2%)
WHO grade
G1	4 (15%)
G2	16 (62%)
G3	3 (12%)
GX	3 (12%)
Initial RT-to-TMPRT interval, mo	89.9 (39.6-157.1)
Tumor focality
Multifocal	5 (19%)
Unifocal	21 (81%)
GTV volume, cm3	47.9 (7.9-70.0)
PTV volume, cm3	192.8 (95.0-301.3)
TMPRT dose, Gy	54.0 (50.4-59.4)
TMPRT technique
3D	4 (15%)
IMRT	22 (85%)
Number of prior resections
0	1 (3.8%)
1	3 (12%)
2	11 (42%)
3	10 (38%)
9	1 (3.8%)
Pre-TMPRT surgery
None	17 (65%)
STR	5 (19%)
GTR	4 (15%)
Number of RT courses before TMPRT
1	19 (73%)
2	5 (19%)
3	1 (3.8%)
6	1 (3.8%)
Number of systemic therapy lines before TMPRT
None	23 (88%)
1	1 (3.8%)
2	1 (3.8%)
13	1 (3.8%)

Abbreviations: 3D = 3-dimensional; GTV = gross target volume; IMRT = intensity modulated radiation therapy; PTV = planning target volume; RT = radiation therapy; TMPRT = temporally-modulated pulsed radiation therapy; WHO = World Health Organization.

^⁎Median (quartile1-quartile3); n (%).

Toxicity

With median follow-up of 61.9 months (IQR, 31.8–112.0) from the start of TMPRT, 3 patients (12%) experienced grade ≥3 acute toxicity. One patient (4%) experienced new-onset seizures which resolved with medical management but resulted in early termination of TMPRT. One patient (4%) experienced grade 3 cerebral edema which was managed with dexamethasone and bevacizumab, extending to a late toxicity. One patient (4%) experienced acute grade 4 cerebral edema with life-threatening consequences and intensive care unit-level care, which resolved with medical management with dexamethasone. Grade 1 fatigue (n = 17) and grade 1-2 dermatitis (n = 11) were found to be the most common acute toxicities, 96% of patients experienced any acute toxicity. Acute toxicity is summarized in Table 2.

Table 2.

Summary of acute toxicities

	CTCAE grade
Toxicity	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Alopecia	5	0	0	0	0
Cerebral edema	1	0	1	1	0
Conjunctivitis	0	1	0	0	0
Dermatitis	9	2	0	0	0
Dysgeusia	2	0	0	0	0
Fatigue	17	1	0	0	0
Headache	3	0	0	0	0
Mucositis	2	0	0	0	0
Nausea	0	1	0	0	0
Neuropathy	0	1	0	0	0
Otitis media	0	1	0	0	0
Seizures	3	0	1	0	0
Vestibular	0	2	0	0	0
Weakness	1	0	0	0	0

Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.

Data are presented as counts.

Twenty-four patients (92%) were evaluable for late toxicity. Of the 11 patients (42%) who experienced late toxicity, grade 1 neuropathy (n = 4) was most common. Three patients (12%) experienced late grade 3 cerebral edema (at an average of 13 months post-TMPRT) which resolved with dexamethasone, one of which required bevacizumab. No late grade 4 or 5 toxicity was observed. Late toxicity is summarized in Table 3.

Table 3.

Summary of late toxicities

	CTCAE grade
Toxicity	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5
Cerebral edema	0	1	3	0	0
Dermatitis	1	0	0	0	0
Fatigue	1	0	0	0	0
Headache	0	1	0	0	0
Neuropathy	4	0	0	0	0
Seizures	2	0	1	0	0
Sinusitis	1	0	0	0	0
Vestibular	1	1	0	0	0
Vision	0	2	0	0	0

Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events.

Data are presented as counts.

On univariate analysis, older age, greater number of prior RT courses, shorter interval from prior RT to TMPRT, and tumor location (P = .089) showed trends toward association with grade ≥3 toxicity, although none reached statistical significance (Table E1). Exploratory analyses demonstrated no clear relationship between TMPRT dose, gross target volume, or PTV volume and the development of grade ≥3 toxicity (Figures E1, E2).

Disease outcomes and survival analyses

At the conclusion of the study, 13 patients (50%) had no evidence of disease progression after TMPRT. Of the 13 patients that had evidence of recurrence after TMPRT, 11 (42%) were in-field failures and 2 (8%) were out-of-field failures. Six patients (23%) from the cohort required further intervention after TMPRT. Two patients underwent additional surgery after reirradiation with TMPRT. Two patients underwent additional TMPRT ± surgery after TMPRT. Two patients underwent stereotactic radiosurgery after TMPRT, and 2 patients underwent fractionated stereotactic RT after TMPRT.

Seven patients (27%) received systemic therapy at some point during their overall disease course. No patients received concurrent systemic therapy with initial RT. No patients received concurrent systemic therapy with TMPRT. Two patients received systemic therapy within 6 months of TMPRT, 1 received osimertinib and 1 received pembrolizumab. One patient received PRRT prior to TMPRT. Three patients received pembrolizumab during their disease course. Two patients received bevacizumab during their disease course.

Figure 1A illustrates OS from time of TMPRT showing median OS of 27.2 months (95% CI, 16.4-73.9 months). Six-month OS, 12-month OS, and 24-month OS were 85% (95% CI, 64%-94%), 77% (95% CI, 55%-89%), and 64% (95% CI, 42%-79%), respectively (Table 4). Eleven patients in the 26-patient cohort remain alive, the 2 longest term survivors at 10.4 and 9.3 years from their TMPRT treatment.

Figure 1.

(A) OS for the entire cohort following TMPRT. (B) PFS for the entire cohort following TMPRT.

Abbreviations: OS = overall survival; PFS = progression-free survival; TMPRT = temporally-modulated pulsed radiation therapy.

Table 4.

Overall survival and progression-free survival at 6, 12, and 24 months

Endpoint	6 months	12 months	24 months
Overall survival	84.6% (64.0-93.9%)	76.6% (55.1-88.7%)	63.9% (41.9-79.4%)
Progression-free survival	76.9% (55.7-88.9%)	65.0% (43.4-80.0%)	51.5% (30.4-69.1%)

Values are Kaplan–Meier estimates with log-log 95% confidence intervals.

Figure 1B illustrates PFS from time of TMPRT showing median PFS of 27.2 months (95% CI, 7.5-46.5 months). PFS-6, 12-month PFS, and 24-month PFS were 77% (95% CI, 56%-89%), 65% (95% CI, 43%-80%), and 52.0% (95% CI, 30%-69%), respectively (Table 4).

Cumulative incidence of LR with death as a competing risk is depicted in Figure 2.

Figure 2.

Cumulative incidence of local recurrence with death as a competing risk for the entire cohort.

On univariate Fine–Gray competing risk analysis, age at time of TMPRT, TMPRT dose, gross target volume coverage, boost, PTV coverage, interval between initial RT and TMPRT, and highest grade of disease were not associated with LR (Table 5). Number of surgeries and PTV volume were significant predictors of LR. No covariates maintained significant association on multivariate analysis using forward selection.

Table 5.

Univariate Fine–Gray competing-risks analysis of local failure

Covariate	Subdistribution hazard ratio (95% CI)	P value
PTV volume, per cm3	1.01 (1.00-1.01)	<.001
Number of prior surgeries	1.30 (1.08-1.56)	.005
Initial RT-to-TMPRT interval, per month	0.99 (0.99-1.00)	.287
PTV coverage	0.17 (0.01-4.64)	.291
Boost	0.89 (0.69-1.16)	.403
GTV coverage	0.13 (0.00-37.43)	.476
TMPRT dose, per Gy	0.97 (0.86-1.08)	.573
WHO grade II vs I	0.70 (0.19-2.54)	.582
Unknown grade vs I	0.49 (0.03-7.52)	.611
WHO grade III vs I	1.23 (0.16-9.70)	.842
Age at TMPRT, per year	1.00 (0.97-1.03)	.973

Abbreviations: GTV = gross tumor volume; PTV = planning target volume; RT = radiation therapy; TMPRT = temporally-modulated pulsed radiation therapy; WHO = World Health Organization.

Death was treated as a competing event.

The homogeneity index was calculated for each beam and for the composite plan, which is shown in Figure E3. Across 14 patients for whom data was available, the median beam-level homogeneity index was 0.058.

Discussion

Despite generally favorable outcomes for patients with meningioma treated with surgical resection and adjuvant radiation, recurrence remains a significant clinical challenge.⁴ Surgical reresection is often limited by tumor location, cumulative treatment-related morbidity, proximity to eloquent areas or critical structures, and patient performance status. Similarly, reirradiation with conventional photon RT is often constrained by the tolerance of previously irradiated normal tissue.³⁰ Although recent investigations have been promising, systemic salvage therapies are generally limited and toxic.³¹

The present study describes outcomes among 26 patients with recurrent meningioma who underwent reirradiation with TMPRT. Patients experienced a median OS of 27 months, a median PFS of 27 months, and acceptable treatment-related toxicity despite extensive prior therapy. Notably, 5 patients (19%) were still alive 10 years following TMPRT, highlighting the potential for durable disease control in carefully selected patients.

The principal finding of this study is that TMPRT may safely expand the role of photon reirradiation to substantially larger treatment volumes than previously reported. To our knowledge, this cohort represents the largest target volumes described in a photon reirradiation series for recurrent meningioma, with a median PTV of 193 cm³. In contrast, published photon reirradiation studies have largely been restricted to highly selected patients with small recurrent tumors treated using stereotactic radiosurgery or fractionated stereotactic RT, with median target volumes on the order of 10 cm³.^30,32, 33, 34, 35 Patients with multiply recurrent tumors of the size treated in the present study are not represented in the literature, as they are poor candidates for local therapy. Despite this, however, TMPRT achieved PFS comparable to previous photon reirradiation studies while maintaining a manageable toxicity profile. These data suggest that TMPRT may permit treatment of patients with photon reirradiation who do not have other local therapeutic options.

Particle therapy has emerged as an important strategy for large-volume meningioma reirradiation because of favorable dosimetry and reduction of cumulative dose to normal tissues. Published particle series have reported 2-year PFS of 56% to 74% with median target volumes of approximately 75 cc and variable rates of grade ≥3 toxicity.21, 22, 23 PRRT has likewise demonstrated encouraging activity, with reported 6-month PFS rates ranging from 50% to 78% across prospective studies,16, 17, 18^,36 although toxicity has varied considerably and follow-up is heretofore limited. In comparison, the present cohort demonstrates that similarly favorable outcomes may be achievable with TMPRT. We have summarized representative reirradiation and PRRT studies in Table E2.

This study has several limitations. Its retrospective, single-institution design introduces the potential for selection bias, and the modest sample size limited statistical power, particularly for analyses of local failure and treatment-related toxicity. The cohort was also highly heterogeneous, reflecting the complexity of recurrent meningioma but limiting definitive subgroup analyses. Furthermore, the absence of a contemporaneous control group precludes direct comparison with conventional photon reirradiation, particle therapy, or PRRT. Finally, quality-of-life and neurocognitive outcomes were not routinely collected and therefore could not be assessed.

As salvage treatment modalities continue to evolve and technical access expands, comparison of TMPRT, particle therapy, PRRT, and systemic therapy is needed to determine optimal sequencing of treatments and refine patient selection. Future prospective studies should incorporate patient-reported quality-of-life, neurocognitive, and functional outcomes.

Disclosures

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. B.E., A.F, A.B., A.A., and W.A.T. report no conflicts of interest. B.A.M reports travel support from Icotec Medical. A.R.B. reports research funding from GE Healthcare and a grant from Siemens. A. Bhatia reports consulting fees from Servier Advisory Board, payment or honoraria from Wisconsin Association of Hematology and Oncology, and service as an Editor for Current Oncology Reports and Medlink Neurology.