Introduction

Meningiomas arise from the dural covering of the brain. They account for 13–26% of all primary intracranial tumors and are the most common benign intracranial neoplasms. Histologically, 4–7% of meningiomas are atypical and 1–2% are anaplastic [1] and surgery has been the primary treatment modality regardless of subtype [2]. The extent of surgery plays an important role in predicting the risk of recurrence and may determine the need for adjuvant therapy [3–5]. In selected patients, stereotactic radiosurgery (SRS) is an effective treatment for benign meningiomas both as an adjunct to subtotal resection and as the primary therapy [6–10]. Benign meningiomas have an indolent natural history and an excellent cure rate with either surgery or radiotherapy [11]. On the other hand, atypical and anaplastic meningiomas tend to recur in the relatively short term even after radical surgical resection. The 5-year survival rate for these histologically aggressive tumors is reportedly 50–70% [11, 12]. We closely followed operated patients with high-grade meningiomas by MRI studies and performed SRS as salvage therapy in patients with tumor progression. Here we report the degree of tumor control, the risk of complications, and the variables that predict treatment outcomes in SRS-treated patients with high-grade meningiomas.

Methods and materials

Between October 1997 and November 2002, 12 patients with atypical or anaplastic meningioma underwent SRS at Kyoto University Hospital. Patients with hemangiopericytoma or neurofibromatosis-type 2 were excluded from this analysis. All included patients had histologically confirmed atypical or anaplastic meningioma diagnosed at the time of their initial craniotomy. There were 8 males and 4 females; their mean age was 58.5 years. All patients provided prior informed consent for inclusion in this study and the investigation was approved the by Ethics Committee of Kyoto University.

According to the 2000 WHO classification, the diagnosis of atypical meningioma is based on a combination of histological features, i.e. increased mitotic activity (4 or more mitoses per 10 high-power fields), hypercellularity, eosinophilic macronucleoli, sheetlike growth, and small cell collections [1, 13]. The diagnosis of anaplastic meningioma is based on the histological features of frank malignancy. These include “carcinoma-like” foci and/or highly mitotically active tumor cells with 10–20 or more mitoses per high-powered field, and far exceed the abnormalities present in atypical meningioma. We reviewed the histopathology of the 30 tumors included in this study; the diagnosis of atypical (WHO grade II) or anaplastic (WHO grade III) meningioma was confirmed by a neuropathologist [7].

In this series, 10 patients (83.3%) had atypical- and 2 (16.7%) had anaplastic meningiomas; all were treated with LINAC-based SRS using 6 MV X-ray beams generated by Clinac-2300c linear accelerator (Varian Inc., Palo Alto, CA) at Kyoto University Hospital. Treatment planning was carried out using the X-knife system (Radionics Inc., Burlington, MA), following a 3 mm-slice contrast-enhanced tumor lesions and critical structures, such as eyes, brain stem and optic nerves, were delineated. The characteristics of the 12 patients with 30 lesions are outlined in Table 1.

Table 1 Summary of 12 meningioma patients treated by SRS and characteristics of their 30 lesions
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As 8 patients harbored 1- and 4 had 2 or more tumors, and 4 patients had undergone 2 or more SRS treatments, a total of 30 tumors were treated in the 12 patients. In 11 patients the tumors recurred after one or more operations, one patient underwent SRS as a primary treatment for late recurrence after surgical resection and 2 patients received external beam radiation therapy after microsurgery and before SRS.

Medical records were reviewed for data such as age and sex and the dates of meningioma diagnosis, completion of radiotherapy, and death or most recent follow-up.

A neurosurgeon, radiation oncologist, and radiation physicist participated in all dosimetry planning. The highest emphasis was placed on designing an isodose line that conformed to the exact tumor shape. The mean radiation dose to the periphery of the lesion was 18.0 Gy (range 12–20 Gy); in most cases delivery was to the 80% isodose line (range 80–100%). All patients were treated with a single isocenter; the collimator diameter ranged from 12.5 to 35 mm. In cases with an irregular target, the treatment plan was modified by changing the weight, plane and angle of the arcs to achieve higher dose conformity.

The radiographs were visually inspected by a radiologist to monitor changes in tumor size over time. Pre- and post-treatment images were available for comparison studies in all patients. Tumor dimensions were compared in the axial, sagittal, and coronal planes. A decrease in any one dimension without a concomitant increase in any other dimension was recorded as a decrease in tumor size, growth in any plane as an increase. The tumor size was recorded as unchanged, decreased, or increased at each point of inspection. Tumor growth adjacent to the irradiated tumor and outside the isodose volume was defined as margin recurrence; tumors that developed at noncontiguous sites were considered distant recurrences.

For statistical analysis we constructed Kaplan–Meier plots for survival and progression-free survival (PFS) using the dates of diagnosis, first surgery, first SRS, follow-up scans, and death or last follow-up. PFS and overall survival time were calculated from the day of the first SRS using the Kaplan–Meier method. Univariate analysis was performed on the Kaplan–Meier curves using the logrank statistic with P < 0.05 set as significant [14]. Standard statistical processing software (SPSS, version 14.0J and Prism, version 4.0) was used.

Results

Of the 12 patients, 11 reported for regular postoperative clinical visits. One patient manifested tumor progression 4 months after undergoing SRS; she underwent surgical resection 17 months from the date of SRS and the diagnosis of atypical meningioma was verified histologically.

The patients were observed for a mean of 43.4 months (range 6–84 months); at the end of the observation period 10 patients were alive. Death in one case was the result of lung metastasis from anaplastic meningioma which was based on the histological features, the other patient died from disease progression. The overall 5-year survival rate was 80.8% (Fig. 1). We treated 14 lesions with a lower radiation dose than 20 Gy to avoid severe anticipated toxicity. Six lesions were in close proximity to the brainstem or optic nerve (to optic nerve, <8 Gy). Two pairs of dual lesions treated simultaneously were close to each other, and 2 lesions were near prior radiosurgery sites. One lesion was located within the high dose volume of a prior EBRT field. One lesion that was treated as a low-grade meningioma was determined to be an atypical meningioma at the time of salvage surgery following progression after SRS. The other 16 lesions were treated by SRS with a marginal dose of 20 Gy. The statistics for PFS at 20 Gy and <20 Gy are shown in Fig. 2; the 2- and 5-year PFS rate for the 12 patients with high-grade meningioma was 48.3%. The median and mean time to recurrence was 4 and 7.7 months, respectively (range 3–23 months); 6 of the 12 patients (13 of 30 lesions) manifested in-field recurrence.

Fig. 1
figure 1

Kaplan–Meier estimate of overall survival curve and progression-free survival curve in all patients after the first SRS for high-grade meningiomas

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Fig. 2
figure 2

Kaplan–Meier progression-free survival curves in all patients after the first SRS for high-grade meningiomas treated with SRS doses of 20 Gy or <20 Gy. The delivery of 20 Gy was a statistically significant factor for longer progression-free survival (P = 0.0139)

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We performed Univariate analysis using the logrank test to assess factors that influence the length of PFS. The variables were sex, age (older or younger than 50 years), tumor location (skull base or non-skull base), target volume (more or <8 cc, and more or <2.87 cc), dose (20 Gy or <20 Gy), and tumor grade (atypical or anaplastic). As shown in Table 2, 9 of 14 (64.3%) lesions treated by SRS with a marginal dose below 20 Gy recurred in the radiation field; the median time to progression (TTP) was 6 months. In contrast, 4 of 16 (25.0%) lesions treated with a marginal dose of 20 Gy exhibited a local recurrence in the radiation field; the median TTP was 21 months. The radiation dose (20 Gy) was the only factor significantly associated with better PFS.

Table 2 Characteristics of lesions treated by SRS with 20 Gy or <20Gy
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Kaplan–Meier plots, generated for overall survival and PFS (Figs. 1, 2) showed that patients treated with doses below 20 Gy had a 1-, 2-, and 5-year PFS of 39.2, 29.4 and 29.4%, respectively. Patients who had received 20 Gy had a 1-, 2-, and 5-year PFS of 85.2%, 63.1%, and 63.1%, respectively (P = 0.0139). The characteristics of lesions treated with 20 Gy or <20 Gy are shown in Table 2. The median and mean volume of all tumors was 2.87 cc and 4.40 cc, respectively (range, 0.29–18 cc). The mean and median tumor volume of lesions treated with less than 20 Gy was 4.10 cc and 1.75 cc, respectively. The mean and median tumor volume of lesions treated with 20 Gy was 4.67 cc and 2.91 cc, respectively. The mean and median dose of lesions treated with <20 Gy was 15.2 Gy and 15 Gy, respectively. PFS was not affected by the tumor size; the 80% dose coverage volume was 98.9% at <20 Gy and 98.4% at 20 Gy (Table 2). In the cases of atypical meningioma (25 lesions), Kaplan–Meier plots, generated for overall survival and PFS showed that patients (12 lesions) treated with doses below 20 Gy had a 5-year PFS of 29.4%. Patients (13 lesions) who had received 20 Gy had a 5-year PFS of 63.1% (P = 0.0213). There were 2 anaplastic meningiomas with 5 lesions. One lesion recurred in 23 months after SRS. The mean follow-up period was 26.5 months. The overall survival rate was 100%, and a 3-year PFS rate was 50% (median PFS, 35 months).

Two (17%) of the 12 patients treated with SRS developed radiation toxicity. They had received doses of 17.6 Gy and 20 Gy. Asymptomatic perifocal edema from radiation-induced angiopathy occurred at 41 months post-SRS treatment in one patient and after 61 months in the other.

Discussion

The results of this study indicate that SRS with a marginal dose of 20 Gy may help to prolong PFS in patients with high-grade meningiomas.

External-beam radiotherapy (EBRT) for high-grade meningiomas

Atypical and anaplastic meningiomas have higher local recurrence- and lower survival rates than benign meningiomas. In the past, the initial treatment for anaplastic meningiomas was surgical removal followed by conventional EBRT. Studies on the clinical course of completely- or partially resected atypical and anaplastic meningiomas with or without additional adjuvant EBRT reported 5-year PFS rates between 32 and 48%, and 5-year overall survival rates between 28 and 95% [11, 15–18]. Goldsmith et al. [15] found that patients with anaplastic meningioma had significantly less favorable outcomes than did patients with tumors of a benign histology; their 5-year overall survival- and PFS rate was 58% and 48%, respectively. These data show that EBRT alone is not sufficient to treat high-grade meningiomas.

SRS for high-grade meningiomas

Stereotactic radiosurgery is now considered an option for the treatment of primary or recurrent meningiomas. It proved useful for benign meningiomas and excellent control rates were obtained when SRS was used as an adjunct to surgical tumor removal. However, as shown in Table 3 [10, 19–22], the effectiveness of SRS in patients with atypical and anaplastic meningioma remained to be elucidated.

Table 3 SRS for atypical and anaplastic meningiomas
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Stafford et al. [10] reported that the cause-specific 5-year survival rate for SRS-treated patients with benign, atypical, and anaplastic meningioma was 100, 76, and 0%, respectively (P < 0.0001); the 5-year local control rate was 89%. PFS rates were correlated with the histological features of the tumors (P < 0.0001); patients with benign tumors had a 5-year PFS rate of 93%; in patients with atypical or anaplastic meningiomas this rate was 68 and 0%, respectively. They also found that SRS-treated patients with high-grade meningiomas manifested high recurrence rates, and that despite aggressive treatment that included surgery, conventional EBRT, and SRS, these patients continued to exhibit lower cause-specific survival rates.

Ojemann et al. [22] who treated 22 anaplastic meningioma patients with gamma knife radiosurgery as boost to conventional EBRT over an 8-year period reported a 5-year overall survival rate of 40%. The 5-year PFS rate was 26%. In their series, age (<50 years) and tumor volume (<8 cc) were significant predictors of time to progression and length of survival. In addition, the 2-year survival rate of patients treated with doses below 15 Gy was 75%; there were no 5-year survivors. On the other hand, patients treated with doses >15 Gy had 2- and 5-year survival rates of 69% and 50%, respectively (P = 0.13 by univariate, P = 0.14 by multivariate analysis). Nineteen of 22 patients experienced progression, despite receiving conventional EBRT (median dose, 55 Gy) 4.5 years earlier. In our series, the PFS rates were longer than in previously reported studies and we posit that the PFS prolongation is attributable to the delivery of a higher radiation dose.

The median and mean tumor volume in our 12 patients were 2.87 cc and 4.40 cc, respectively (range 0.29–18 cc) and thus smaller than in previously reported studies; only 5 tumors exceeded 8 cc. Three of 14 lesions treated for tumor volumes exceeding 2.87 cc exhibited local recurrence in the radiation field. And 10 of 16 lesions treated for tumor volumes <2.87 cc recurred in the radiation field. However, the tumor size had no significant effect on PFS.

Modha et al. [23] stated SRS has now become part of the armamentarium when treating high-grade meningiomas. It could probably be offered to the patient as soon as possible postoperatively for any nodular residual tumor, along with conventional EBRT to the tumor bed. Certainly, the invasive nature of these tumors has to be considered, and SRS may not have any effect on infiltrative areas not appreciated during treatment planning. Its role after complete resection of a high-grade meningioma is also less clear. Instead, conventional EBRT to the tumor bed should be administered. Huffman et al. [21] proposed early SRS for incompletely resected residual high-grade meningiomas. For gross totally resected tumors, conventional EBRT should be considered. If focal recurrences develop after resection or margin or distant recurrent high-grade meningiomas develop after radiosurgery, SRS is an alternative to repeated microsurgery. In our series, 2 patients received EBRT after operation and before SRS. Ten patients did not receive EBRT before SRS. Only 1 lesion recurred in the EBRT field. Excepting this lesion, we performed Univariate analysis using logrank test, a marginal dose of 20 Gy was a statistically significant factor for longer PFS (P = 0.0173).

High-grade meningiomas are not highly sensitive to conventional EBRT and even SRS fails to inhibit tumor growth for a prolonged period. As the marginal dose delivered to previously reported tumors (between 14 and 18 Gy) failed to achieve adequate tumor control, where possible, we increased it to 20 Gy. In patients with tumors near critical organs and in those who had undergone previous irradiation therapy, and in cases of the tumors of the close proximity to each other, to avoid creating of hotspots in the normal brain tissue, we had to restrict the marginal dose to 14–18 Gy. The dose coverage volume was over 95% for all lesions. Although our study population is relatively small, the 2- and 5-year PFS rate was 48.3%. The 5-year PFS of patients treated with 20 Gy was 63.1% compared to 29.4% in those who received <20 Gy (P = 0.0139). Since there was no significant difference in tumor volume between both groups, the extension of PFS had been contributed by higher marginal dose (Table 2). The latter had a median PFS of 6 months and significantly earlier in-field tumor recurrence. Based on our observations and the results of earlier studies that showed that the progression of low-grade meningiomas can be controlled with relatively low doses (15–18 Gy), we conclude that in patients with high-grade meningiomas, SRS should deliver a marginal dose exceeding 20 Gy.

Huffmann et al. [21] who treated 21 lesions by SRS at doses ranging from 14 to 18 Gy reported only one instance of in-field recurrence. Their patient with a local relapse was treated with an SRS dose of 15 Gy. In our series, a marginal dose exceeding 20 Gy was the only statistically significant factor for longer PFS in patients with high-grade meningiomas (P = 0.0139). According to Harris et al., [20] the aggressive use of early boost-SRS after craniotomy and conventional EBRT is an important adjuvant management strategy for residual or recurrent high-grade meningiomas. In patients with no disease progression and in those with smaller tumor volumes, there was a statistically significant correlation between early SRS delivered soon after craniotomy and better survival rates. Their findings support our hypothesis that early SRS with a marginal dose exceeding 20 Gy contributes to the prolongation of PFS in patients with high-grade meningiomas.

In the present retrospective analysis, dose reduction was shown to be significantly associated with the shorter PFS. The limitation of this study was the exsistence of the considerable bias between the lower dose group and the higher dose group, especially in the tumor location, because the prescribed dose was reduced, in most cases, to avoid the location-specific toxicity. Nevertheless, the radiation dose in SRS seemed to be one of the substantial factors in control of high-grade meningiomas, considering that the radiobiological characteristic of the tumor was unlikely to depend on the tumor location.

Complications

Shaw et al. [24, 25] reported the findings of a multicenter trial in which escalating doses were delivered to recurrent, previously irradiated primary and metastatic tumors until unacceptable central nervous system (CNS) toxicity was reached. Variables significantly related to toxicity were a tumor diameter >21 mm, higher Karnofsky performance status scores, and a higher tumor dose. The maximum tolerated SRS doses in their study population were 24 Gy, 18 Gy, and 15 Gy for tumors </= 20 mm, 21–30 mm, and 31–40 mm in maximum diameter. Unacceptable CNS toxicity, defined as irreversible severe neurological symptoms, clinically, radiographically, or histologically verified radiation necrosis, or death, was more likely to occur in patients with larger tumors. On the other hand, local tumor control depended primarily on the type of the recurrent tumor and the treatment unit. In our study, the tumor volume and SRS dose were not significantly related to toxicity. We delivered 20 Gy to 14 lesions; 2 patients treated with doses of 17.6 Gy and 20 Gy developed asymptomatic radiation necrosis.

In conclusions, based on our findings, we suggest that recurrent high-grade meningiomas be treated by SRS with a marginal dose exceeding 20 Gy. Because of the rarity of these tumors, a multicenter trial would be required to evaluate these issues in a prospective study.