Efficacy and toxicity of particle radiotherapy in WHO

NEUROSURGICAL

FOCUS Neurosurg Focus 46 (6):E12, 2019

MeningioMas are the most common primary brain tumor, accounting for approximately 33.8% of all central nervous system (CNS) tumors in the US.65

Based on the World Health Organization (WHO) classi-fication, meningiomas are divided into benign (grade I), atypical (grade II), and anaplastic (grade III) subtypes.9,55 Atypical and anaplastic meningiomas are rare and account for 1%–25% of all meningiomas.27 Atypical meningiomas have high recurrence rates (28%–41%) following surgery without additional therapy.3,51 Malignant anaplastic me-

ningiomas are the most aggressive, with recurrence rates ranging from 50% to 94% and significant risk for invasion and metastasis.62

The current standard of care for symptomatic or grow-ing meningioma consists of maximal resection.62 Photon-based radiotherapy, including both stereotactic radiosur-gery (SRS) and conventional stereotactic radiotherapy, is usually recommended as adjuvant therapy or as primary treatment for meningioma.45 However, alternative radiation techniques collectively known as “particle radiotherapy”

ABBREVIATIONS CNS = central nervous system; IMPT = intensity-modulated proton therapy; OCEBM = Oxford Centre for Evidence-based Medicine; PICOS = popula-tion, 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.

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 meningio-mas 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.FOCUS1967KEYWORDS meningioma; atypical; malignant; particle radiotherapy

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

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Wu et al.

Neurosurg Focus Volume 46 • June 20192

have emerged for treating meningiomas and other tumors of the CNS, including proton therapy, carbon ion therapy, or boron neutron capture therapy (BNCT). And although photon-based radiotherapy is used worldwide for the treat-ment of meningioma, particle radiation therapy could re-duce the risk of the adverse radiation effects caused by photon-based radiotherapy.

In fact, particle-based therapies offer several tantalizing advantages. A primary concern associated with radiation therapy is inadvertent dose deposition in nontarget tissue. While acute deficits associated with radiation-induced brain injury are often transient, other impairments often result from permanent morphological alterations, such as hypoxic tissue damage (with subsequent cognitive de-cline)11,52 and radiation necrosis, caused by inflammatory responses to radiation damage.58 Tissue damage resulting from off-target radiation damage has been associated with numerous neurological deficiencies later in life, including losses in memory, attention, and executive decision-mak-ing,29 as well as high rates of dementia and a reduced long-term quality of life.26,59 In addition to concerns regarding neurological decline, brain irradiation is associated with increases in the incidence of secondary malignancies. Longitudinal monitoring of pediatric cancer patients has suggested that the receipt of conventionally fractionated radiation therapy is associated with an increased risk of secondary neoplasms later in life.43,47

Particle-based radiotherapy could reduce unwanted tis-sue damage from off-target radiation. Dosimetry studies comparing the deposition pattern of protons to that of pho-tons have shown that proton therapy reduces ionizing radi-ation exposure in normal tissue proximal to the radiation target.41 Photon-based methods deposit a significant frac-tion of their dosage before reaching the target. Conversely, particle-based radiation techniques, whose deposition pat-tern is characterized by a Bragg curve, deliver the bulk of the beam energy to the target, regardless of its depth, and minimize the unwanted damage to surrounding tissue.46 Moreover, particle radiation therapy minimizes unwanted exit dose, therefore reducing tissue damage to structures distal to the target.

While the efficacy and toxicity associated with parti-cle-based radiation techniques have been explored in sys-tematic reviews on low-grade primary brain tumors, few studies have explored the effect of particle radiotherapy in high-grade CNS malignancies.38,60 While the role of photon-based radiotherapy for high-grade meningioma has been investigated, additional studies are needed to elucidate the role of particle therapy in controlling these aggressive tumor histologies.15,32 The aim of the present analysis was to systematically review the studies address-ing the safety and efficacy of particle radiotherapy for atypical and anaplastic meningiomas.

MethodsA systematic review on the efficacy of particle or com-

bined photon and particle treatments in the management of WHO grade II and III meningiomas was performed according to PRISMA guidelines. Our literature search was developed by defining the population, intervention,

comparison, outcomes, and study design (PICOS; Fig. 1). Inclusion criteria, outcome measures, and search strategy were defined in advance.

Search StrategyOur review included studies on the use of particle-based

radiotherapy in high-grade meningioma (WHO grades II and III) in the adult population (age > 18 years old), with 5 or more subjects, and written in the English language. Upfront exclusion criteria included review articles, book chapters, editorials, and articles in languages other than English. Other exclusion criteria were studies including pediatric patients, having fewer than 5 subjects, or re-porting outcomes different from those detailed in Fig. 1. In order to ensure exhaustive canvassing of the published literature, we, in collaboration with a university librarian (H.N.W.), designed a comprehensive search strategy for each of three electronic databases (PubMed, Embase, and Scopus). Synonymous words for included search terms, such as “proton” and “carbon” for “particle” and “radio-therapy” for “radiation therapy,” were included to main-tain high inclusivity for our initial search. Strategies also utilized medical subject headings (MeSH) and Boolean operators to capture all relevant publications.

Using a Boolean search scheme analogous to that ap-plied in our literature search, we identified ongoing trials from clinicaltrials.gov, a database of clinical trials curated by the US National Library of Medicine at the National Institutes of Health. Only studies exploring particle-based radiotherapy in high-grade meningiomas were included.

Data ExtractionA comprehensive analysis of PubMed, Embase, and

Scopus revealed 474 studies published between 1961 and 2019, and 189 of them were duplicates removed prior to screening. Eligibility, abstract, and full-text screening was performed independently in a standardized manner by re-viewers (A.W. and M.C.J.). Disagreements were resolved by discussion between the two reviewers, with a third re-viewer for cases in which no agreement could be reached (H.N.W.). Eleven studies, all of which were published between 2000 and 2018, explored the efficacy of particle or combined photon and particle treatments in the man-agement of WHO grade II and III meningiomas and were included in our systematic review. Outcome variables in-cluded number of patients with a diagnosis of high-grade meningioma within each cohort, type of radiotherapy ad-ministered, median age, median dose, local control rate, overall survival rate, median length of follow-up, treat-ment planning details, and type and timing of toxicities. Two independent reviewers (A.W. and M.C.J.) assessed ar-ticle quality according to the Oxford Centre for Evidence-based Medicine (OCEBM) guidelines. Metrics evaluated to ascertain levels of evidence included randomization, cohort size, and length of follow-up.

ResultsEleven studies with 240 patients were included in the

final data extraction and analysis (Fig. 1 and Table 1). Of note, five of the studies included only patients with high-grade meningiomas (WHO grade II or grade III),10,12,17,32,42


Wu et al.

Neurosurg Focus Volume 46 • June 2019 3

while the other studies also included patients with benign meningiomas (WHO grade 1) and gliomas.18,19,22,23,44,64 None of the studies were randomized or prospective.

Particle Radiotherapy Techniques and Treatment Plan Schema

Seven of the studies investigated the effects of combi-nation particle therapy (proton + photon, 50 Gy photon + 18 Gy median carbon boost).

In order to plan treatment, the gross tumor volume (GTV) was first mapped with an additional margin, rang-ing from 5 to 20 mm for high-grade meningiomas, and then creating a clinical target volume (CTV) based on pre-therapy imaging. At minimum, the GTV comprises the tu-mor as well as any dural extension or hyperostotic change involved with the lesion. The margin added to high-grade meningioma is usually greater than the tumor edges be-cause of the tumor’s infiltrative pattern of growth. Typi-cal imaging modalities used to characterize extent of the tumor include high-resolution contrast CT and MRI with some practitioners utilizing formats such as 68Ga-DOTA-TOC-PET.19 Final treatment plans were then generated on 3D planning systems.

Local Tumor ControlIn the five studies on high-grade meningioma only, lo-

cal control rates at 5 years or at the end of the follow-up (median 145 months in Chan et al.12) ranged from 46.7% 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.

Overall SurvivalOverall survival rates ranged from 0% to 100% in stud-

ies focusing solely on high-grade meningioma, with a few studies reporting separate overall survival rates for WHO grade II and grade III meningiomas.12,23,32 Specifically, atypical meningiomas (WHO grade II) have better prog-nosis in terms of overall survival rates and median over-all survival time as compared to malignant meningiomas (WHO grade III) in the studies by Chan et al. (100% vs 0%), Hug et al. (89% vs 51% at 5 years), and El Shafie et al. (median overall survival time 238.7 vs 173.6 months).12,23,32

Adverse EffectsRadiation necrosis was the most commonly observed

complication across the studies investigating particle ther-apy in high-risk meningiomas, affecting 3 patients across three study cohorts composed of 77 patients (3.9%; Table 2). Other less frequent adverse events included alopecia, skin irritation, and seizures. The vast majority of observed complications were categorized as grades 1 and 2, ac-cording to the Common Terminology Criteria for Adverse Events (CTCAE), whereas only one study reported the di-agnosis of grade 3 toxicity (radiation necrosis).42 It is worth noting that the patient in this case had previously received pituitary radiation and was being treated for a radiation-induced meningioma; symptoms associated with radiation necrosis were resolved following treatment with pentoxi-fylline supplemented with vitamin E and hyperbaric oxy-gen. None of the included studies reported any secondary malignancies.

DiscussionAdverse Events Following Particle Therapy

Generally, the incidence of radiation-induced necrosis, which refers to the morphological changes in brain vascu-

FIG. 1. Comprehensive literature search schematic. The PICOS framework was used to formulate study inclusion criteria; evalua-tion of screened studies was conducted adhering to PRISMA guidelines.


Wu et al.


TABL

E 1.

Lite

ratu

re su

mm

ary o

f 11 s

tudi

es o

n W

HO g

rade

II an

d III

men

ingi

omas

trea

ted

with

par

ticle

ther

apy

Auth

ors &

Yea

r (tum

ors s

tudie

d)

Coho

rt Si

ze*

Type

of R

adiot

hera

py†

Med

ian C

ohor

t Ag

e in y

rs‡

Med

ian D

ose

Loca

l Con

trol R

ates

Over

all S

urviv

al Ra

tes

Med

ian

FU (m

os)

Leve

l of

Evide

nce§

Bosk

os et

al., 2

009 (

Gr II

–III

menin

gioma

s)24

Proto

n + ph

oton (

24)

52.5

34 C

GE46

.7% (5

yrs)

53.2

% (5

yr)

32.2

IV

Chan

et al

., 201

2 (Gr

II–I

II me

ningio

mas)

6Pr

oton +

photo

n (6)

4668

.4 Gy

(Gr I

I), 72

Gy (

Gr II

I)83

.3% (e

nd of

FU)

100%

(Gr I

I), 0%

(Gr

III)14

5IV

Comb

s et a

l., 20

1318

(mult

iple

tumor

type

s)36

Photo

n + ca

rbon

boos

t (36

); pr

oton

(176)

; car

bon (

84)

NA (4

8)NA

54%

(1 yr

)NA

12IV

Comb

s et a

l., 20

1319

(Gr I

–III

menin

gioma

s)27

Proto

n (38

); ca

rbon

(17)

; pho

ton +

ca

rbon

(15)

NA (5

5)50

GyE

+ 18

Gy b

oost

81.4%

(end

of F

U)10

0% (e

nd of

FU)

6IV

Comb

s et a

l., 20

10 (G

r II–

III

menin

gioma

s)10

Photo

n + ca

rbon

(10)

5250

.4 Gy

E +

18 G

y boo

st86

% (5

yrs)

90%

(5 yr

s)77

IV

El S

hafie

et al

., 201

822 (G

r I–I

II me

ningio

mas)

31Pr

oton (

8); c

arbo

n (34

)NA

(54)

60 G

y (Gr

II), 5

6 Gy (

Gr II

I)71

% (1

yr)

238.7

mos

(Gr I

I),

173.

6 mos

(Gr I

II)NA

IV

El S

hafie

et al

., 201

823 (G

r I–I

II me

ningio

mas)

8Pr

oton (

2), ph

oton +

carb

on (6

)NA

(52)

Proto

n (NA

), ph

oton +

carb

on

(50 G

y + 18

Gy)

100%

(3 yr

s), 9

6.6%

(5

yrs)

96.2

% (5

yrs),

92%

(7

yrs)

46.8

IV

Hug e

t al.,

2000

(Gr I

I–III

me

ningio

mas)

31Ph

otons

+ pr

otons

(16)

49¶

160 M

eV pr

otons

, 62 G

y ph

otons

¶ (Gr

II), 5

8 Gy

photo

ns¶ (

Gr II

I)

80%

(5 yr

s)89

% (5

yrs,

Gr II)

, 51%

(5

yrs,

Gr II

I)59

IV

McD

onald

et al

., 201

5 (Gr

II–I

II me

ningio

mas)

22Pr

oton (

22)

4262

Gy (

Gr II

, III)

71.1%

(5 yr

s)10

0% (e

nd of

FU)

39IV

Mur

ray e

t al.,

2017

(Gr I

–III

menin

gioma

s)35

Proto

n (96

)NA

(52.

8)NA

86.4%

(5 yr

s)88

.2%

(5 yr

s)56

.9IV

Web

er et

al., 2

012 (

Gr I–

III

menin

gioma

s)10

Proto

n (39

)NA

(48.

3¶)

56 G

y84

.8% (5

yrs)

81.8%

(5 yr

s)28

.7IV

CGE

= Co

balt G

ray e

quiva

lent; F

U =

follo

w-up

; GR

= gr

ade;

GyE

= Gr

ay e

quiva

lent; N

A =

not a

vaila

ble.

* Num

ber o

f pat

ients

in th

e stu

dy co

hort

who h

ad a

diagn

osis

of W

HO gr

ade I

I or I

II men

ingiom

a.† V

alues

in pa

rent

hese

s ref

er to

the t

otal

numb

er of

patie

nts t

reate

d with

the i

ndica

ted t

hera

py re

gard

less o

f whe

ther

they

had W

HO gr

ade I

I or I

II men

ingiom

a.‡ V

alues

outsi

de of

pare

nthe

ses r

epre

sent

the m

edian

age o

f the

WHO

grad

e II–

III co

hort,

whe

reas

value

s with

in pa

rent

hese

s rep

rese

nt th

e med

ian ag

e of p

atien

ts wi

th W

HO gr

ade I

–III m

ening

ioma o

r mult

iple t

umor

typ

es.

§ Eva

luatio

n of e

viden

ce le

vel is

in ac

cord

ance

with

OCE

BM gu

idelin

es.

¶ Mea

n valu

e.


Wu et al.


lature and cell composition following ionizing radiation, can range from 5.9% to 27% for patients undergoing cra-nial photon-based radiosurgery.24,25 A study investigating the effects of fractionated photon-based radiation therapy for intracranial low-grade neoplasms revealed that a total dose of more than 7.3 Gy in 2-Gy fractions to the bilateral hippocampus was associated with lasting deficits in list-learning delayed verbal recall.28 In comparative studies of radiation dosage to “organs at risk,” which include the hippocampi, cochlea, optical structures, and thalami, par-ticle radiation therapy plans actually resulted in an overall dosing reduction in all locations as compared to plans for 3D conformal radiotherapy and intensity-modulated ra-diotherapy.1,2,20

Furthermore, pediatric patients receiving conventional photon-based radiation to fields encompassing cerebral vasculature demonstrated a significant risk of vasculopa-thy, with nearly 20% of subjects experiencing either a transient ischemic attack or an infarction within 13 years following therapy.50 In the present review, the high-risk meningioma studies reported that the most common tox-icity was radiation necrosis but at a rate lower than the ra-diation necrosis rates cited for photon-treated high-grade meningiomas, which range from 6.6% to 23%.36,49,53

A number of the included studies described cases of alopecia and seizures.10,12,16,42 According to prior stud-ies, the symptoms associated with tissue radiation dam-age appear to correlate with target location, with patients presenting with posterior fossa tumors especially at risk for proton-induced complications.33 The limited number of studies and patients in which particle-based therapies have been applied to grade II and III meningiomas hin-ders meaningful correlative analyses between target loca-tion and treatment-induced complications; however, future trials of particle therapy for high-risk meningiomas could shed further light on the factors influencing the incidence of side effects of such treatment.

The risk of secondary malignancies induced by ioniz-ing radiation is also of great concern.35,40,56 In a retrospec-tive study on the incidence rate of secondary malignancies following various radiation modalities in benign menin-gioma, proton therapy was found to be associated with a lower risk of radiation-induced cancers (1.3 vs 2.8 cases per 10,000 patient-years).5 Additionally, dosimetric studies have shown that reduced proton therapies are associated with reduced in-field dosages, where the majority of sec-ondary malignancies occur.6 None of the studies included in our review reported any secondary malignancies. How-

ever, it should be noted that the longest median follow-up was 145 months in a limited cohort of 6 patients (Table 1). Additional studies with longer follow-ups are necessary to better understand the risk of radiation-induced cancers following proton-based radiotherapy.

Prognostic Factors for Local Tumor Control and Overall Survival

Treatment with proton or carbon radiation leads to relatively high rates of local control (46.7%–86%) and overall survival (53.2%–100%) in atypical and anaplastic meningioma. Otherwise, rates of local control for grade II meningioma range from 41.7% to 95% following pho-ton-based SRS.8,14,34 Survival rates are especially poor for grade III meningioma treated with photon therapy, rang-ing from 40% to 44% at 5 years.49,66

Local control (72%–82.6%) and freedom from recur-rence have been favorable but variable for atypical me-ningioma treated with any form of radiation therapy.3,4,57 Chen et al. found several significant prognostic factors for local control in grade II meningiomas treated with sur-gery and adjuvant therapy, for example, achieving gross-total resection, using adjuvant radiation therapy, and even having a history of previous cranial radiation therapy.13 In our systematic review, a target dose greater than 60 Gy was a significant prognostic factor for local tumor control in the high-grade meningioma cohorts in Hug et al.32 and McDonald et al.42 On the other hand, a study on Gamma Knife treatment for grade II and III meningiomas found that patient sex and a margin dose below 13 Gy were sig-nificant factors associated with local control.63

A high histopathological tumor grade generally cor-relates with poor survival because of poor local tumor control and a high risk of recurrence and metastasis. As a result, overall survival rates at 5 years for WHO grade II (75.9%) and grade III (55.4%) meningiomas remain much lower than the rate for their benign grade I counterpart (85.5%), according to a comprehensive national database study.54 Rates of progression-free survival (0% by the end of follow-up and 43% at 10 years) and overall sur-vival (20% by the end of follow-up) were poor for grade III meningioma treated with nonparticle SRS.21,37 In our cohorts, some of the significant tumor-related prognostic factors for survival were histological grade at diagnosis and prior local control. With regard to treatment selection, combined photon and proton radiation therapy as well as whether proton therapy was administered for primary versus recurrent tumor also had a significant association

TABLE 2. Particle radiation therapy toxicities and adverse side effects for patients with WHO grade II or III meningioma

Authors & YearEarly Toxicity

(<6 mos) Late Toxicity (>6 mos)No. of

Patients

Boskos et al., 2009 Seizures Alopecia (9 & 13 mos); radiation necrosis (16 mos) 3Chan et al., 2012 Seizures (grade 1); skin toxicity (grade 1, 3 pts; grade 2, 3 pts) 7Combs et al., 201017 Grade 1 or 2 alopecia, skin erythema, conjunctivitis, mucositis, xerostomia, headache, nausea NAHug et al., 2000 NA Radiation necrosis (10 & 28 mos); optic neuropathy (22 mos) 3McDonald 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.


Wu et al.


TABL

E 3.

Ongo

ing

clini

cal t

rials

expl

orin

g pa

rticl

e the

rapy

in h

igh-

grad

e men

ingi

oma

Stud

y ID

Stud

y Nam

ePh

ase

Enro

llmen

t (n

o. of

patie

nts)

Inter

venti

onPr

imar

y Outc

ome

Seco

ndar

y Outc

ome

Comp

letion

Da

teAs

socia

ted

Publi

catio

ns

NCT0

1166

321

Carb

on Io

n Rad

iothe

rapy

for A

typica

l Men

ingio-

mas (

MAR

CIE)

II40

Carb

on bo

ost

PFS

(3 yr

s)OS

(3 yr

s)12

/202

0Co

mbs e

t al.,

2010

NCT0

1795

300

Comp

ariso

n of P

roton

and C

arbo

n Ion

Rad

iothe

ra-

py W

ith A

dvan

ced P

hoton

Rad

iothe

rapy

in S

kull

Base

Men

ingiom

as: T

he P

INOC

CHIO

Trial

NA80

Carb

on R

T, pr

oton

RT, H

F ph

oton

RT, p

hoton

RT

Toxic

ity (1

yr)

OS (3

yrs)

5/20

22NA

NCT0

2693

990

A Tr

ial of

Incr

ease

d Dos

e Inte

nsity

Mod

ulated

Pro

-ton

The

rapy

(IM

PT) f

or H

igh-G

rade

Men

ingio-

mas

I/II

60IM

PTTo

xicity

(2 yr

s)Lo

cal c

ontro

l (5 yr

s), O

S (2

yrs),

linea

r ene

rgy

trans

fer

2/20

24NA

NCT0

3267

836

Neoa

djuva

nt Av

eluma

b and

Hyp

ofra

ction

ated P

ro-

ton R

adiat

ion T

hera

py F

ollow

ed by

Sur

gery

for

Recu

rrent

Radia

tion-

refra

ctory

Men

ingiom

a

I12

Avelu

mab +

pr

oton R

TIm

muno

genic

ity (2

yrs)

Toxic

ity (7

mos

), ra

dio-

logica

l & pa

tholo

gical

resp

onse

(3 m

os),

PFS

(2 yr

s), O

S (2

yrs)

7/202

0NA

NCT0

2978

677

Proto

n Dos

e Esc

alatio

n for

Pati

ents

With

Atyp

ical

or A

napla

stic M

ening

iomas

(PAN

AMA)

NA90

Photo

n/pro

ton R

T/bo

ost

PFS

(5 yr

s)To

xicity

(late

/acute

; 5 yr

s),

OS (5

yrs),

recu

rrenc

e (5

yrs),

QOL

(5 yr

s)

12/2

028

NA

HF =

hypo

fracti

onate

d; IM

PT =

inte

nsity

-mod

ulate

d pro

ton t

hera

py; O

S =

over

all su

rviva

l; PFS

= pr

ogre

ssion

-free

surv

ival; Q

OL =

quali

ty of

life; R

T =

radio

ther

apy.

A tot

al of

five o

ngoin

g clin

ical s

tudie

s inv

estig

ating

the u

tility

of pa

rticle

ther

apy i

n atyp

ical a

nd an

aplas

tic m

ening

ioma w

ere i

dent

ified.

Toxic

ity is

mea

sure

d acc

ordin

g to t

he C

omm

on Te

rmino

logy C

riter

ia fo

r Adv

erse

Ev

ents

(CTC

AE).

Quali

ty of

life is

grad

ed ac

cord

ing to

the E

urop

ean O

rgan

isatio

n for

Res

earc

h and

Trea

tmen

t of C

ance

r Qua

lity of

Life

of Ca

ncer

Pat

ients

(EOR

TC-Q

LQ-C

30) a

nd B

rain

Canc

er P

atien

ts (E

ORTC

-QLQ

-BN

20) c

riter

ia.


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with survival outcome. Further studies are necessary to characterize the efficacy and utility of radiation therapy for aggressive subtypes of meningioma.

Ongoing Investigations Into Particle Therapy in High-Risk Meningiomas

Particle radiotherapy is a field of active investigation to define its use and outcomes in the clinical setting, to de-velop new and highly precise delivery strategies, and to define the radiobiological effects of these techniques in a laboratory setting. The majority of studies in our review identified the use of protons in combination with confor-mal photon therapy; however, investigations into alter-native delivery methods, such as proton-based SRS and intensity-modulated proton therapy (IMPT), have shown promise. Photon-based SRS involves the administration of a radioablative dose to the target in either a single fraction or a hypofractionated scheme and has been a mainstay of meningioma radiotherapy for decades.67 While compre-hensive investigations are yet to be completed in the set-ting of atypical and anaplastic meningiomas, a compari-son of proton SRS and photon SRS in the management of brain metastases has suggested that protons have minimal treatment-related toxicity and reduce the integral normal tissue radiation dose.7 IMPT, as compared to the more common scattered proton therapy, offers increased modu-lation of radiation deposition proximal to the target and improved conformality of dosage application.30 Moreover, IMPT administration in small patient cohorts has shown promising results.39 One case series (15 patients) examined short-term disease control and toxicity profiles in patients with skull base malignancies treated with IMPT. Dur-ing the 27-month follow-up, none of the patients reported grade 3–5 adverse events, although two patients developed either local or distant disease recurrence.31 Meningiomas, which often form near the delicate structures easily dam-aged by ionizing radiation, such as the brainstem and cra-nial nerves, could be ideal candidates for IMPT use in the future.

In addition to investigations focusing on the develop-ment and refinement of radiotherapeutic technology, re-cent and ongoing clinical studies seek to determine the effectiveness of particle therapy for brain tumors. While particle therapy is well established for the treatment of a number of tumor types, efficacy has not been established in high-grade meningioma. Our review identified 11 stud-ies analyzing outcomes and toxicity associated with par-ticle-based radiotherapy in the setting of high-grade me-ningioma. However, all of the studies were retrospective analyses, and our analysis of the strength of evidence per OCEBM guidelines revealed a lack of definitive evidence supporting the use of particle therapy in atypical and ana-plastic meningioma (Table 1). We also identified five phase I and II clinical trials actively exploring the efficacy and toxicity associated with the use of ions in the manage-ment of grade II and III meningiomas;16 however, results are not expected until 2020 at the earliest (Table 3). The primary outcome evaluated in the majority of the ongo-ing trials (3/5 studies) is treatment-related complications; the other two studies are assessing toxicity as a secondary outcome. Overall survival is either a primary or second-

ary endpoint in all five trials, and three of the five trials are also collecting data on progression-free survival. The studied interventions are diverse, with two trials explor-ing carbon-based radiotherapy and one evaluating proton radiotherapy in combination with immunotherapy. Results from these studies, in combination with future phase III trials, are critical for improving our understanding of the role of particle therapy in the setting of high-grade menin-gioma.

Considering the Cost-Effectiveness of Particle TherapyOngoing concerns regarding particle therapy are cen-

tered around patient access and treatment cost. While the US has yet to construct a clinically operational heavy ion therapy center, the number of proton centers has expanded from six 10 years ago to thirty-one as of February 2019 (https://www.ptcog.ch/index.php/facilities-in-operation). However, insurance approval for proton radiotherapy re-mains challenging and could pose significant hurdles to the timely delivery of this treatment.48 Other logistical hurdles to particle radiotherapy, such as upfront treat-ment cost, could also pose formidable barriers. Statistical modeling of the expected lifetime costs associated with proton therapy for pediatric medulloblastoma offers opti-mism, with some studies suggesting an eightfold reduction in costs given the reduced incidence of treatment-related adverse events.61 However, upfront costs for proton ra-diotherapy remain high. Furthermore, cost-effectiveness studies of proton therapy in CNS malignancies have been largely limited to pediatric medulloblastoma with no cost-effectiveness studies published on the treatment of grade II and III meningiomas specifically.

Limitations and Future Directions for StudyOur systematic review on particle radiation therapy for

grade II and grade III meningiomas included eleven stud-ies with various cohort sizes, five of which were specific for high-grade meningiomas. Selection bias and confounding factors related to patient inclusion and treatment selection are inherent to retrospective studies, particularly those on uncommon diseases or treatment modalities without stan-dardization of care. Furthermore, our systematic review is limited to the type of analyses each study included, mak-ing it potentially difficult to make generalizable conclu-sions regarding local control and overall survival without future prospective and randomized studies. The strengths of our review include its focus on describing particle radia-tion therapy as an alternative treatment option for high-risk meningiomas, which are more difficult to manage than their benign counterpart.

ConclusionsIn summary, our systematic review about particle ra-

diotherapy for grade II and III meningiomas suggests that particle radiation, whether as proton or carbon ions in combination with photons or as stand-alone therapy, is an acceptable alternative to photon therapy in terms of sur-vival benefit and risk profile. High-grade meningiomas are difficult to manage, and the addition of proton or carbon radiation results in relatively high rates of local control


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and overall survival specifically in atypical and anaplastic meningioma cohorts. More data need to be collected to inform the optimal dosing strategy given the variability (operator dependent) in the median doses administered. Overall, particle radiotherapy carries benefit and is safe for patients with aggressive forms of meningioma. Given the current limits of few studies with small cohorts, additional studies, especially pending prospective trials, are certainly warranted to investigate the utility of particle radiotherapy as an additional treatment option for grade II and III me-ningiomas.

AcknowledgmentsWe gratefully acknowledge support for this study from Joe and

Rika Mansueto, Craig and Kim Darian, and Carol Bade (S.D.C.).

References 1. Adeberg S, Harrabi SB, Bougatf N, Bernhardt D, Rieber

J, Koerber SA, et al: Intensity-modulated proton therapy, volumetric-modulated arc therapy, and 3D conformal radiotherapy in anaplastic astrocytoma and glioblastoma: a dosimetric comparison. Strahlenther Onkol 192:770–779, 2016

2. Adeberg S, Harrabi SB, Bougatf N, Verma V, Windisch P, Bernhardt D, et al: Dosimetric comparison of proton radiation therapy, volumetric modulated arc therapy, and three-dimensional conformal radiotherapy based on intracranial tumor location. Cancers (Basel) 10:10, 2018

3. Aghi MK, Carter BS, Cosgrove GR, Ojemann RG, Amin-Hanjani S, Martuza RL, et al: Long-term recurrence rates of atypical meningiomas after gross total resection with or without postoperative adjuvant radiation. Neurosurgery 64:56–60, 2009

4. Aizer AA, Arvold ND, Catalano P, Claus EB, Golby AJ, Johnson MD, et al: Adjuvant radiation therapy, local recurrence, and the need for salvage therapy in atypical meningioma. Neuro Oncol 16:1547–1553, 2014

5. Arvold ND, Niemierko A, Broussard GP, Adams J, Fullerton B, Loeffler JS, et al: Projected second tumor risk and dose to neurocognitive structures after proton versus photon radiotherapy for benign meningioma. Int J Radiat Oncol Biol Phys 83:e495–e500, 2012

6. Athar BS, Paganetti H: Comparison of second cancer risk due to out-of-field doses from 6-MV IMRT and proton therapy based on 6 pediatric patient treatment plans. Radiother Oncol 98:87–92, 2011

7. Atkins KM, Pashtan IM, Bussière MR, Kang KH, Niemierko A, Daly JE, et al: Proton stereotactic radiosurgery for brain metastases: a single-institution analysis of 370 patients. Int J Radiat Oncol Biol Phys 101:820–829, 2018

8. Attia A, Chan MD, Mott RT, Russell GB, Seif D, Daniel Bourland J, et al: Patterns of failure after treatment of atypical meningioma with gamma knife radiosurgery. J Neurooncol 108:179–185, 2012

9. Backer-Grøndahl T, Moen BH, Torp SH: The histopathological spectrum of human meningiomas. Int J Clin Exp Pathol 5:231–242, 2012

10. Boskos C, Feuvret L, Noel G, Habrand JL, Pommier P, Alapetite C, et al: Combined proton and photon conformal radiotherapy for intracranial atypical and malignant meningioma. Int J Radiat Oncol Biol Phys 75:399–406, 2009

11. Brown WR, Thore CR, Moody DM, Robbins ME, Wheeler KT: Vascular damage after fractionated whole-brain irradiation in rats. Radiat Res 164:662–668, 2005

12. Chan AW, Bernstein KD, Adams JA, Parambi RJ, Loeffler

JS: Dose escalation with proton radiation therapy for high-grade meningiomas. Technol Cancer Res Treat 11:607–614, 2012

13. Chen WC, Magill ST, Wu A, Vasudevan HN, Morin O, Aghi MK, et al: Histopathological features predictive of local control of atypical meningioma after surgery and adjuvant radiotherapy. J Neurosurg 130:443–450, 2018

14. Cho M, Joo JD, Kim IA, Han JH, Oh CW, Kim CY: The role of adjuvant treatment in patients with high-grade meningioma. J Korean Neurosurg Soc 60:527–533, 2017

15. Coke CC, Corn BW, Werner-Wasik M, Xie Y, Curran WJ Jr: 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 D, Jäkel O, et al: Treatment of patients with atypical meningiomas Simpson grade 4 and 5 with a carbon ion boost in combination with postoperative photon radiotherapy: the MARCIE trial. BMC Cancer 10:615, 2010

17. Combs SE, Hartmann C, Nikoghosyan A, Jäkel O, Karger CP, Haberer T, et al: Carbon ion radiation therapy for high-risk meningiomas. Radiother Oncol 95:54–59, 2010

18. Combs SE, Kessel K, Habermehl D, Haberer T, Jäkel O, Debus J: Proton and carbon ion radiotherapy for primary brain tumors and tumors of the skull base. Acta Oncol 52:1504–1509, 2013

19. Combs SE, Welzel T, Habermehl D, Rieken S, Dittmar JO, Kessel K, et al: Prospective evaluation of early treatment outcome in patients with meningiomas treated with particle therapy based on target volume definition with MRI and 68Ga-DOTATOC-PET. Acta Oncol 52:514–520, 2013

20. Ding X, Zhou J, Li X, Blas K, Liu G, Wang Y, et al: Improving dosimetric outcome for hippocampus and cochlea sparing whole brain radiotherapy using spot-scanning proton arc therapy. Acta Oncol 58:483–490, 2019

21. El-Khatib M, El Majdoub F, Hoevels M, Kocher M, Müller RP, Steiger HJ, et al: Stereotactic LINAC radiosurgery for incompletely resected or recurrent atypical and anaplastic meningiomas. Acta Neurochir (Wien) 153:1761–1767, 2011

22. El Shafie RA, Czech M, Kessel KA, Habermehl D, Weber D, Rieken S, et al: Clinical outcome after particle therapy for meningiomas of the skull base: toxicity and local control in patients treated with active rasterscanning. Radiat Oncol 13:54, 2018

23. El Shafie RA, Czech M, Kessel KA, Habermehl D, Weber D, Rieken S, et al: Evaluation of particle radiotherapy for the re-irradiation of recurrent intracranial meningioma. Radiat Oncol 13:86, 2018

24. Fang P, Jiang W, Allen P, Glitza I, Guha N, Hwu P, et al: Radiation necrosis with stereotactic radiosurgery combined with CTLA-4 blockade and PD-1 inhibition for treatment of intracranial disease in metastatic melanoma. J Neurooncol 133:595–602, 2017

25. Fetcko K, Lukas RV, Watson GA, Zhang L, Dey M: Survival and complications of stereotactic radiosurgery: A systematic review of stereotactic radiosurgery for newly diagnosed and recurrent high-grade gliomas. Medicine (Baltimore) 96:e8293, 2017

26. Frytak S, Shaw JN, O’Neill BP, Lee RE, Eagan RT, Shaw EG, et al: Leukoencephalopathy in small cell lung cancer patients receiving prophylactic cranial irradiation. Am J Clin Oncol 12:27–33, 1989

27. Fuller GN: The WHO Classification of Tumours of the Central Nervous System, 4th edition. Arch Pathol Lab Med 132:906, 2008

28. Gondi V, Hermann BP, Mehta MP, Tomé WA: Hippocampal dosimetry predicts neurocognitive function impairment after fractionated stereotactic radiotherapy for benign or low-grade adult brain tumors. Int J Radiat Oncol Biol Phys 85:348–354, 2013


Wu et al.


29. Greene-Schloesser D, Robbins ME, Peiffer AM, Shaw EG, Wheeler KT, Chan MD: Radiation-induced brain injury: a review. Front Oncol 2:73, 2012

30. Grosshans DR, Mohan R, Gondi V, Shih HA, Mahajan A, Brown PD: The role of image-guided intensity modulated proton therapy in glioma. Neuro Oncol 19 (Suppl 2):ii30–ii37, 2017

31. Grosshans DR, Zhu XR, Melancon A, Allen PK, Poenisch F, Palmer M, et al: Spot scanning proton therapy for malignancies of the base of skull: treatment planning, acute toxicities, and preliminary clinical outcomes. Int J Radiat Oncol Biol Phys 90:540–546, 2014

32. Hug EB, Devries A, Thornton AF, Munzenride JE, Pardo FS, Hedley-Whyte ET, et al: Management of atypical and malignant meningiomas: role of high-dose, 3D-conformal radiation therapy. J Neurooncol 48:151–160, 2000

33. Indelicato DJ, Flampouri S, Rotondo RL, Bradley JA, Morris CG, Aldana PR, et al: Incidence and dosimetric parameters of pediatric brainstem toxicity following proton therapy. Acta Oncol 53:1298–1304, 2014

34. Jang CK, Jung HH, Chang JH, Chang JW, Park YG, Chang WS: Long-term results of Gamma Knife radiosurgery for intracranial meningioma. Brain Tumor Res Treat 3:103–107, 2015

35. Kaschten B, Flandroy P, Reznik M, Hainaut H, Stevenaert A: Radiation-induced gliosarcoma. Case report and review of the literature. J Neurosurg 83:154–162, 1995

36. Klinger DR, Flores BC, Lewis JJ, Hatanpaa K, Choe K, Mickey B, et al: Atypical meningiomas: recurrence, reoperation, and radiotherapy. World Neurosurg 84:839–845, 2015

37. Kondziolka D, Madhok R, Lunsford LD, Mathieu D, Martin JJ, Niranjan A, et al: Stereotactic radiosurgery for convexity meningiomas. J Neurosurg 111:458–463, 2009

38. Lesueur P, Calugaru V, Nauraye C, Stefan D, Cao K, Emery E, et al: Proton therapy for treatment of intracranial benign tumors in adults: A systematic review. Cancer Treat Rev 72:56–64, 2019

39. Liu W, Mohan R, Park P, Liu Z, Li H, Li X, et al: Dosimetric benefits of robust treatment planning for intensity modulated proton therapy for base-of-skull cancers. Pract Radiat Oncol 4:384–391, 2014

40. Liwnicz BH, Berger TS, Liwnicz RG, Aron BS: Radiation-associated gliomas: a report of four cases and analysis of postradiation tumors of the central nervous system. Neurosurgery 17:436–445, 1985

41. Lomax AJ, Bortfeld T, Goitein G, Debus J, Dykstra C, Tercier PA, et al: A treatment planning inter-comparison of proton and intensity modulated photon radiotherapy. Radiother Oncol 51:257–271, 1999

42. McDonald MW, Plankenhorn DA, McMullen KP, Henderson MA, Dropcho EJ, Shah MV, et al: Proton therapy for atypical meningiomas. J Neurooncol 123:123–128, 2015

43. Meadows AT, Friedman DL, Neglia JP, Mertens AC, Donaldson SS, Stovall M, et al: Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study cohort. J Clin Oncol 27:2356–2362, 2009

44. Murray FR, Snider JW, Bolsi A, Lomax AJ, Walser M, Kliebsch U, et al: Long-term clinical outcomes of pencil beam scanning proton therapy for benign and non-benign intracranial meningiomas. Int J Radiat Oncol Biol Phys 99:1190–1198, 2017

45. Nabors LB, Portnow J, Ammirati M, Baehring J, Brem H, Butowski N, et al: NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017. J Natl Compr Canc Netw 15:1331–1345, 2017

46. Newhauser WD, Zhang R: The physics of proton therapy. Phys Med Biol 60:R155–R209, 2015

47. Ng J, Shuryak I: Minimizing second cancer risk following radiotherapy: current perspectives. Cancer Manag Res 7:1–11, 2014

48. Ning MS, Gomez DR, Shah AK, Kim CR, Palmer MB, Thaker NG, et al: The insurance approval process for proton radiation therapy: a significant barrier to patient care. Int J Radiat Oncol Biol Phys [in press], 2018

49. Ojemann SG, Sneed PK, Larson DA, Gutin PH, Berger MS, Verhey L, et al: Radiosurgery for malignant meningioma: results in 22 patients. J Neurosurg 93 (Suppl 3):62–67, 2000

50. Omura M, Aida N, Sekido K, Kakehi M, Matsubara S: Large intracranial vessel occlusive vasculopathy after radiation therapy in children: clinical features and usefulness of magnetic resonance imaging. Int J Radiat Oncol Biol Phys 38:241–249, 1997

51. Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM: Meningioma grading: an analysis of histologic parameters. Am J Surg Pathol 21:1455–1465, 1997

52. Reinhold HS, Calvo W, Hopewell JW, van der Berg AP: Development of blood vessel-related radiation damage in the fimbria of the central nervous system. Int J Radiat Oncol Biol Phys 18:37–42, 1990

53. Rosenberg LA, Prayson RA, Lee J, Reddy C, Chao ST, Barnett GH, et al: Long-term experience with World Health Organization grade III (malignant) meningiomas at a single institution. Int J Radiat Oncol Biol Phys 74:427–432, 2009

54. Rydzewski NR, Lesniak MS, Chandler JP, Kalapurakal JA, Pollom E, Tate MC, et al: Gross total resection and adjuvant radiotherapy most significant predictors of improved survival in patients with atypical meningioma. Cancer 124:734–742, 2018

55. Sahm F, Reuss DE, Giannini C: WHO 2016 classification: changes and advancements in the diagnosis of miscellaneous primary CNS tumours. Neuropathol Appl Neurobiol 44:163–171, 2018

56. Simmons NE, Laws ER Jr: Glioma occurrence after sellar irradiation: case report and review. Neurosurgery 42:172–178, 1998

57. Simon M, Boström J, Koch P, Schramm J: Interinstitutional variance of postoperative radiotherapy and follow up for meningiomas in Germany: impact of changes of the WHO classification. J Neurol Neurosurg Psychiatry 77:767–773, 2006

58. Song YP, Colaco RJ: Radiation Necrosis—a growing problem in a case of brain metastases following whole brain radiotherapy and stereotactic radiosurgery. Cureus 10:e2037, 2018

59. Sundgren PC, Cao Y: Brain irradiation: effects on normal brain parenchyma and radiation injury. Neuroimaging Clin N Am 19:657–668, 2009

60. Thurin E, Nyström PW, Smits A, Werlenius K, Bäck A, Liljegren A, et al: Proton therapy for low-grade gliomas in adults: A systematic review. Clin Neurol Neurosurg 174:233–238, 2018

61. Verma V, Mishra MV, Mehta MP: A systematic review of the cost and cost-effectiveness studies of proton radiotherapy. Cancer 122:1483–1501, 2016

62. Wang N, Osswald M: Meningiomas: overview and new directions in therapy. Semin Neurol 38:112–120, 2018

63. Wang WH, Lee CC, Yang HC, Liu KD, Wu HM, Shiau CY, et al: Gamma Knife radiosurgery for atypical and anaplastic meningiomas. World Neurosurg 87:557–564, 2016

64. Weber DC, Schneider R, Goitein G, Koch T, Ares C, Geismar JH, et al: Spot scanning-based proton therapy for intracranial meningioma: long-term results from the Paul Scherrer Institute. Int J Radiat Oncol Biol Phys 83:865–871, 2012

65. Wiemels J, Wrensch M, Claus EB: Epidemiology and etiology of meningioma. J Neurooncol 99:307–314, 2010

66. Zhang GJ, Zhang GB, Zhang YS, Li H, Li CB, Zhang LW,


Wu et al.


et al: World Health Organization grade III (nonanaplastic) meningioma: experience in a series of 23 cases. World Neurosurg 112:e754–e762, 2018

67. Zhang M, Ho AL, D’Astous M, Pendharkar AV, Choi CY, Thompson PA, et al: CyberKnife stereotactic radiosurgery for atypical and malignant meningiomas. World Neurosurg 91:574–581, 581.e1, 2016

DisclosuresThe authors report no conflict of interest concerning the materi-als or methods used in this study or the findings specified in this paper.

Author ContributionsConception and design: Wu, Jin, Meola, Chang. Acquisition of data: Wu, Jin, Wong. Analysis and interpretation of data: Wu, Jin. Drafting the article: Wu, Jin. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Wu. Study supervision: Chang.

CorrespondenceAdela Wu: Stanford University School of Medicine, Stanford, CA. [email protected].


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Efficacy and toxicity of particle radiotherapy in WHO