NcXHF

MENINGIOMA MANAGEMENT
generally ranges between 50 and 56 Gy and is delivered in
fractions of 1.8 to 2.0 Gy. After a median follow-up of 43
months (range, 2 to 144 months), Soldà etal 122 reported similar
local control rates for fractionated radiotherapy as reported
for radiosurgery; 5- and 10- year local control rates
were 93% and 86%, respectively. For higher-grade meningiomas,
there is greater concern for brain invasion and, therefore,
the target volume includes an additional margin for
microscopic spread, typically 1 to 2 cm. Because of the more
aggressive biology, higher doses of radiation are generally
used for higher-grade meningiomas, ranging between 60
66 Gy. 108,112,123
Proton Therapy
Proton therapy provides the potential benefıt of a more conformal
dose distribution that can cover the tumor with a
higher dose of radiation while minimizing entry, exit, and
overall integral radiation dose. At the present time, the ability
to generate a highly conformal proton radiotherapy plan is
user and center dependent. Using standard fraction sizes of
1.8 Gy and total doses of 50.4 to 66.6 Gy for grade 1 meningiomas
and doses of 54.0 to 72.0 Gy for grade 2 meningiomas,
the results from Loma Linda show a 5-year actuarial control
rate of 96%, with better control for grade 1 meningiomas
(99% at 5 years) compared with grade 2 meningiomas (50%
at 5 years). No associations with local control and total dose
were seen in this retrospective review, but increased optic
neuropathy was seen with higher doses delivered to tumors
in close proximity to the optic apparatus. 124 Gudjonsson et
al 125 reported their outcomes of stereotactic hypofractionated
proton radiotherapy using doses between 14 Gy in three
fractions to 24 Gy in four fractions. They reported no signs of
tumor progression after 36 months of follow-up of 19 patients
with partially resected grade 1 (15 patients) or unresectable
(4 patients) meningiomas. However, two patients
developed clinical signs and radiologic evidence of a radiation
reaction with this hypofractionated approach. 125
SYSTEMIC THERAPIES
Systemic therapies are usually considered in patients who experience
progression after exhaustion of all local treatment
options (surgical resection, radiotherapy) and in the rare
cases of metastatic meningiomas. Unfortunately, the lack of
adequately designed and powered clinical trials on systemic
therapeutics in meningiomas prohibits treatment planning
on a high level of evidence. On the basis of documented
low response rates and progression-free survival times, a
number of drugs, including hydroxyurea, interferon alfa,
octreotide analogs (sandostatin, pasireotide), mifepristone,
megestrol acetate, imatinib, erlotinib, and gefıtinib
are not considered benefıcial agents. 126 However, some
agents have shown promising signs of effıcacy in preclinical
investigations and small clinical studies that may
translate into clinically relevant activity if confırmed in
larger, prospective clinical trials.
Evidence from several studies indicates that antiangiogenic
agents may have some therapeutic value in meningiomas.
Indeed, pathologic neoangiogenesis and upregulation of angiogenic
pathways, such as the vascular endothelial growth factor
axis, repeatedly have been shown in meningiomas, thus providing
a pathobiologic rationale for such agents. 86,127,128 Some case
reports and small retrospective patient series have shown relatively
high 6-month progression-free survival rates for recurrent/progressive
meningiomas treated with the VEGF-Abinding
monoclonal antibody bevacizumab. 129-134 Further data
on the effıcacy of bevacizumab is awaited from ongoing
single-arm phase II trials enrolling patients with recurrent, progressive
WHO grade 1, 2, and 3 meningiomas (NCT01125046,
NCT00972335). So far, no unexpected toxicities of bevacizumab
were seen in this patient population. Of note, bevacizumab has a
marked antiedematous effect that may lead to clinical improvements
and reduced corticosteroid need. 135
Vatalinib (PTK787/ZK22584), a tyrosine kinase inhibitor
of VEGFR1 to VEGFR3, was tested in a series of 24 patients
with meningiomas of all grades. Toxicities were manageable
and included fatigue (60%), hypertension (24%), and elevated
transaminases. Favorable 6-month progression-free
survival rates of 64.3% and 37.5% were seen in grade 2 and 3
tumors, respectively. 136
A recent publication reported the results of a prospective,
multicenter, phase II trial that enrolled patients with surgery
and radiation-refractory recurrent grade 2 to 3 meningioma
in a primary cohort and patients with WHO grade 1 meningioma,
hemangiopericytoma, or hemangioblastoma in an exploratory
cohort. 126 Patients were treated with the tyrosine
kinase inhibitor sunitinib, which targets VEGF, plateletderived
growth factor (PDGF), c-KIT, FLT, macrophage
colony-stimulating factor (CSF-1R), and RET. Thirty-six patients
were enrolled in the primary cohort and 13 patients in
the exploratory cohort. In the primary cohort, the 6-month
progression-free survival rate was 42%, which met the primary
endpoint. Toxicity, however, was substantial with one
grade 5 intratumoral hemorrhage, two grade 3 and one grade
4 CNS/intratumoral hemorrhages, one grade 3 and one grade
4 thrombotic microangiopathy, and one grade 3 gastrointestinal
perforation. Interestingly, tumoral VEGFR2 expression correlated
with favorable outcome, thus introducing a potential biomarker
for response to sunitinib therapy.
Several upcoming clinical trials have been designed according
to preclinical data and may introduce novel medical
options for the therapy of meningiomas. The EORTC-1320
trial will evaluate in a randomized fashion the effect of trabectedin
on progression-free survival versus local standardof-care
therapy. Trabectedin is a tetrahydroisoquinoline
originally isolated from the sea squirt Ecteinascidia turbinate
and is approved for the treatment of advanced sarcoma and
recurrent ovarian cancer. Trabectedin binds to the minor
groove of the DNA, induces apoptosis in tumor cells as well
as depletion of tumor-associated macrophages, and has antiangiogenic
properties. 137,138 Another multicentric clinical
trial will prospectively evaluate the effıcacy of SMO and
AKT1 inhibitors in mutation-bearing meningiomas.
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