Neuro Oncol 2014
Neuro Oncol 2014
Neuro Oncol 2014
Atypical meningiomas (AMs) and malignant meningiomas (MMs) are tumors with a lower incidence and poorer prognosis than benign
meningiomas. The role of radiotherapy as an adjuvant to surgical resection, especially for AMs, is incompletely defined. In this study,
the English-language literature was systematically reviewed for studies that reported tumor characteristics, treatment parameters,
and clinical outcomes after adjuvant radiotherapy for AM and MM, including overall survival, progression-free survival, and/or time
to recurrence or mortality. Clinical outcomes were further assessed in the context of resection status, timing of administration, and
radiation dose. Outcomes after stereotactic radiosurgery were also examined. Treatment toxicity and other potential prognostic or
confounding factors were appraised. Ten and 11 studies for AM and MM, respectively, met the inclusion criteria. The median 5-year
progression-free survival and overall survival after adjuvant radiotherapy were 54.2% and 67.5%, respectively, for AM and 48% and
55.6% for MM. The complication rates were 11.1% for AM and 5.1% for MM. Incomplete resection and radiation dose ,50 Gy conferred
significantly poorer 5-year progression-free survival. Most studies were unable to demonstrate a statistically significant prognostic
benefit for adjuvant radiotherapy in AM. In conclusion, adjuvant radiotherapy significantly improved local control of AMs and MMs,
especially after subtotal resection. Study limitations, including inadequate statistical power, may underlie the studies inability to demonstrate a statistically significant benefit for adjuvant radiotherapy in AM. Because these tumors preferentially recur within 5 years of
surgical resection, future studies should define whether early adjuvant therapy should become part of the standard treatment paradigm for completely excised tumors.
Keywords: atypical meningioma, high-grade meningioma, malignant meningioma, radiotherapy, radiation therapy.
Meningiomas are the most commonly reported primary intracranial neoplasms in adults, comprising over one-third of all central
nervous system tumors.1 Meningiomas have an incidence of 6
in 100 000 but are often incidentally discovered during autopsy or
on neuroimaging.2 Their incidence increases with age and peaks
after the fifth decade of life. They are histologically characterized
as benign, atypical, or malignant (also known as anaplastic) by
the 3-tiered World Health Organization (WHO) classification
scheme. Meningiomas are thought to originate from the arachnoidal cap cells3 that form the outer layer of arachnoid
mater and the arachnoid villi, of which the latter facilitate cerebrospinal fluid drainage into the dural sinuses and veins. While
most are slow-growing, benign meningiomas (BMs), atypical
meningiomas (AMs) and the rare malignant meningiomas
(MMs) are considerably more aggressive.3 While their precise
incidence is difficult to ascertain,4 AMs and MMs have a higher recurrence rate and poorer overall prognosis than BMs.3 Although
as few as 2% of primary BMs undergo malignant transformation,
28.5% of all recurrences of BMs are found to be atypical or
malignant.2
The WHO scheme has been dramatically reworked in recent
years, including a major revision in 2000. The latest update in
2007 resulted in the redistribution of many meningiomas into different classes.4 Some previously benign meningiomas have been
reclassified as AMs, while the incidence of MMs has fallen due
to stricter criteria for this subtype.5 According to previous classification schemes, 90% of meningiomas were classified as benign, 5% 7% as atypical, and 3% 5% as malignant.6 The new
WHO 2000 and 2007 criteria have been gradually but not reliably
adopted into clinical practice, and the use of inconsistent
628
Corresponding Author: Andrew T. Parsa, MD, PhD, Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, 676
N. St. Clair Street, Suite 2210, Chicago, IL 60611-2911 ([email protected]).
Review
Neuro-Oncology
629
definitions of malignant pathology has complicated interpretation of published data.7 However, when these criteria have
been applied, 20%35% of meningiomas have been classified
as grade II.8 12 The recent adoption of modern WHO grading criteria and the rarity of the malignant subtype have limited the
amount of available data on the clinical behavior, outcomes, and
optimal management of meningiomas.13
A particularly controversial management issue is the optimal
role and timing of radiotherapy (RT) for AMs treated with gross
total resection (GTR). Though meningiomas were historically considered radioresistant,14 RT has since been shown to improve
local control of AM and MM.7 The treatment approach to AM
has largely been extrapolated from data on BM and MM, leading
to nonuniform practice across institutions. While adjuvant RT is
standardly used at many institutions after subtotal resection
(STR) of AM, its role after GTR is controversial.15 17
In this article, the literature was systematically reviewed to determine the prognostic impact of adjuvant RT on the whole and in
the context of resection status (GTR vs STR), timing of administration (initial diagnosis vs recurrence), and radiation dose, as these
are incompletely defined for AM and MM.5 Outcomes after stereotactic radiosurgery (SRS) were also examined. The treatment toxicity of adjuvant RT was further appraised. Lastly, an attempt was
made to identify other potential prognostic or confounding factors in this patient population.
Review
Results
Study Characteristics
630
Fourteen total studies dating from 1994 to 2011 met the eligibility
criteria for this systematic review.5,7,13,15,16,23 31 Their study populations carried diagnoses of AM, MM, or an aggregate of these. Ten
AM studies were included with initial diagnoses occurring between
1966 and 2005.7,13,15,16,25 27,29 31 The mean or median follow-up
interval for these studies ranged from 28 to 63.6 months. Eleven
MM studies were included with initial diagnoses occurring between
1967 and 2009.5,7,13,23,24,26 31 The mean or median follow-up
interval for these studies ranged from 28 to 60 months. When it
was reported, the proportion of WHO grade II or III meningiomas
among all meningiomas was below 10% in all but 2 studies.24,27
The radiation dose was reported for all but 1 study and ranged between 40 and 65 Gy. Stereotactic radiosurgery was utilized in
5 studies.5,15,16,29,31 Progression was variably defined in 8 studies
as pathological23,27 or radiological5,16,23 27,29 31 evidence of
tumor growth or recurrence and/or clinical neurologic decline.23,24,27,29,30 Twelve studies5,7,13,15,16,23,25,27 30 performed
univariate or multivariate regression analyses in order to identify
potential prognostic or confounding factors.
Neuro-Oncology
Table 1. Summary of study characteristics, radiation dose, survival outcomes, and complications in selected studies of atypical meningioma
Study
Period
1966 1990
Milosevic
Total
Received
Malignancy
Proportion
AM, n
RT, n
Definition
Modality
18
WHO 1979
40 mo (7114)
Surgery + RT (n 17)
50 Gy (40 60)
n/a
51% at 5 y
3.39% related to
12.6% related to
18
et al27
Median
Treatment
Dose
Progression-free Survival
Overall
Complications
Survival
III)
RT
Pasquier
1971 2005
30
n/a
WHO 2000
n/a
4.1 y
Surgery + RT
54 Gy (40 66)
62% at 5 y
67.5% at 5 y
et al13
Hug et al7
1973 1995
15
15
WHO 1993
n/a
28 mo (7155)
Surgery + photon
62 Gy (50 68)
38% at 5 y
RT
89% at 5 y (90% for 6.67% related to
Mahmood
et al
1976 1990
22
WHO 1993
38 mo (3186)
26, a
RT (n 4) vs
.60 Gy vs 0%
(n 11)
Surgery (n 14), surgery + RT
50 62 Gy
48% at 5 y; 33% at 10 y
58.33% at 5 y;
(n 6)
22
WHO 1979
RT
n/a
41.67% at 10 y
54 Gy (35 59.4)
Surgery: 70% at 5 y;
(n 8)
1997 2002
10
10
WHO 2000
n/a
44 mo (684)
Surgery + SRS
18 Gy (12 20)
48.3% at 5 y
80.8% at 5 ya
16.7% related to
Yang et al29
1986 2004
40
23
WHO 2000
63.6 mo (0.6
154.5)
Surgery, surgery + RT
n/a
87.1% at 10 y
89% at 10 y
n/a
Aghi et al15
1993 2004
108
WHO 2000
n/a
39 mo (1168)
Kano et al
surgery + RT:
100% at 5 y
31
SRSa
(n 8)
Boskos
et al30
1999 2006
19
19
n/a
n/ab
48 mo(1 87)
Surgery + RT
12.5% related to
surgery: 44% at 5 y
65 CGE
(proton 34.1
RT
46.7% at 5 ya
53.2% at 5 ya
16.7% related to
RTa
Surgery: 40%;
surgery + RT: 60%
n/a
n/a
CGE;
photon 31 Gy)
Mair et al16
2001 2010
114
30
WHO 2000
n/a
n/a
51.8 Gy
Review
631
Downloaded from http://neuro-oncology.oxfordjournals.org/ by guest on December 3, 2014
Review
632
Table 2. Summary of study characteristics, radiation dose, survival outcomes, and complications in selected studies of malignant meningioma
Malignancy
Definition
Proportion of All
Meningiomas
Follow-up
Interval, mo
(range)
Treatment Modality
Dose
Progression-free
Survival
Overall Survival
Complications
42
WHO 1979
40 (7 114)
Surgery + RT (n 29)
50 Gy (40 60)
n/a
27% at 5 y
23
23
Unique grading
scale
68.6% (grade
II/III)
16.4% (grade
III)
40 (2 213)
Surgery + RT
5400 cGy
(4462 6926)
n/a
WHO 2000
n/a
49.2
54 Gy (40 66)
16
16
WHO 1993
n/a
28 (7 155)
Surgery + RT (all
recurrent)
Surgery + RT (n 11),
surgery + RT
+ proton RT (n 5)
3.38% related
to RT
3.6% related
to RT
Mahmood 1976
et al26, a
1990
1984
Dziuk
1992
et al23
22
WHO 1993
38 (3 186)
38
13
8.0% (grade
II/III)
n/a
Russell/
Rubinstein
classification
(1997)
WHO 2000
n/a
n/a
24
17
WHO 2000
13
13
Sughrue
et al28
63
29
Study
Period
Milosevic
et al27
Goldsmith
et al24
1966
1990
1967
1990
42
Pasquier
et al13
Hug et al7
1971
2005
1973
1995
1986
2009
Total
MM, n
Received
RT,n
3 144
18 Gy (12 20)
48.3% at 5 ya
80.8% at 5 ya
n/ab
48 mo (1 72) Surgery + RT
53.2% at 5 y a
WHO 2007
7.2% (grade
II/III)
n/a
63.6 (0.6
154.5)
n/a
46.7% at 5 ya
65 CGE
(proton 34.1
CGE;
photon 31 Gy)
13 Gy (10 21)
29% at 5 y
WHO 2000
5 y (1 22)
Surgery, surgery + RT
35% at 5 y
12.6% related
to RT
12.5% related
to RT
n/a
n/a
16.7% related
to SRSa
16.7% related
to RTa
n/a
23% related to
surgery; 7%
related to
RT or SRS
19% related to
surgery; none
reported for RT
Review
Neuro-Oncology
Radiation Dose
Seven of 8 studies found that higher radiation doses were associated with improved clinical outcomes. Dziuk et al23 reported
that for both AM and MM, a dose of 50 Gy was independently
associated with a higher 5-year cause-specific OS of 42%, compared with 0% using lower doses. These authors also linked radiation doses ,54 Gy to poorer long-term outcomes in their STR
group. Goldsmith et al24 reported a 5-year PFS of 63% in MM
patients receiving at least 53 Gy versus 17% with lower doses. Milosevic et al27 similarly found a dose of 50 Gy to be strongly
associated with improved cause-specific OS in their group of AM
and MM patients. Hug et al7 reported significantly better 5-year
and 8-year PFS and OS for both AM and MM using target doses
60 Gy. Analyzed separately, the actuarial 5- and 8-year local
control rates for AM were significantly higher using doses
60 Gy (90% and 45%, respectively) versus ,60 Gy (0% and
0%). Actuarial 5- and 8-year local control rates for MM were
also significantly higher using doses 60 Gy (100% and 33%, respectively) versus ,60 Gy (0% and 0%). Akin to the findings of
Hug et al, Boskos et al30 reported that doses .60 Gy with combined proton-photon RT significantly improved PFS (P , .05) and
OS (P , .05) in their cohort of AM and MM patients, according to
univariate analysis. Multivariate analysis confirmed this positive
association between doses .60 Gy and improved OS (RR 8.3;
P .029). There was also a trend toward increased OS with
doses .65 Gy according to univariate analysis. Using SRS, Kano
et al31 observed that a marginal dose .20 Gy (n 13) was a significant positive prognostic factor in the univariate analysis (P
.0139), as the 5-year PFS was 63.1% compared with 29.4% for
those receiving ,20 Gy (n 12). In contrast, Pasquier et al,13
who used a median dose of 54.6 Gy to treat AM and MM patients,
found external beam (EB)RT not to be a significant prognostic factor for either OS (P .28) or PFS (P . .05), but they did not define
the doses that were compared.
633
Review
Treatment Toxicity
The incidence of treatment toxicity ranged from 3.4% to
16.7%7,13,15,16,25 27,29 31 for AM and 0% to 16.7% for
MM5,7,13,23,24,26 28,30,31 after adjuvant RT. Cerebral necrosis occurred in 0.1%,13 4.2%,30 12.5%,15 and 23.1% of patients.5 Blindness due to irradiation of the optic apparatus occurred in 5% of
patients receiving 50 Gy radiation and in 50% of patients receiving 65 Gy. Hypopituitarism was reported in up to 50% of patients
at 1 11 years, even after low-dose treatment. Hypogonadism
and cognitive disturbance were reported in 1.7% 5.9% of
patients.13,27 Seizures and alopecia were reported in 4.2% and
8.3% of patients, respectively.30
Discussion
The aim of this systematic review was to define the role of adjuvant RT in the management of AM and MM, which are clinically
aggressive forms of meningioma. Fourteen studies met our inclusion criteria and were analyzed to determine the impact of adjuvant RT upon clinical outcomes, including OS, PFS, and time to
recurrence or mortality. Outcomes in RT-treated patients were
further analyzed in the context of resection status (GTR vs STR),
634
time of administration (initial diagnosis or recurrence), and radiation dose. Outcomes after SRS were reviewed, although small
sample sizes precluded comparison with EBRT. Lastly, we
assessed RT-related treatment toxicity and potential prognostic
or confounding factors in this patient population.
This systematic review revealed that adjuvant RT generally
improves local control and OS in AM and MM, although available
data did not support this paradigm in the controversial subset of
totally excised AMs. It was apparent that AM treated with resection only, particularly when subtotal, was highly prone to recurrence. Studies reported disparate results with respect to the
clinical course of completely excised AMs. In the view of the
authors, the lack of statistical significance seen in these analyses
is a result of flaws in the included studies. While several studies
showed trends toward clinical benefit with adjuvant RT, the lack
of statistical significance is likely a result of small sample sizes,
limiting the statistical power to detect any differences between
groups. Furthermore, the nearly universal association between
increased radiation dose and improved prognosis in the included
studies makes it improbable that adjuvant RT has no prognostic
benefit relative to surgery alone.
The included studies were fraught with other limitations. This
point was clearly illustrated by the lack of a statistically significant
correlation between adjuvant RT and improved local control in the
study by Aghi et al,15 despite a local control rate of 100% in 8 totally excised, irradiated AMs. A number of studies treated all
patients with adjuvant radiation, precluding any analysis of
whether adjuvant RT improved outcomes relative to nonirradiated patients. The timing of RT administration, at initial diagnosis versus recurrence, was not clearly reported in the study by
Goyal et al,25 which further complicates interpretation of their
results. Yang et al29 achieved extremely effective local control
with resection alone in their study, ostensibly making it more difficult to demonstrate a statistically significant risk reduction in the
recurrence rate in patients who also received adjuvant RT. Moreover, it must be noted that the retrospective studies in this review
cannot indicate improvements in clinical outcomes per se, but
only correlations.
This review confirmed that MMs are highly likely to recur regardless of resection status, though less so after GTR. Most studies demonstrated some benefit to adjuvant RT, particularly at
high doses. Another finding of this review was that adjuvant RT
is significantly more likely to succeed when administered at initial
diagnosis rather than at recurrence of AM, which led most study
authors to recommend this practice. This is consistent with the
overarching goal of preventing recurrence at all costs. There are
a myriad of reasons for this, including transformation to a higher
grade upon recurrence, as occurs in one quarter of AMs treated
with surgery alone32; the morbidity risk of reoperation; and the
elevated probability of second recurrence and/or mortality.
Adjuvant RT for AM and MM were found to cause modest treatment toxicity, most commonly in the form of cerebral necrosis
and optic neuropathy. It is imperative to use a radiation dose
that maximizes efficacy and minimizes toxicity. In this review, a
commonly recommended protocol for MM and AM was 60 Gy
with standard fractionation of 180 200 cGy per day in a single
session.7,15,23,30 Another study recommended 54 Gy for MM,24
while 3 studies found no improvement or only situational efficacy
using doses ranging from 51.8 to 54.6 Gy.13,16,25 Doses below
Review
Funding
This work was supported by grants from the Howard Hughes Medical Institute (G.K., E.T.S.), the Reza and Georgianna Khatib Endowed Chair in
Skull Base Tumor Surgery at UCSF (A.T.P.), and the Michael J. Marchese Professor and Chair at Northwestern University (A.T.P.).
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
Conclusion
10.
Pearson BE, Markert JM, Fisher WS, et al. Hitting a moving target:
evolution of a treatment paradigm for atypical meningiomas amid
changing diagnostic criteria. Neurosurg Focus. 2008;24(5):E3.
11.
Neuro-Oncology
635
50 Gy are considered inadequate for treating AM or MM.13 However, the roles of both dose escalation (.5560 Gy) and radiosurgery have yet to be explored in a controlled, prospective study.13
Radiation oncologists must exercise proper patient selection and
adherence to radiosensitivity thresholds for surrounding structures. Treatment planning should also incorporate patient age,
clinical condition, tumor characteristics, and extent of resection.
Relatedly, the studies in this review provided limited insight
into the efficacy of SRS relative to EBRT, as outcomes data were
provided for only a total of 23 patients who were given this treatment. While their outcomes were generally poor, except for the
cohort of Kano et al,31 their recurrence status and the palliative
intent of this therapy confound any interpretation of these
data. It is unclear whether SRS is an appropriate therapeutic modality for high-grade meningiomas, which are more infiltrative
than BMs, due to the use of small or no margins on the target volume.33 Instead, radiosurgery conventionally emphasizes targeting the enhancing disease rather than the clinical tumor
volume.33 The optimal target volume definition for AMs and
MMs has yet to be prospectively defined and is obfuscated by
the scarcity of high-quality evidence. Thus, of particular interest
is the prospective Radiation Therapy Oncology Group 0539 protocol, established in June 2009. This protocol utilizes very large
margins for AMs and MMs, that is, the gross tumor volume plus
1 to 2 cm.33
This systematic review is limited by the evidence upon which it
is based. Weaknesses of the included studies were their retrospective and noncomparative design with respect to treatment
groups, low statistical power due to the paucity of AM and MM
cases, aggregation of AM and MM into a single histologic category
for analysis in some cases, the use of conventional megavoltage
RT protocols with conservative dose regimens, and the obsolescence of older studies by modern advances in radiotherapeutic
modalities and techniques. Importantly, many of the outcome
differences reviewed here may be due to the use of heterogeneous grading systems at institutions and over time, as well as
nonuniform use of the WHO guidelines. Indeed, few of the
included studies actually used the 2000 or 2007 WHO grading criteria that form the basis for modern meningioma classification.
This point is illustrated by the percentage of all meningiomas
that were classified as atypical in the included studies, which
was generally below the 20% or 25% that would be expected
under current histopathologic guidelines.
Prospective multicenter trials should be undertaken to provide
the statistical power necessary to clarify unanswered questions:
the role of adjuvant RT in totally excised AMs and the upper limit
of radiation dosing at the intersection of maximal efficacy and acceptable toxicity. Because these tumors preferentially recur within
the first 5 years after surgical resection, future studies should define whether early adjuvant therapy should become part of the
standard treatment paradigm for completely excised tumors.
Review
23.
13.
24.
17.
18.
19.
Ho DM, Hsu CY, Ting LT, et al. Histopathology and MIB-1 labeling
index predicted recurrence of meningiomas: a proposal of
diagnostic criteria for patients with atypical meningioma. Cancer.
2002;94(5):15381547.
26.
27. Milosevic MF, Frost PJ, Laperriere NJ, et al. Radiotherapy for atypical
or malignant intracranial meningioma. Int J Radiat Oncol Biol Phys.
1996;34(4):817 822.
28.
29.
Yang SY, Park CK, Park SH, et al. Atypical and anaplastic
meningiomas: prognostic implications of clinicopathological
features. J Neurol Neurosurg Psychiatry. 2008;79(5):574 580.
30.
31.
21.
32.
22.
33.
636
16.
25. Goyal LK, Suh JH, Mohan DS, et al. Local control and overall survival in
atypical meningioma: a retrospective study. Int J Radiat Oncol Biol
Phys. 2000;46(1):57 61.