Efficacy and Toxicity of Particle Radiotherapy in WHO Grade II and Grade III Meningiomas: a Systematic Review

NEUROSURGICAL FOCUS Neurosurg Focus 46 (6):E12, 2019

Efficacy and toxicity of particle radiotherapy in WHO grade II and grade III meningiomas: a systematic review

*Adela Wu, MD,1 Michael C. Jin, BS,2 Antonio Meola, MD, PhD,1 Hong-nei Wong, MLIS, DVM,3 and Steven D. Chang, MD1

1Department of Neurosurgery, Stanford Health Care, Palo Alto; 2Stanford University School of Medicine, Stanford; and 3Lane Medical Library, Stanford Medicine, Palo Alto, California

OBJECTIVE Adjuvant radiotherapy has become a common addition to the management of high-grade meningiomas, as immediate treatment with radiation following resection has been associated with significantly improved outcomes. Recent investigations into particle therapy have expanded into the management of high-risk meningiomas. Here, the authors systematically review studies on the efficacy and utility of particle-based radiotherapy in the management of high-grade meningioma. METHODS A literature search was developed by first defining the population, intervention, comparison, outcomes, and study design (PICOS). A search strategy was designed for each of three electronic databases: PubMed, Embase, and Scopus. Data extraction was conducted in accordance with the PRISMA guidelines. Outcomes of interest included local disease control, overall survival, and toxicity, which were compared with historical data on photon-based therapies. RESULTS Eleven retrospective studies including 240 patients with atypical (WHO grade II) and anaplastic (WHO grade III) meningioma undergoing particle radiation therapy were identified. Five of the 11 studies included in this systematic review focused specifically on WHO grade II and III meningiomas; the others also included WHO grade I meningioma. Across all of the studies, the median follow-up ranged from 6 to 145 months. Local control rates for high-grade meningiomas ranged from 46.7% to 86% by the last follow-up or at 5 years. Overall survival rates ranged from 0% to 100% with better prognoses for atypical than for malignant meningiomas. Radiation necrosis was the most common adverse effect of treatment, occurring in 3.9% of specified cases. CONCLUSIONS Despite the lack of randomized prospective trials, this review of existing retrospective studies suggests that particle therapy, whether an adjuvant or a stand-alone treatment, confers survival benefit with a relatively low risk for severe treatment-derived toxicity compared to standard photon-based therapy. However, additional controlled studies are needed. https://thejns.org/doi/abs/10.3171/2019.3.FOCUS1967 KEYWORDS meningioma; atypical; malignant; particle radiotherapy

eningiomas are the most common primary brain ningiomas are the most aggressive, with recurrence rates tumor, accounting for approximately 33.8% of all ranging from 50% to 94% and significant risk for invasion central nervous system (CNS) tumors in the US.65 and metastasis.62 MBased on the World Health Organization (WHO) classi- The current standard of care for symptomatic or grow- fication, meningiomas are divided into benign (grade I), ing meningioma consists of maximal resection.62 Photon- atypical (grade II), and anaplastic (grade III) subtypes.9,55 based radiotherapy, including both stereotactic radiosur- Atypical and anaplastic meningiomas are rare and account gery (SRS) and conventional stereotactic radiotherapy, is for 1%–25% of all meningiomas.27 Atypical meningiomas usually recommended as adjuvant therapy or as primary have high recurrence rates (28%–41%) following surgery treatment for meningioma.45 However, alternative radiation without additional therapy.3,51 Malignant anaplastic me- techniques collectively known as “particle radiotherapy”

ABBREVIATIONS CNS = central nervous system; IMPT = intensity-modulated proton therapy; OCEBM = Oxford Centre for Evidence-based Medicine; PICOS = population, intervention, comparison, outcomes, and study design; SRS = stereotactic radiosurgery; WHO = World Health Organization. SUBMITTED February 1, 2019. ACCEPTED March 25, 2019. INCLUDE WHEN CITING DOI: 10.3171/2019.3.FOCUS1967. * A.W. and M.C.J. contributed equally to this work and share first authorship.

©AANS 2019, except where prohibited by US copyright law Neurosurg Focus Volume 46 • June 2019 1

Unauthenticated | Downloaded 09/29/21 02:11 PM UTC Wu et al. have emerged for treating meningiomas and other tumors comparison, outcomes, and study design (PICOS; Fig. 1). of the CNS, including proton therapy, carbon ion therapy, Inclusion criteria, outcome measures, and search strategy or boron neutron capture therapy (BNCT). And although were defined in advance. photon-based radiotherapy is used worldwide for the treatment of meningioma, particle radiation therapy could re- Search Strategy duce the risk of the adverse radiation effects caused by Our review included studies on the use of particle-based photon-based radiotherapy. radiotherapy in high-grade meningioma (WHO grades II In fact, particle-based therapies offer several tantalizing and III) in the adult population (age > 18 years old), with advantages. A primary concern associated with radiation 5 or more subjects, and written in the English language. therapy is inadvertent dose deposition in nontarget tissue. Upfront exclusion criteria included review articles, book While acute deficits associated with radiation-induced chapters, editorials, and articles in languages other than brain injury are often transient, other impairments often English. Other exclusion criteria were studies including result from permanent morphological alterations, such pediatric patients, having fewer than 5 subjects, or re- as hypoxic tissue damage (with subsequent cognitive de- porting outcomes different from those detailed in Fig. 1. cline)11,52 and radiation necrosis, caused by inflammatory In order to ensure exhaustive canvassing of the published responses to radiation damage.58 Tissue damage resulting literature, we, in collaboration with a university librarian from off-target radiation damage has been associated with (H.N.W.), designed a comprehensive search strategy for numerous neurological deficiencies later in life, including each of three electronic databases (PubMed, Embase, and losses in memory, attention, and executive decision-mak- Scopus). Synonymous words for included search terms, ing,29 as well as high rates of dementia and a reduced long- such as “proton” and “carbon” for “particle” and “radio- term quality of life.26,59 In addition to concerns regarding therapy” for “radiation therapy,” were included to main- neurological decline, brain irradiation is associated with tain high inclusivity for our initial search. Strategies also increases in the incidence of secondary malignancies. utilized medical subject headings (MeSH) and Boolean Longitudinal monitoring of pediatric cancer patients has operators to capture all relevant publications. suggested that the receipt of conventionally fractionated Using a Boolean search scheme analogous to that ap- radiation therapy is associated with an increased risk of plied in our literature search, we identified ongoing trials secondary neoplasms later in life.43,47 from clinicaltrials.gov, a database of clinical trials curated Particle-based radiotherapy could reduce unwanted tis- by the US National Library of Medicine at the National Institutes of Health. Only studies exploring particle-based sue damage from off-target radiation. Dosimetry studies radiotherapy in high-grade meningiomas were included. comparing the deposition pattern of protons to that of photons have shown that proton therapy reduces ionizing radi- Data Extraction ation exposure in normal tissue proximal to the radiation target.41 Photon-based methods deposit a significant frac- A comprehensive analysis of PubMed, Embase, and tion of their dosage before reaching the target. Conversely, Scopus revealed 474 studies published between 1961 and particle-based radiation techniques, whose deposition pat- 2019, and 189 of them were duplicates removed prior to tern is characterized by a Bragg curve, deliver the bulk of screening. Eligibility, abstract, and full-text screening was the beam energy to the target, regardless of its depth, and performed independently in a standardized manner by re- minimize the unwanted damage to surrounding tissue.46 viewers (A.W. and M.C.J.). Disagreements were resolved Moreover, particle radiation therapy minimizes unwanted by discussion between the two reviewers, with a third re- exit dose, therefore reducing tissue damage to structures viewer for cases in which no agreement could be reached distal to the target. (H.N.W.). Eleven studies, all of which were published While the efficacy and toxicity associated with parti- between 2000 and 2018, explored the efficacy of particle or combined photon and particle treatments in the man- cle-based radiation techniques have been explored in sys- agement of WHO grade II and III meningiomas and were tematic reviews on low-grade primary brain tumors, few included in our systematic review. Outcome variables in- studies have explored the effect of particle radiotherapy 38,60 cluded number of patients with a diagnosis of high-grade in high-grade CNS malignancies. While the role of meningioma within each cohort, type of radiotherapy ad- photon-based radiotherapy for high-grade meningioma ministered, median age, median dose, local control rate, has been investigated, additional studies are needed to overall survival rate, median length of follow-up, treat- elucidate the role of particle therapy in controlling these 15,32 ment planning details, and type and timing of toxicities. aggressive tumor histologies. The aim of the present Two independent reviewers (A.W. and M.C.J.) assessed ar- analysis was to systematically review the studies address- ticle quality according to the Oxford Centre for Evidence- ing the safety and efficacy of particle radiotherapy for based Medicine (OCEBM) guidelines. Metrics evaluated atypical and anaplastic meningiomas. to ascertain levels of evidence included randomization, cohort size, and length of follow-up. Methods A systematic review on the efficacy of particle or com- Results bined photon and particle treatments in the management Eleven studies with 240 patients were included in the of WHO grade II and III meningiomas was performed final data extraction and analysis (Fig. 1 and Table 1). Of according to PRISMA guidelines. Our literature search note, five of the studies included only patients with high- was developed by defining the population, intervention, grade meningiomas (WHO grade II or grade III),10,12,17,32,42

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FIG. 1. Comprehensive literature search schematic. The PICOS framework was used to formulate study inclusion criteria; evaluation of screened studies was conducted adhering to PRISMA guidelines. while the other studies also included patients with benign ies focusing solely on high-grade meningioma, with a few meningiomas (WHO grade 1) and gliomas.18,19,22,23,44,64 studies reporting separate overall survival rates for WHO None of the studies were randomized or prospective. grade II and grade III meningiomas.12,23,32 Specifically, atypical meningiomas (WHO grade II) have better prog- Particle Radiotherapy Techniques and Treatment Plan nosis in terms of overall survival rates and median over- Schema all survival time as compared to malignant meningiomas Seven of the studies investigated the effects of combi- (WHO grade III) in the studies by Chan et al. (100% vs nation particle therapy (proton + photon, 50 Gy photon + 0%), Hug et al. (89% vs 51% at 5 years), and El Shafie et al. 18 Gy median carbon boost). (median overall survival time 238.7 vs 173.6 months).12,23,32 In order to plan treatment, the gross tumor volume (GTV) was first mapped with an additional margin, rang- Adverse Effects ing from 5 to 20 mm for high-grade meningiomas, and Radiation necrosis was the most commonly observed then creating a clinical target volume (CTV) based on pre- complication across the studies investigating particle ther- therapy imaging. At minimum, the GTV comprises the tu- apy in high-risk meningiomas, affecting 3 patients across mor as well as any dural extension or hyperostotic change three study cohorts composed of 77 patients (3.9%; Table involved with the lesion. The margin added to high-grade 2). Other less frequent adverse events included alopecia, meningioma is usually greater than the tumor edges be- skin irritation, and seizures. The vast majority of observed cause of the tumor’s infiltrative pattern of growth. Typi- complications were categorized as grades 1 and 2, ac- cal imaging modalities used to characterize extent of the cording to the Common Terminology Criteria for Adverse tumor include high-resolution contrast CT and MRI with 68 Events (CTCAE), whereas only one study reported the di- some practitioners utilizing formats such as Ga-DOTA- agnosis of grade 3 toxicity (radiation necrosis).42 It is worth TOC-PET.19 Final treatment plans were then generated on noting that the patient in this case had previously received 3D planning systems. pituitary radiation and was being treated for a radiation- Local Tumor Control induced meningioma; symptoms associated with radiation necrosis were resolved following treatment with pentoxi- In the five studies on high-grade meningioma only, lo- fylline supplemented with vitamin E and hyperbaric oxy- cal control rates at 5 years or at the end of the follow-up 12 gen. None of the included studies reported any secondary (median 145 months in Chan et al. ) ranged from 46.7% malignancies. to 86% (Table 1).10,12,17,32,42 Unfortunately, no data specific to grade II versus grade III meningioma local control rates were reported in the included studies. Discussion Adverse Events Following Particle Therapy Overall Survival Generally, the incidence of radiation-induced necrosis, Overall survival rates ranged from 0% to 100% in stud- which refers to the morphological changes in brain vascu-

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IV IV IV IV IV IV IV IV IV IV IV Level of Evidence§

6 NA 12 32.2 59 77 28.7 39 46.8 56.9 145 Median FU (mos) 173.6 mos III) (Gr 173.6 III) (7 yrs) (5 yrs,(5 Gr III) Overall Survival Rates NA 53.2% yr) (5 100% of FU) (end 238.7 mos II), (Gr 100% (Gr II), 0% 100% (Gr II), (Gr 96.2% 92% yrs), (5 90% yrs) (5 89% (5 yrs, Gr II), 51% 89% yrs, (5 Gr 51% II), 100% of FU) (end 88.2% yrs) (5 81.8% (5 yrs) (5 81.8% (5 yrs) Local Control Rates 54% (1 yr) (1 54% 46.7% (5 yrs) 46.7% (5 81.4% (end of FU) (end 81.4% 71% (1 yr) (1 71% 83.3% of FU) (end 100% (3 yrs), 96.6% yrs), 100% (3 86% yrs) (5 80% yrs) (5 71.1% (5 yrs) (5 71.1% 86.4% (5 yrs) 86.4% (5 84.8% yrs) (5 Median Dose Median (50 Gy + 18 Gy) (50 Gy + 18 photons¶ 58 II), (Gr Gy photons¶ III) (Gr NA 34 CGE 50 Gy GyE boost + 18 60 56 Gy II), (Gr Gy III) (Gr 68.4 Gy 72 Gy III) (Gr II), (Gr Proton photon (NA), + carbon 50.4 Gy GyE boost + 18 160 MeV protons,160 MeV 62 Gy 62 Gy (Gr II, III) II, (Gr Gy 62 NA 56 Gy Age in yrs‡ NA (48) 52.5 NA (55) NA (54) 46 NA (52) 52 49¶ 42 NA (52.8) NA (48.3¶) NA Median CohortMedian Type of Radiotherapy†Type (176); carbon(176); (84) carbon (15) Photon + carbon boost proton (36); Proton + photon (24) Proton (38); carbon (17); photon carbon + Proton (38); (17); Proton (8); carbonProton (8); (34) Proton + photon (6) Proton (2), photonProton + carbon (2), (6) Photon + carbon (10) Photons + protons (16) Proton (22) Proton (96) Proton (39)

31 31 10 24 10 27 36 35 22 6 8 Size* Cohort (Gr I–III (Gr (Gr I–III (Gr 22 23 (multiple (multiple I–III (Gr 18 19 meningiomas) tumor types) tumor meningiomas) meningiomas) meningiomas) meningiomas) meningiomas) meningiomas) meningiomas) meningiomas) meningiomas) Authors & Year (tumors studied) studied) (tumors Year & Authors Boskos 2009 al., et II–III (Gr Combs 2013 al., et TABLE 1. Literature 1. TABLE summary studies of 11 on WHO grade II and III meningiomas treated with particle therapy CGE = Cobalt Gray equivalent; FU = follow-up; GR = grade; GyE = Gray equivalent; NA = not available. * Number of patients in the study cohort who had a diagnosis of WHO grade II or III meningioma. † Values in parentheses refer to the total number of patients treated with the indicated therapy regardless of whether they had WHO grade II or III meningioma. ‡ Values outside of parentheses represent the median age of the WHO grade II–III cohort, whereas values within parentheses represent the median age of patientstypes. with WHO grade I–III meningioma or multiple tumor § Evaluation of evidence level is in accordance with OCEBM guidelines. ¶ Mean value. Chan et al., 2012 (Gr II–III (Gr 2012 Chan al., et Combs et al., 2010 (Gr II–IIICombs (Gr 2010 al., et El ShafieEl 2018 et al., Hug 2000 al., et II–III (Gr El ShafieEl 2018 et al., Combs 2013 al., et McDonald II–III (Gr 2015 al., et Murray et al., 2017 (Gr I–III (Gr Murray 2017 al., et Weber et al., 2012 (Gr I–III (Gr Weber 2012 al., et

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TABLE 2. Particle radiation therapy toxicities and adverse side effects for patients with WHO grade II or III meningioma Early Toxicity No. of Authors & Year (<6 mos) Late Toxicity (>6 mos) Patients Boskos et al., 2009 Seizures Alopecia (9 & 13 mos); radiation necrosis (16 mos) 3 Chan et al., 2012 Seizures (grade 1); skin toxicity (grade 1, 3 pts; grade 2, 3 pts) 7 Combs et al., 201017 Grade 1 or 2 alopecia, skin erythema, conjunctivitis, mucositis, xerostomia, headache, nausea NA Hug et al., 2000 NA Radiation necrosis (10 & 28 mos); optic neuropathy (22 mos) 3 McDonald et al., 2015 Grade 1 or 2 fatigue, temporary alopecia, mild radiation necrosis, grade 3 radiation necrosis NA Only studies whose cohorts were entirely composed of patients with high-grade meningiomas were included. lature and cell composition following ionizing radiation, ever, it should be noted that the longest median follow-up can range from 5.9% to 27% for patients undergoing cra- was 145 months in a limited cohort of 6 patients (Table 1). nial photon-based radiosurgery.24,25 A study investigating Additional studies with longer follow-ups are necessary the effects of fractionated photon-based radiation therapy to better understand the risk of radiation-induced cancers for intracranial low-grade neoplasms revealed that a total following proton-based radiotherapy. dose of more than 7.3 Gy in 2-Gy fractions to the bilateral hippocampus was associated with lasting deficits in list- Prognostic Factors for Local Tumor Control and Overall learning delayed verbal recall.28 In comparative studies Survival of radiation dosage to “organs at risk,” which include the Treatment with proton or carbon radiation leads to hippocampi, cochlea, optical structures, and thalami, par- relatively high rates of local control (46.7%–86%) and ticle radiation therapy plans actually resulted in an overall overall survival (53.2%–100%) in atypical and anaplastic dosing reduction in all locations as compared to plans for meningioma. Otherwise, rates of local control for grade 3D conformal radiotherapy and intensity-modulated ra- II meningioma range from 41.7% to 95% following pho- diotherapy.1,2,20 ton-based SRS.8,14,34 Survival rates are especially poor for Furthermore, pediatric patients receiving conventional grade III meningioma treated with photon therapy, rang- photon-based radiation to fields encompassing cerebral ing from 40% to 44% at 5 years.49,66 vasculature demonstrated a significant risk of vasculopa- Local control (72%–82.6%) and freedom from recur- thy, with nearly 20% of subjects experiencing either a rence have been favorable but variable for atypical me- transient ischemic attack or an infarction within 13 years ningioma treated with any form of radiation therapy.3,4,57 following therapy.50 In the present review, the high-risk Chen et al. found several significant prognostic factors for meningioma studies reported that the most common tox- local control in grade II meningiomas treated with sur- icity was radiation necrosis but at a rate lower than the ra- gery and adjuvant therapy, for example, achieving gross- diation necrosis rates cited for photon-treated high-grade total resection, using adjuvant radiation therapy, and even meningiomas, which range from 6.6% to 23%.36,49,53 having a history of previous cranial radiation therapy.13 In A number of the included studies described cases of our systematic review, a target dose greater than 60 Gy alopecia and seizures.10,12,16,42 According to prior stud- was a significant prognostic factor for local tumor control ies, the symptoms associated with tissue radiation dam- in the high-grade meningioma cohorts in Hug et al.32 and age appear to correlate with target location, with patients McDonald et al.42 On the other hand, a study on Gamma presenting with posterior fossa tumors especially at risk Knife treatment for grade II and III meningiomas found for proton-induced complications.33 The limited number that patient sex and a margin dose below 13 Gy were sig- of studies and patients in which particle-based therapies nificant factors associated with local control.63 have been applied to grade II and III meningiomas hin- A high histopathological tumor grade generally cor- ders meaningful correlative analyses between target loca- relates with poor survival because of poor local tumor tion and treatment-induced complications; however, future control and a high risk of recurrence and metastasis. As a trials of particle therapy for high-risk meningiomas could result, overall survival rates at 5 years for WHO grade II shed further light on the factors influencing the incidence (75.9%) and grade III (55.4%) meningiomas remain much of side effects of such treatment. lower than the rate for their benign grade I counterpart The risk of secondary malignancies induced by ioniz- (85.5%), according to a comprehensive national database ing radiation is also of great concern.35,40,56 In a retrospec- study. 54 Rates of progression-free survival (0% by the tive study on the incidence rate of secondary malignancies end of follow-up and 43% at 10 years) and overall sur- following various radiation modalities in benign menin- vival (20% by the end of follow-up) were poor for grade gioma, proton therapy was found to be associated with a III meningioma treated with nonparticle SRS.21,37 In our lower risk of radiation-induced cancers (1.3 vs 2.8 cases cohorts, some of the significant tumor-related prognostic per 10,000 patient-years).5 Additionally, dosimetric studies factors for survival were histological grade at diagnosis have shown that reduced proton therapies are associated and prior local control. With regard to treatment selection, with reduced in-field dosages, where the majority of sec- combined photon and proton radiation therapy as well ondary malignancies occur.6 None of the studies included as whether proton therapy was administered for primary in our review reported any secondary malignancies. How- versus recurrent tumor also had a significant association

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Date 7/2020 5/2022 2/2024 12/2020 12/2028 Completion - Secondary Outcome (2 yrs), linear energy energy linear yrs), (2 transfer logical pathological & response PFS mos), (3 yrs) OS (2 yrs), (2 recurrenceOS yrs), (5 QOL yrs) yrs), (5 (5 OS (3 yrs) OS (3 OS (3 yrs) OS (3 Local control OS yrs), (5 radio (7Toxicity mos), (late/acute;Toxicity 5 yrs), Primary Outcome PFS (3 yrs) (3 PFS Toxicity (1 yr) (1 Toxicity yrs) (2 Toxicity yrs) Immunogenicity (2 yrs) (5 PFS Intervention RT, HF photon RT, photon RT RT, proton RT boost Carbon boost Carbon RT, protonCarbon RT, IMPT Avelumab + Photon/proton RT/

12 40 80 60 90 (no. of patients) Enrollment I II I/II NA NA Phase - - - - - Pro Meningioma Study Name (MARCIE) py Withpy Advanced Photon Radiotherapy in Skull Base Meningiomas: The PINOCCHIO Trial Anaplasticor Meningiomas (PANAMA) mas ton Therapy (IMPT) for High-Grade Meningio mas ton Radiation Therapy Followed Surgery by for Radiation-refractoryRecurrent Carbon Ion Radiotherapy for Atypical Meningio Comparison of Proton and Carbon Ion Radiothera of IncreasedA Trial Dose Intensity Modulated Pro Proton Dose Escalation for Patients With Atypical Neoadjuvant Avelumab and Hypofractionated and Avelumab Neoadjuvant Study ID Study TABLE 3. OngoingTABLE clinical trials exploring particle therapy in high-grade meningioma HF = hypofractionated; IMPT = intensity-modulated proton therapy; OS = overall survival; PFS = progression-free survival; QOL = quality of life; RT = radiotherapy. A total of five ongoing clinical studies investigating the utility of particle therapy in atypical and anaplastic meningioma were identified.Toxicity is measuredEvents (CTCAE). Quality according of life to is gradedthe TerminologyCommon according Criteria to the European for Adverse Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients (EORTC-QLQ-C30) criteria. BN20) and Brain Cancer Patients (EORTC-QLQ- NCT01166321 NCT01795300 NCT02693990 NCT02978677 NCT03267836

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Unauthenticated | Downloaded 09/29/21 02:11 PM UTC Wu et al. with survival outcome. Further studies are necessary to ary endpoint in all five trials, and three of the five trials characterize the efficacy and utility of radiation therapy are also collecting data on progression-free survival. The for aggressive subtypes of meningioma. studied interventions are diverse, with two trials exploring carbon-based radiotherapy and one evaluating proton Ongoing Investigations Into Particle Therapy in High-Risk radiotherapy in combination with immunotherapy. Results Meningiomas from these studies, in combination with future phase III Particle radiotherapy is a field of active investigation to trials, are critical for improving our understanding of the define its use and outcomes in the clinical setting, to de- role of particle therapy in the setting of high-grade menin- velop new and highly precise delivery strategies, and to gioma. define the radiobiological effects of these techniques in a laboratory setting. The majority of studies in our review Considering the Cost-Effectiveness of Particle Therapy identified the use of protons in combination with confor- Ongoing concerns regarding particle therapy are cen- mal photon therapy; however, investigations into alter- tered around patient access and treatment cost. While the native delivery methods, such as proton-based SRS and US has yet to construct a clinically operational heavy ion intensity-modulated proton therapy (IMPT), have shown therapy center, the number of proton centers has expanded promise. Photon-based SRS involves the administration of from six 10 years ago to thirty-one as of February 2019 a radioablative dose to the target in either a single fraction (https://www.ptcog.ch/index.php/facilities-in-operation). or a hypofractionated scheme and has been a mainstay of However, insurance approval for proton radiotherapy re- meningioma radiotherapy for decades.67 While compre- mains challenging and could pose significant hurdles to hensive investigations are yet to be completed in the set- the timely delivery of this treatment.48 Other logistical ting of atypical and anaplastic meningiomas, a compari- hurdles to particle radiotherapy, such as upfront treat- son of proton SRS and photon SRS in the management of ment cost, could also pose formidable barriers. Statistical brain metastases has suggested that protons have minimal modeling of the expected lifetime costs associated with treatment-related toxicity and reduce the integral normal proton therapy for pediatric medulloblastoma offers opti- tissue radiation dose.7 IMPT, as compared to the more mism, with some studies suggesting an eightfold reduction common scattered proton therapy, offers increased modu- in costs given the reduced incidence of treatment-related lation of radiation deposition proximal to the target and adverse events.61 However, upfront costs for proton ra- improved conformality of dosage application.30 Moreover, diotherapy remain high. Furthermore, cost-effectiveness IMPT administration in small patient cohorts has shown studies of proton therapy in CNS malignancies have been promising results.39 One case series (15 patients) examined largely limited to pediatric medulloblastoma with no cost- short-term disease control and toxicity profiles in patients effectiveness studies published on the treatment of grade II with skull base malignancies treated with IMPT. Dur- and III meningiomas specifically. ing the 27-month follow-up, none of the patients reported grade 3–5 adverse events, although two patients developed Limitations and Future Directions for Study 31 either local or distant disease recurrence. Meningiomas, Our systematic review on particle radiation therapy for which often form near the delicate structures easily dam- grade II and grade III meningiomas included eleven stud- aged by ionizing radiation, such as the brainstem and cra- ies with various cohort sizes, five of which were specific for nial nerves, could be ideal candidates for IMPT use in the high-grade meningiomas. Selection bias and confounding future. factors related to patient inclusion and treatment selection In addition to investigations focusing on the develop- are inherent to retrospective studies, particularly those on ment and refinement of radiotherapeutic technology, re- uncommon diseases or treatment modalities without stan- cent and ongoing clinical studies seek to determine the dardization of care. Furthermore, our systematic review is effectiveness of particle therapy for brain tumors. While limited to the type of analyses each study included, mak- particle therapy is well established for the treatment of a ing it potentially difficult to make generalizable conclu- number of tumor types, efficacy has not been established sions regarding local control and overall survival without in high-grade meningioma. Our review identified 11 stud- future prospective and randomized studies. The strengths ies analyzing outcomes and toxicity associated with par- of our review include its focus on describing particle radia- ticle-based radiotherapy in the setting of high-grade me- tion therapy as an alternative treatment option for high- ningioma. However, all of the studies were retrospective risk meningiomas, which are more difficult to manage analyses, and our analysis of the strength of evidence per than their benign counterpart. OCEBM guidelines revealed a lack of definitive evidence supporting the use of particle therapy in atypical and anaplastic meningioma (Table 1). We also identified five phase Conclusions I and II clinical trials actively exploring the efficacy and In summary, our systematic review about particle ra- toxicity associated with the use of ions in the manage- diotherapy for grade II and III meningiomas suggests that ment of grade II and III meningiomas;16 however, results particle radiation, whether as proton or carbon ions in are not expected until 2020 at the earliest (Table 3). The combination with photons or as stand-alone therapy, is an primary outcome evaluated in the majority of the ongo- acceptable alternative to photon therapy in terms of sur- ing trials (3/5 studies) is treatment-related complications; vival benefit and risk profile. High-grade meningiomas are the other two studies are assessing toxicity as a secondary difficult to manage, and the addition of proton or carbon outcome. Overall survival is either a primary or second- radiation results in relatively high rates of local control

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Unauthenticated | Downloaded 09/29/21 02:11 PM UTC Wu et al. and overall survival specifically in atypical and anaplastic JS: Dose escalation with proton radiation therapy for high- meningioma cohorts. More data need to be collected to grade meningiomas. Technol Cancer Res Treat 11:607– inform the optimal dosing strategy given the variability 614, 2012 13. Chen WC, Magill ST, Wu A, Vasudevan HN, Morin O, Aghi (operator dependent) in the median doses administered. MK, et al: Histopathological features predictive of local Overall, particle radiotherapy carries benefit and is safe for control of atypical meningioma after surgery and adjuvant patients with aggressive forms of meningioma. Given the radiotherapy. J Neurosurg 130:443–450, 2018 current limits of few studies with small cohorts, additional 14. Cho M, Joo JD, Kim IA, Han JH, Oh CW, Kim CY: The studies, especially pending prospective trials, are certainly role of adjuvant treatment in patients with high-grade warranted to investigate the utility of particle radiotherapy meningioma. J Korean Neurosurg Soc 60:527–533, 2017 as an additional treatment option for grade II and III me- 15. Coke CC, Corn BW, Werner-Wasik M, Xie Y, Curran WJ Jr: ningiomas. Atypical and malignant meningiomas: an outcome report of seventeen cases. J Neurooncol 39:65–70, 1998 16. Combs SE, Edler L, Burkholder I, Rieken S, Habermehl Acknowledgments D, Jäkel O, et al: Treatment of patients with atypical We gratefully acknowledge support for this study from Joe and meningiomas Simpson grade 4 and 5 with a carbon ion boost Rika Mansueto, Craig and Kim Darian, and Carol Bade (S.D.C.). in combination with postoperative photon radiotherapy: the MARCIE trial. BMC Cancer 10:615, 2010 17. Combs SE, Hartmann C, Nikoghosyan A, Jäkel O, Karger References CP, Haberer T, et al: Carbon ion radiation therapy for high- 1. Adeberg S, Harrabi SB, Bougatf N, Bernhardt D, Rieber risk meningiomas. Radiother Oncol 95:54–59, 2010 J, Koerber SA, et al: Intensity-modulated proton therapy, 18. Combs SE, Kessel K, Habermehl D, Haberer T, Jäkel O, volumetric-modulated arc therapy, and 3D conformal Debus J: Proton and carbon ion radiotherapy for primary radiotherapy in anaplastic astrocytoma and glioblastoma: a brain tumors and tumors of the skull base. Acta Oncol dosimetric comparison. Strahlenther Onkol 192:770–779, 52:1504–1509, 2013 2016 19. Combs SE, Welzel T, Habermehl D, Rieken S, Dittmar JO, 2. 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et al: World Health Organization grade III (nonanaplastic) Author Contributions meningioma: experience in a series of 23 cases. World Conception and design: Wu, Jin, Meola, Chang. Acquisition of Neurosurg 112:e754–e762, 2018 data: Wu, Jin, Wong. Analysis and interpretation of data: Wu, Jin. 67. Zhang M, Ho AL, D’Astous M, Pendharkar AV, Choi CY, Drafting the article: Wu, Jin. Critically revising the article: all Thompson PA, et al: CyberKnife stereotactic radiosurgery authors. Reviewed submitted version of manuscript: all authors. for atypical and malignant meningiomas. World Neurosurg Approved the final version of the manuscript on behalf of all 91:574–581, 581.e1, 2016 authors: Wu. Study supervision: Chang. Correspondence Adela Wu: Stanford University School of Medicine, Stanford, CA. Disclosures [email protected]. The authors report no conflict of interest concerning the materi- als or methods used in this study or the findings specified in this paper.

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