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Stereotactic Radiosurgery for Atypical and Malignant Meningiomas
Randa Zakhary, A.B*
Daniel J. Brat, M.D., Ph.D.†
Jeffery Williams, M.D.y, ¶,§
*The Johns Hopkins University School of Medicine,
Departments of†Pathology, and yNeurosurgery
¶Division of Radiation Oncology, Department of Oncology
811 Harvey Building, 600 North Wolfe Street.
The Johns Hopkins Hospital,
Baltimore, Maryland, 21205
Phone: (410) 614-2886
Fax: (410) 614-2982
§To whom correspondence should be addressed.
Running title: Atypical and Malignant Meningiomas
Atypical and malignant meningiomas are aggressive tumors that frequently recur after surgical resection. Stereotactic radiosurgery and stereotactic radiotherapy offer precise irradiation of many tumors. The role of stereotactic radiosurgery and stereotactic radiotherapy in the management of atypical and malignant meningiomas remains undefined.
Patients & Methods:
To evaluate the response to radiosurgery we reviewed our 7 year experience with the treatments for 10 patients (7 women, 3 men) having histologically confirmed atypical (5) or malignant (5) meningiomas. Patients were followed for a median of 47.5 months (range: 10-84 months). The mean age of patients with atypical vs. malignant meningiomas was 61 vs. 59 years. Two patients had antecedent total surgical resections. For these two patients, one had postoperative conventional external beam radiotherapy while the other did not. For the remaining 8 patients having prior subtotal resections, 4 had postoperative conventional external beam radiotherapy. For all patients receiving postoperative irradiation the mean dose was 52 Gy. Tumor diameters before radiosurgery or stereotactic radiotherapy ranged from 0.84 cm to 7.0 cm. For radiosurgery, the doses ranged from 9 Gy administered in five fractions (Biologically Effective Dose = 14 Gy) to 54 Gy administered in 30 fractions (Biologically Effective Dose = 86.4 Gy).
Nine patients remained neurologically stable following radiosurgery with radiographic evidence of tumor control. One of these nine patients developed new focal hyperintensity in the surrounding brain on T2-weighted MRI consistent with possible radiation effect. One patient with atypical meningioma and pre-existing neurological deficits had increasing neurologic deficit three years after radiosurgery with tumor recurrence confirmed radiographically.
This initial experience shows high proportions of tumor control over a protracted follow-up period. These results compare favorably to those reported for combined traditional surgical resection and conventional radiotherapy. These results suggest that stereotactic radiosurgery and stereotactic radiotherapy hold promise for the treatment of atypical and malignant meningiomas.
Stereotactic radiosurgery, stereotactic radiotherapy, meningioma, atypical meningioma, malignant meningioma, brain tumor.
Unlike benign meningiomas, the atypical and malignant meningiomas are aggressive tumors for which standard management remains undefined. Benign meningiomas, also known as typical meningiomas, are common, comprising 15-20% of all intracranial tumors (1, 2). Among meningiomas, the atypical and malignant meningiomas variably comprise 1-14% of clinical series (3-6). Although complete surgical resection is the accepted initial goal, this therapy results in high rates of recurrence for the atypical and malignant meningiomas in particular. Recurrence rates for these higher grade meningiomas following complete or subtotal resection range from 38% to 100%(7-11) and are significantly higher than that for benign tumors.
Furthermore, many factors often preclude total resection for both benign and malignant meningiomas. When significant vascular or neural structures are encased or infiltrated, total resection may be impossible without high risk (12). For cavernous sinus meningiomas in particular, the morbidity after aggressive microsurgical removal is very high (13). Therefore, subtotal resection is often preferred.
Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) are proven alternatives to surgical resection of small to moderately sized meningiomas. Multiple studies have confirmed the role of SRS (14-17) as either an adjuvant or alternative to surgical resection. Tumor control rates are excellent, ranging from 54%-100% (14-18). The meningiomas have several features that render them well suited for either stereotactic radiosurgery or stereotactic radiotherapy (SRS/T). They are often ellipsoid or spherical and are well defined by both CT and MRI, are encapsulated, and usually well-demarcated from adjacent brain. Thus, the conformal dose distribution of radiosurgery further optimizes their treatment. The role of SRS/T in the management of atypical or malignant meningiomas, however, remains unexplored. We therefore evaluated the clinical and radiographic response of histologically confirmed atypical and malignant meningiomas to SRS/T.
Patients and Methods
We reviewed the records of all patients with atypical or malignant meningiomas who received SRS/T at the Johns Hopkins Hospital between 1990 and 1996. Patient characteristics are listed in Table I. Ten patients (7 women, 3 men) had histologically confirmed atypical (5) or malignant (5) meningiomas. For histological diagnosis, standard criteria were utilized in the diagnosis (19) (Fig. 1). Atypical meningiomas were hypercellular, contained increased mitotic rates, and displayed foci of necrosis (Fig. 1B). In addition to these features, malignant meningiomas showed microscopic evidence of brain invasion (Fig. 1C).
The mean ages of patients with atypical vs. malignant meningiomas were similar: 61 vs. 59 years (p = NS). Radiographic analysis of location showed four meningiomas that primarily invaded the parasagittal sinus. Two tumors were frontal, and single tumors were occipital, sphenoidal, and cerebellar (Table II). One tumor occupied the cavernous sinus. Tumor diameters ranged from 0.84 cm - 7.0 cm (mean: 3.54 cm) (Table III). Two patients had prior total resection of their meningiomas (Table IV). One of the two had postoperative conventional external beam radiotherapy. The remaining 8 patients had only subtotal resections. Four of these 8 had postoperative conventional radiotherapy. The mean dose of conventional radiotherapy was 52 Gy (Table V). No patients were lost to follow-up.
After placement of the Brown-Roberts-Wells frame, a contrast-enhanced CT scan of the brain was obtained. The CT images containing the Brown-Roberts-Wells fiducials were analyzed using a computer program. The borders of the enhancing tumor were defined, and both the optimal position of the isocenter(s) and the diameters of the collimators were selected. Median collimator diameter was 28 mm (range: 16 to 34 mm). Multiple, non-coplanar arcs were sequentially selected and tested for the best coverage of the target. Both differential weighting and modification of the size of arcs helped to provide conformational shaping of the dose to enclose the target and to exclude surrounding normal structures. The analysis of the dose-volume histogram allowed critical evaluation of the treatment plan. Most plans enclosed the target within the 80th percentile isodose line. Treatment was delivered using a modified 10 MeV linear accelerator.
Treatment was administered in 1 to 30 daily fractions. For analysis of the intensity of treatments, the biologically effective dose ((BED), (a/b=3))(20), was calculated to allow a comparison of potential radiation effects among the disparate treatment regimens. Doses ranged from 9 Gy administered in a five fractions (BED = 14 Gy) to 54 Gy administered in 30 fractions (BED = 86.4 Gy) (Table V). Considerations for the radiosurgical treatment dosages included prior conventional external beam radiotherapy treatments, the size of the tumor and the proximity to critical structures (usually the optic apparatus).
Patients were seen 1 month after radiosurgery and every 3-6 months thereafter (Table VI). Follow-up included both imaging studies and physician evaluation. The median clinical follow-up was 47.5 months (range: 10-84 months). Nine patients remained neurologically stable following radiosurgery and showed no clinical evidence of tumor recurrence. One patient with atypical meningioma who had preoperative visual disturbances experienced decreased vision 36 months after radiosurgery. Concurrent imaging studies for this patient revealed recurrent meningioma, prompting a repeat subtotal resection.
All patients had follow-up MRI scans at 3-6 month intervals posttreatment (Table VI). Although clinical follow-up ranged from 10-84 months, radiographic follow-up ranged from 6-82 months. Nine patients had radiographic evidence of tumor control. One of the ten patients had radiographic tumor recurrence.
One patient developed new focal hyperintensity on T2-weighted MRI in the surrounding brain consistent with possible radiation effect (21). No other complications of SRS/T were observed.
Although resection, conventional external beam radiation, SRS, and SRT are effective in the treatment of benign meningiomas, the optimal management for atypical and malignant meningiomas remains controversial. Reasons for this controversy include the infrequency of such tumors and the absence of reports of consistent treatments. Furthermore, comparisons regarding tumor control rates that are based on observations following subtotal resections are less likely to be definitive than those based on total resections (7,11,22,23)
After gross total resection of benign meningiomas, the rates of recurrence are significant: 5% at five years, 10% at 10 years and 32% at 15 years (12). Another study reported a recurrence rate of 3% for benign meningiomas 5 years after complete removal (7). After subtotal resection, the cumulative rates of recurrence for benign meningioma are even higher at 37%, 55%, and 91% after 5, 10, and 15 years, respectively (7,24). In one series of completely resected benign meningiomas, tumors recurred within a median time of 7.5 years (7). Partially resected benign meningiomas recur more quickly: in one series median time to recurrence in patients receiving postoperative irradiation was 5.5 years (22).
Fewer series have been reported for atypical and malignant meningiomas than for benign meningiomas. For atypical and malignant meningiomas the recurrence rate 5 years after total resection was 50% in one series (8). Following subtotal resections of atypical and malignant meningiomas, the 5-year recurrence rates are even higher, ranging from 38% to 100% (7-11). Partially resected atypical and malignant meningiomas recurred within a median time of 2.4 years and 3.5 years respectively (7). Although meningiomas of any histologic classification are less likely to recur following gross resection compared to subtotal resection, resection is less likely to be succesful for atypical and malignant tumors because of extension along dural planes (25) and extension into adjacent cortex (2,26).
Malignant meningiomas result in significant morbidity and are frequently lethal (27,28). Multiple large series have reported the prevalence of atypical and malignant meningiomas to range from 1-14% (3-6), and studies show that these meningiomas are highly likely to recur following any combination of resection and radiation. The two most important factors that predict recurrence are mitotic rate and degree of resection (29). Atypical and malignant meningiomas grow at similar rates but much faster than benign meningiomas (26), presumably accounting for the difference in recurrence rates and shorter time to recurrence. The higher mitotic rate of cells associated with atypical and malignant meningiomas may render them extremely sensitive to fractionated SRS/T. The difficulty of achieving total resection without significant morbidity and the aggressive biologic behavior of atypical and malignant meningioma together underscores the necessity to find an effective alternative or adjunct therapy to microsurgery such as SRS /T.
Conventional external beam radiotherapy is a useful adjunct to microsurgical resection, though rates of recurrence remain high. A role for radiation therapy in the management of benign meningiomas has been confirmed in retrospective studies (22, 24). In a series of 140 patients with benign intracranial meningiomas having subtotal resection and postoperative irradiation, the rates of local control were comparable to total resection alone (23). In the same report, however, postoperative irradiation after subtotal resection of 23 malignant meningiomas resulted in significantly decreased survival compared to the benign group. In that study the overall 5 year survival was only 58% for the malignant meningioma group, and the 5-year progression-free survival was only 48%. In a different series, 4 of 5 malignant meningiomas recurred despite post-resection irradiation (7). The efficacy of radiation may be higher than reported since tumors selected for irradiation are more likely difficult to resect (7) and perhaps more likely to recur than nonirradiated tumors.
SRS/T successfully treats both benign and malignant tumors of numerous histologic types. For the treatment of meningioma, the role of SRS/T is difficult to assess in the absence of large, prospective studies. Long-term disease-free survival rates for benign meningioma can exceed 90% (14, 18). No studies, however, have presented the outcome of radiosurgery for the atypical and malignant meningiomas prior to this report.
For SRT, fractionation maximizes the therapeutic ratio by providing the highest effective dose in the target volume while sparing normal tissue. SRT may be desirable when patients harbor lesions that are proximal to critical structures (17). Moreover, fractionation of treatments for more rapidly dividing tumors may result in higher tumor control for any given level of risk to surrounding normal brain (30). Our results following a combination of total or subtotal resection, with or without external beam radiation, and SRS/T in 10 patients yielded recurrence in only 1 patient. which is far below the 38 - 100% range reported for atypical or malignant meningiomas (7-11) and is comparable to that expected for benign meningiomas.
These results suggest that SRS/T may provide improved local control with low toxicity for patients having a malignant or atypical meningioma. Larger, prospective studies may be necessary to clearly define the role of SRS/T for the treatment of these tumors.
Table I. Characteristics of patients
with atypical or malignant meningiomas
Mean age Male Female
Atypical 61 (41-72) 2 3
Malignant 59 (22-77) 1 4
Table II. Tumor location in patients
with atypical and malignant meningiomas
Location Atypical Malignant Total
Cavernous sinus 1 0 1
Parasaggital 2 2 4
Occipital 1 0 1
Sphenoid wing 0 1 1
Cerebellar 0 1 1
Frontal 1 1 2
Table III. Pretreatment tumor diameters
Diameter (cm) Atypical Malignant Total
< 1 1 1 2
1-5 3 3 6
5-10 1 1 2
Table IV. Prior treatment of atypical and malignant meningiomas
Total Resection Subtotal Resection
Irradiated Nonirradiated Irradiated Nonirradiated
Atypical 0 1 3 1
Malignant 1 0 1 3
Table V. Radiation Dosimetry
Histopathology Case Prior XRT1 SRT SRT
(Gy) Total dose/fractions (BED)2
Atypical 1 50 900 / 05 14
2 56 1500 / 01 90
3 0 1600 / 01 101
4 0 3000 / 06 80
5 36 1000 / 01 43
Malignant 6 54 1500 / 01 90
7 0 5400 / 30 86
8 64 1600 / 01 101
9 0 1699 / 01 113
10 0 4500 / 09 120
1XRT: Radiation therapy (dose prior to receiving SRT (Gy)). Treatments were given using standard fractionation (1.8 - 2.0 Gy).
2BED: Biologically Effective Dose (Gy), (a /ß = 3). Please see text for details.
Table VI. Outcome in patients with atypical or malignant meningiomas
Deficit 6 - 12 12 - 24 24 - 48 48 - 72
Improved 0 1 0 0 No change 3 0 0 5 New/worse 0 0 1 0
Tumor size 6 - 12 12 - 24 24 - 48 48 - 72
Decrease 1 0 0 0 No change 2 1 0 5 Increase 0 0 1 0
Figure 1. Histopathologic classification of meningiomas.
Typical or benign meningiomas are composed of fascicles and whorls of spindled meningothelial cells and lack high cellularity, high mitotic rates, and foci of necrosis (A). Atypical meningiomas (B) contain necrotic foci, high mitotic rates, and display hypercellularity. In addition to the features of atypical meningiomas, malignant meningiomas (C) have tumor projections that infiltrate brain parenchyma (arrows).
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