Single-Fractionated Stereotactic Radiosurgery for Intracranial Meningioma in Elderly Patients: 25-Year Experience at a Single Institution

Single-Fractionated Stereotactic Radiosurgery for Intracranial Meningioma in Elderly Patients:... Abstract BACKGROUND Stereotactic radiosurgery (SRS) has been accepted as a therapeutic option for intracranial meningiomas; however, the detailed data on outcomes in elderly patients remain unclear. OBJECTIVE To delineate the efficacy of SRS for meningiomas in elderly patients. METHODS The outcomes of 67 patients aged ≥65 yr who underwent SRS for benign intracranial meningioma (World Health Organization grade I) between 1990 and 2014 at our institution were retrospectively analyzed. The median age was 71 yr (range, 65-83 yr), and the mean and median follow-up were 62 and 52 mo (range, 7-195 mo), respectively. Tumor margins were irradiated with a median dose of 16 Gy, and the median tumor volume was 4.9 cm3 (range, 0.7-22.9 cm3). RESULTS Actuarial local tumor control rates at 3, 5, and 10 yr after SRS were 92%, 86%, and 72%, respectively. Previous surgery and parasagittal/falcine location were statistically significant predictive factors for failed tumor control. Mild or moderate adverse events were noted in 9 patients. No severe adverse event was observed. A higher margin dose was significantly associated with adverse events by univariate analysis. CONCLUSION SRS is one of the standard therapies for meningiomas in elderly patients, providing both favorable tumor control and a low risk of adverse events under minimum invasiveness. Intracranial meningioma, Stereotactic radiosurgery, Elderly population ABBREVIATIONS ABBREVIATIONS CT computed tomography DFS disease-free survival GKRS gamma knife radiosurgery LTC local tumor control MRI magnetic resonance imaging SRS stereotactic radiosurgery Currently, we are facing a worldwide trend of an aging society. In the early 1980s, the average life expectancy of the global population was approximately 62 yr. Today, it is estimated to be 71 yr, based on a World Health Organization (WHO) report from 2013. The investigators who authored Profiles of Ageing by the United Nations predict that this number will be over 77 yr in about 30 yr. Meningiomas are the most common benign intracranial tumors, and their incidence increases with age.1,2 Considering the aging of the global population, one would easily expect that the number of elderly patients who require treatment for meningiomas is increasing. Surgery is the standard treatment3,4; however, it is not always ideal for elderly patients for a variety of reasons, including multiple comorbidities, decreased organ function, etc. It is widely accepted that elderly patients tend toward higher surgery-associated mortality and complication rates than younger patients; the 1-yr mortality rate after surgery among the elderly population is estimated as 7% to 16%.1,5-7 Thus, radiotherapies play more and more important roles in elderly patients. Among the radiotherapies, stereotactic radiosurgery (SRS) is minimally invasive and is open to elderly patients.8-11 Its efficacy for meningiomas in adult patients has been gradually elucidated since the 1990s.12-22 Nevertheless, to our knowledge, the detailed outcomes in elderly patients have not been determined yet. The goal of this study is to determine the efficacy of SRS in elderly patients by directly analyzing the outcomes of this special subpopulation in detail. METHODS Patient Selection We retrospectively reviewed 374 consecutive treatment records for 297 patients who suffered from intracranial meningioma treated with SRS between 1990 and 2014 at our institution. The following cases were excluded from this study: WHO grade II/III meningiomas or meningiomas with histologically confirmed brain invasion,23 neurofibromatosis type II-related meningiomas, follow-up periods of less than 6 mo without a significant clinical indication, multiple meningiomas arising separately at the initial SRS, and radiation-induced meningiomas. We defined the beginning of elderly as the chronological age of 65 yr. Therefore, 67 patients at a median age of 71 yr (range, 65-83 yr) were included in the study. Written informed consent was obtained from all patients according to the ethical principles for medical research involving human subjects as defined by the World Medical Association-Helsinki Declaration. The review board of our institute approved the study protocol. Decisions about each patient's treatment were meticulously made during a neurosurgical conference among radiation oncologists. Basically, incidentally revealed asymptomatic tumors were first observed and followed by serial imaging studies. Tumors increasing in size, symptomatic tumors, and postoperative residual tumors were considered candidates for treatment. The mean and median follow-up were 62.1 and 52.0 mo (range, 7-195 mo), respectively. Among them, 29 patients (43.3%) were followed for ≥5 yr, and 11 patients (16.4%) were followed for ≥10 yr. A meningioma diagnosis was made by histopathological analysis (n = 28) or by clinical course combined with computed tomography (CT) and magnetic resonance imaging (MRI) analysis (n = 39). Detailed tumor locations are shown in Table 1. Tumors located in the falcine and the parasagittal regions were considered as inhabiting 1 location, because tumors in these 2 regions are sometimes difficult to distinguish, and because numerous prior studies have revealed unique characteristics of these 2 groups.20,21,24 Significant comorbidities were defined as coexistence of diseases that might lead to a hesitation in aggressive surgery or general anesthesia: cardiac ischemia and arrhythmias (n = 6), diabetes mellitus (n = 6), decreased renal function (n = 2), systemic autoimmune diseases (n = 2), chronic liver disease (n = 1), and bronchial asthma (n = 1). Basic characteristics of the patients are summarized in Table 2. TABLE 1. Locations of Treated Meningioma Locationa  No. (%)  Nonskull base  21 (31)   Convexity  12 (18)    Frontal  6 (9)    Temporal  1 (1)    Parietal  3 (4)    Occipital  2 (3)   Parasagittal region  4 (6)   Falcine region  4 (6)   Intraventricle  1 (1)  Skull base  46 (69)   Anterior fossa  2 (3)   Orbit  1 (1)   Cavernous sinus  12 (18)   Sphenoid ridge  1 (1)   Tentorial region  4 (6)   Petroclival region  10 (15)   Cerebellopontine angle  13 (19)   Cerebellar region  2 (3)   Jugular foramen  1 (1)  Total  67 (100)  Locationa  No. (%)  Nonskull base  21 (31)   Convexity  12 (18)    Frontal  6 (9)    Temporal  1 (1)    Parietal  3 (4)    Occipital  2 (3)   Parasagittal region  4 (6)   Falcine region  4 (6)   Intraventricle  1 (1)  Skull base  46 (69)   Anterior fossa  2 (3)   Orbit  1 (1)   Cavernous sinus  12 (18)   Sphenoid ridge  1 (1)   Tentorial region  4 (6)   Petroclival region  10 (15)   Cerebellopontine angle  13 (19)   Cerebellar region  2 (3)   Jugular foramen  1 (1)  Total  67 (100)  aTumor location was determined by the location of its main mass if the tumor spreads over more than 1 anatomic location. View Large TABLE 2. Baseline Characteristics of the Patients Variables  Value (median)  Median age (range), years  71 (65-83)  Male, no. (%)  20 (30)  History of significant comorbidities, no. (%)  13 (19)  History of previous surgery, no. (%)  28 (42)  Median tumor volume (range), cm3  4.9 (0.7-22.9)  Median V12 volume (range), cm3  12.1 (1.01-31.96)  Median maximum diameter (range), mm  26 (12-52)  Median margin dose (range), Gy  16 (12-18)  Median follow-up periods (range), months  52 (7-195)  Variables  Value (median)  Median age (range), years  71 (65-83)  Male, no. (%)  20 (30)  History of significant comorbidities, no. (%)  13 (19)  History of previous surgery, no. (%)  28 (42)  Median tumor volume (range), cm3  4.9 (0.7-22.9)  Median V12 volume (range), cm3  12.1 (1.01-31.96)  Median maximum diameter (range), mm  26 (12-52)  Median margin dose (range), Gy  16 (12-18)  Median follow-up periods (range), months  52 (7-195)  View Large Radiosurgical Techniques The radiosurgical treatment was performed using Leksell Gamma Knife (Elekta Instruments, Inc, Stockholm, Sweden). The techniques used in the present study were previously reported.25-27 Briefly, after head fixation using a Leksell frame (Elekta Instruments, Inc., Stockholm, Sweden), stereotactic imaging (CT before July 1996, MRI thereafter) was performed to obtain precise data on the shape, volume, and 3D coordinates of the tumors. Dedicated neurosurgeons and radiation oncologists used commercially available software to plan treatments (KULA planning system until 1998, Leksell Gamma Plan thereafter; Elekta Instruments, Inc., Stockholm, Sweden). Because we did not usually set a margin for setup uncertainty, the target volume was simply the same as the tumor volume defined by imaging studies. Volume irradiated with ≥12 Gy, known as V12, was retrospectively calculated in each patient using Leksell Gamma Plan. In the present cohort, V12 was calculable in 57 patients. The dosimetry data are summarized in Table 2. Follow-up, Definition of Tumor Progression, and Adverse Events After SRS, patients were evaluated at regular intervals by the attending physicians at our institution or its associated hospitals. MRIs were obtained at 6-mo intervals for the first 3 yr and annually thereafter. A tumor was considered progressive if the diameter increased in size by a minimum of 2 mm in any direction, and was considered controlled otherwise.22 Tumor progression was further classified into 3 groups: intrafield tumor progression, which was defined as tumor regrowth within the target volume; marginal tumor progression, which was defined as tumor regrowth adjacent to the target volume but within the 20% isodose volume; and remote tumor progression, which was defined as tumor growth beyond the 20% isodose volume (Figure 1).28 FIGURE 1. View largeDownload slide A schematic drawing of the types of tumor progression. FIGURE 1. View largeDownload slide A schematic drawing of the types of tumor progression. The patient's functional status was fully recorded at each clinical visit, and the mRS was assigned based on this data; functional outcomes were classified as dependent (mRS 3-5) or independent (mRS 0-2).29 Adverse events were prospectively recorded at each visit, and the severity were assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.0. Neurological deterioration due to tumor progression was not considered an adverse event. To assess the true risk of deterioration of disability or dependence in the daily activities after SRS, the risk of deteriorated mRS was evaluated. Failure was defined as deterioration of mRS related to tumor progression, additional treatment, or radiation side effects; deterioration of mRS due to events unrelated to meningiomas, including senility and other coexisting diseases, was not included in the failure. Statistical Analysis Kaplan–Meier curves to determine local tumor control (LTC), disease-free survival (DFS), and risk of deterioration in mRS were plotted using the following: the dates of gamma knife radiosurgery (GKRS), clinical and radiographical follow-up, and the state of tumor progression. Tumor-related death, intrafield progression, and marginal progression were considered failed LTC. DFS was defined as survival without tumor progression. Factors potentially affecting LTC and DFS were evaluated using log-rank test for univariate analysis and Cox proportional hazard model for multivariate analysis. Factors potentially affecting adverse events were evaluated by logistic regression analysis. A history of previous surgery, significant comorbidities, biological sex, and tumor locations were used as categorical variables; age, tumor volume, maximum diameter, and radiosurgical dose were used as continuous variables or binary variables in a dichotomous manner using the median values. All analyses were performed using JMP Pro 11 software (SAS Institute Inc, North Carolina). RESULTS Tumor Control Six intrafield, 7 marginal, and 3 remote progressions were observed in 11 patients after a median interval of 59 mo (range, 19-190 mo; Table 3) from initial GKRS; thus, LTC was achieved in 81% of the patients at the time of analysis. Actuarial LTC rates were 92%, 86%, and 72% at 3, 5, and 10 yr after GKRS, respectively. In 2 patients with intrafield progressions, after certain periods of tumor control, the tumors showed rapid growth. They underwent surgical resection, which disclosed anaplastic progression of the histology (cases 2 and 9 in Table 3). TABLE 3. Detailed Data of the Patients Showing Tumor Progression After SRS       Interval from first  Current tumor status,  WHO  Last visit  Final    Max diameter  Vol  Margin  No  Age, sex  Progression  GKRS (month)  additional treatment  gra  (month)  mRS  Location  (mm)  (cm3)  dose (Gy)  1  67, M  ITP  148  Observed due to senility    151  2b  Cavernous  29  6.7  14  2  75, F  ITP  19  Anaplastic meningioma was confirmed and controlled after additional salvage surgery + adjuvant EBRT  III  52  2c  Orbit  23  4.8  16  3  75, F  ITP  37  Controlled after surgical resection  I  38  2b  Parasagittal  31  10.1  16  4  81, M  ITP  23  Observed due to senility    30  5d  Parasagittal  21  8.6  16  5  66, M  MTP  106  Controlled after 2nd GKRS    169  2b  Petroclival  25  3.7  18  6  69, M  MTP  59  Controlled after 2nd GKRS    84  0  CP angle  12  0.7  16  7  65, F  MTP  95  Controlled after 2nd GKRS    122  0  Cavernous  28  3.7  16  8  72, M  MTP + MTP + MTP  23, 47, 57  Controlled after additional 3 sessions of GKRS for repeated MTP    61  1b  Occipital convexity  12  1.6  16  9  66, F  MTP + ITP + ITP  35, 60, 77  Active tumor after additional 2 sessions of GKRS, and anaplastic meningioma was confirmed after salvage surgery  III  109  5d  Parasagittal  40  12.7  12  10  67, F  RTP  92  Observed due to asymptomatic tumor    141  1b  Falcine  29  12.9  16  11  69, F  RTP + RTP  87, 190  Controlled after additional GKRS    201  1b  CP angle  20  3.2  16        Interval from first  Current tumor status,  WHO  Last visit  Final    Max diameter  Vol  Margin  No  Age, sex  Progression  GKRS (month)  additional treatment  gra  (month)  mRS  Location  (mm)  (cm3)  dose (Gy)  1  67, M  ITP  148  Observed due to senility    151  2b  Cavernous  29  6.7  14  2  75, F  ITP  19  Anaplastic meningioma was confirmed and controlled after additional salvage surgery + adjuvant EBRT  III  52  2c  Orbit  23  4.8  16  3  75, F  ITP  37  Controlled after surgical resection  I  38  2b  Parasagittal  31  10.1  16  4  81, M  ITP  23  Observed due to senility    30  5d  Parasagittal  21  8.6  16  5  66, M  MTP  106  Controlled after 2nd GKRS    169  2b  Petroclival  25  3.7  18  6  69, M  MTP  59  Controlled after 2nd GKRS    84  0  CP angle  12  0.7  16  7  65, F  MTP  95  Controlled after 2nd GKRS    122  0  Cavernous  28  3.7  16  8  72, M  MTP + MTP + MTP  23, 47, 57  Controlled after additional 3 sessions of GKRS for repeated MTP    61  1b  Occipital convexity  12  1.6  16  9  66, F  MTP + ITP + ITP  35, 60, 77  Active tumor after additional 2 sessions of GKRS, and anaplastic meningioma was confirmed after salvage surgery  III  109  5d  Parasagittal  40  12.7  12  10  67, F  RTP  92  Observed due to asymptomatic tumor    141  1b  Falcine  29  12.9  16  11  69, F  RTP + RTP  87, 190  Controlled after additional GKRS    201  1b  CP angle  20  3.2  16  CP: cerebellopontine, EBRT: external beam radiation therapy, SRS: stereotactic radiosurgery, ITP: intra-field tumor progression, mRS: modified Rankin Scale, MTP: marginal tumor progression, RTP: remote tumor progression aWHO grade confirmed by salvage surgery after progression bdue to senility cdue to senility and disturbed visual acuity after the initial surgery ddue to progressive tumor View Large History of previous surgery and falcine/parasagittal tumor location were significantly associated with failed LTC as determined by multivariate analysis, though the latter did not quite achieve statistical significance via univariate analysis (Figure 2; Table 4). Falcine/parasagittal tumor location was also a significant negative predictive factor for DFS, as determined by both univariate and multivariate analyses. We did not identify any significant association between age and tumor control (Table 4). FIGURE 2. View largeDownload slide The Kaplan–Meyer curves for actuarial rates of LTC, DFS, and risk of deterioration of mRS are shown A. History of previous surgery and falcine/parasagittal locations were significantly associated with failed LTC B and C, whereas the latter was also a significant risk factor for DFS D and E. LTC = local tumor control, DFS = disease-free survival, mRS = modified Rankin Scale. FIGURE 2. View largeDownload slide The Kaplan–Meyer curves for actuarial rates of LTC, DFS, and risk of deterioration of mRS are shown A. History of previous surgery and falcine/parasagittal locations were significantly associated with failed LTC B and C, whereas the latter was also a significant risk factor for DFS D and E. LTC = local tumor control, DFS = disease-free survival, mRS = modified Rankin Scale. TABLE 4. The Result of Univariate and Multivariate Analysis for LTC and DFS Analysis for LTC  Univariate analysis  Multivariate analysis  Factors  P value  Factors  P value  HR (95% CI)  Age > 71  .59  Age  .38  1.1 (0.90-1.3)  Falcine/parasagittal location  .036*  Falcine/parasagittal location  .14  3.9 (0.6-23)  Male sex  .23  Male sex  .70  1.4 (0.27-6.6)  Maximum diameter > 25 mm  .75  Maximum diameter  NT  NT  Planned tumor volume > 5 cm3  .79  Planned tumor volume  .87  0.87 (0.69-1.1)  Margin dose > 16 Gy  .17  Margin dose  .18  0.71 (0.43-1.2)  History of surgery  .0047*  History of surgery  .013*  11 (1.6-220)  Analysis for LTC  Univariate analysis  Multivariate analysis  Factors  P value  Factors  P value  HR (95% CI)  Age > 71  .59  Age  .38  1.1 (0.90-1.3)  Falcine/parasagittal location  .036*  Falcine/parasagittal location  .14  3.9 (0.6-23)  Male sex  .23  Male sex  .70  1.4 (0.27-6.6)  Maximum diameter > 25 mm  .75  Maximum diameter  NT  NT  Planned tumor volume > 5 cm3  .79  Planned tumor volume  .87  0.87 (0.69-1.1)  Margin dose > 16 Gy  .17  Margin dose  .18  0.71 (0.43-1.2)  History of surgery  .0047*  History of surgery  .013*  11 (1.6-220)  Analysis for DFS  Univariate analysis  Multivariate analysis  Factors  P value  Factors  P value  HR (95% CI)  Age > 71  .84  Age  .66  1.0 (0.88-1.2)  Falcine/parasagittal location  .0060*  Falcine/parasagittal location  .029*  5.7 (1.2-28)  Male sex  .72  Male sex  .89  0.90 (0.19-3.8)  Maximum diameter > 25 mm  .74  Maximum diameter  NT  NT  Planned tumor volume > 5 cm3  .71  Planned tumor volume  .35  0.92 (0.75-1.1)  Margin dose >16 Gy  .059  Margin dose  .18  0.75 (0.48-1.1)  History of surgery  .060  History of surgery  .14  2.9 (0.70-15)  Analysis for DFS  Univariate analysis  Multivariate analysis  Factors  P value  Factors  P value  HR (95% CI)  Age > 71  .84  Age  .66  1.0 (0.88-1.2)  Falcine/parasagittal location  .0060*  Falcine/parasagittal location  .029*  5.7 (1.2-28)  Male sex  .72  Male sex  .89  0.90 (0.19-3.8)  Maximum diameter > 25 mm  .74  Maximum diameter  NT  NT  Planned tumor volume > 5 cm3  .71  Planned tumor volume  .35  0.92 (0.75-1.1)  Margin dose >16 Gy  .059  Margin dose  .18  0.75 (0.48-1.1)  History of surgery  .060  History of surgery  .14  2.9 (0.70-15)  CI: confident interval; DFS: disease-free survival; HR: hazard ratio; LTC: local tumor control; NT: not tested. *P value < .05 is considered significant. View Large Additional Treatments Ten sessions of GKRS were performed for recurrent tumors (Table 3). Among them, 9 tumors (90%), including 7 marginal and 2 remote progressions, were controlled successfully. One intrafield progression tumor (patient number 9) again showed intrafield progression at 17 mo, which was subsequently confirmed as anaplastic meningioma after salvage surgery (Figure 3). Salvage surgery was performed in 3 cases with intrafield progression. FIGURE 3. View largeDownload slide A detailed case report of patient no. 9 was shown. This patient was first referred to us because of progressive recurrence 5 yr after the first near-total resection of the parasagittal meningioma. During the second surgery at our institution, a small portion of the tumor could not be resected due to its location adjacent to the intact superior sagittal sinus, and was subsequently treated with SRS A. Three years after SRS, a follow-up MRI showed marginal progression at the falcine region B, which was then treated with a secondary SRS C. Two years after the secondary SRS, intrafield progression of the initially treated tumor was observed D. This was treated with a third SRS E. The initial tumor again regrew 17 mo after the third SRS F, and a histopathological diagnosis of anaplastic meningioma (World Health Organization grade III) was confirmed at surgical resection. Finally, the patient's family chose to decline further intervention, and she was referred to an extended care hospital. FIGURE 3. View largeDownload slide A detailed case report of patient no. 9 was shown. This patient was first referred to us because of progressive recurrence 5 yr after the first near-total resection of the parasagittal meningioma. During the second surgery at our institution, a small portion of the tumor could not be resected due to its location adjacent to the intact superior sagittal sinus, and was subsequently treated with SRS A. Three years after SRS, a follow-up MRI showed marginal progression at the falcine region B, which was then treated with a secondary SRS C. Two years after the secondary SRS, intrafield progression of the initially treated tumor was observed D. This was treated with a third SRS E. The initial tumor again regrew 17 mo after the third SRS F, and a histopathological diagnosis of anaplastic meningioma (World Health Organization grade III) was confirmed at surgical resection. Finally, the patient's family chose to decline further intervention, and she was referred to an extended care hospital. Adverse Events and Post-Treatment Edema Ten patients (15%) developed peritumoral edema at 4 to 15 mo (median 7 mo) after GKRS. Only 3 (4%) of them were symptomatic, with 1 patient presenting with mild hemiparesis, 1 with mild sensory disturbance, and 1 with new onset seizures. No significant association was found between post-treatment edema and the following factors: age, tumor volume, maximum diameter, tumor location (falcine/parasagittal vs the other), margin dose, and previous surgical history (Table 5). TABLE 5. Potential Risk Factors for Peritumoral Edema and Symptomatic AEs   Peritumoral edema  Symptomatic AEs    P value  P value  Factors  Univariate analysis  Multivariate analysis  Univariate analysis  Multivariate analysis  Age  .87  .84  .12  .16  Parasagittal/falcine locations  .41  .31  .95  .85  Male sex  .47  .99  .60  .40  Maximum diameter  .82  NT  .79  NT  Planned tumor volume  .56  NT  .84  .32  V12 volume  .25  .39  .97  NT  Margin dose  .66  .60  .042*  .055  History of surgery  .43  .21  .20  .18    Peritumoral edema  Symptomatic AEs    P value  P value  Factors  Univariate analysis  Multivariate analysis  Univariate analysis  Multivariate analysis  Age  .87  .84  .12  .16  Parasagittal/falcine locations  .41  .31  .95  .85  Male sex  .47  .99  .60  .40  Maximum diameter  .82  NT  .79  NT  Planned tumor volume  .56  NT  .84  .32  V12 volume  .25  .39  .97  NT  Margin dose  .66  .60  .042*  .055  History of surgery  .43  .21  .20  .18  AE: adverse event; NT: not tested. *P value < .05 is considered significant. View Large After GKRS, 9 patients (13%) developed Common Terminology Criteria for Adverse Events grade 1 to 2 adverse events (Table 6). The median interval between the onset of adverse events and GKRS was 9 mo (range, 3-30 mo). These adverse events were basically managed with oral corticosteroids. A higher margin dose was a significant risk factor by univariate analysis (P = .042), whereas no factor was significant by multivariate analysis (Table 5). We did not observe any acute complications, including dizziness, headache, memory impairment, or alopecia. TABLE 6. Summary of AEs After SRS Age,  Interval from first    CTCAE  Final    Max diameter  Vol  Margin dose  sex  GKRS (month)  Symptoms of AEs  grade  mRS  Location  (mm)  (cm3)  (Gy)  66, M  12  Mild unilateral motor weakness  2  3  Petroclival  25  3.7  18  68, M  14  Slight weakness in lower extremity  1  2  Falx  44  8.9  16  65, F  5  Sensory disturbance  1  1  Frontal  18  1.5  18  65, F  3  Sensory disturbance  1  1  JF  30  11.9  18  65, F  4  Trigeminal neuralgia  2  1  Petroclival  25  2.8  18  69, F  6  Trigeminal neuralgia  2  1  Petroclival  15  1.2  16  68, F  23  Sensory disturbance  1  1  Tentorial  31  14.9  14  78, F  30  Trigeminal neuralgia  2  1  Tentorial  17  2.9  16  83, F  5  Generalized seizure  2  1  Frontal  29  13.3  14  Age,  Interval from first    CTCAE  Final    Max diameter  Vol  Margin dose  sex  GKRS (month)  Symptoms of AEs  grade  mRS  Location  (mm)  (cm3)  (Gy)  66, M  12  Mild unilateral motor weakness  2  3  Petroclival  25  3.7  18  68, M  14  Slight weakness in lower extremity  1  2  Falx  44  8.9  16  65, F  5  Sensory disturbance  1  1  Frontal  18  1.5  18  65, F  3  Sensory disturbance  1  1  JF  30  11.9  18  65, F  4  Trigeminal neuralgia  2  1  Petroclival  25  2.8  18  69, F  6  Trigeminal neuralgia  2  1  Petroclival  15  1.2  16  68, F  23  Sensory disturbance  1  1  Tentorial  31  14.9  14  78, F  30  Trigeminal neuralgia  2  1  Tentorial  17  2.9  16  83, F  5  Generalized seizure  2  1  Frontal  29  13.3  14  AE: adverse event; CTCAE: Common Terminology Criteria for Adverse Events ver. 4.0; SRS: stereotactic radiosurgery; JF: jugular foramen; mRS: modified Rankin Scale. View Large Deterioration of mRS after SRS Four of 67 patients (6%) showed deterioration of mRS, 2 because of adverse events (12 and 14 mo after SRS, Table 6), 1 because of complication after additional surgical resection for tumor progression (97 mo after SRS, case 9 in Table 3), and 1 because of tumor progression itself (23 mo after SRS, case 4 in Table 3). The Kaplan–Meier analysis revealed that the actuarial risks of deterioration in mRS after SRS were 5% at 3 and 5 yr, and 13% at 10 yr (Figure 2). Two patients died of unrelated causes (1 case of massive intestinal bleeding due to ulcerative colitis and 1 case of myelodysplastic syndrome); thus, 62 (93%) patients could maintain independence at the final follow-up examination. DISCUSSION Tumor Control It is not yet well understood how increasing age affects the treatment outcomes. There were some studies that suggested increasing age was one of the risk factors for failed tumor control based on the outcomes of all-ages cohorts,22,30 whereas a previous study reported that age did not significantly affect the clinical outcomes.31 However, these studies lacked detailed and direct analysis of the actual outcomes of elderly patients, which is essential to determine the real usefulness of SRS. In the present study, we directly analyzed the outcomes of elderly patients and found that SRS is a safe and effective treatment modality, providing 86% LTC at 5 yr. Long-term tumor control is also favorable, with actuarial 10-yr LTC reaching 72%. As far as we know, this may be the first report describing detailed outcomes of SRS for meningioma in this subpopulation. We found that previous surgery and falcine/parasagittal location were associated with failed LTC. In particular, falcine/parasagittal location was also a risk factor for failed DFS. These findings were similar to those of previous reports describing meningiomas in all ages.22 One of the advantages of GKRS is its very sharp fall-off of radiosurgical dose. This advantage, however, requires an accurate definition of tumor contour. In cases of falcine/parasagittal meningiomas, it is sometimes difficult to differentiate the tumor margin from normal anatomic structures including dural tissue, the superior sagittal sinus, and cortical veins, which may lead to relatively lower tumor control rates. In theory, fractionated radiotherapy such as cyber knife could effectively cover the tumor margin, leading to better tumor control. However, a previous study revealed that even fractionated radiotherapy failed to show sufficient tumor control in falcine meningiomas.32 In our opinion, close serial follow-up should be mandatory to manage this type of failure, but it is still controversial whether we should include originally involved sinus, falx, and dural attachment in the treatment volume. Another issue that we need to emphasize herein is an association between recurrence and previous surgery. In the present study, all intrafield/marginal progression meningiomas were recurrent tumors after surgery. As with falcine/parasagittal meningiomas, postoperative scar tissues can appear enhanced on MRI, becoming indistinguishable from tumor tissue in the treatment of postoperative tumors. This may result in decrease in LTC. Additionally, recurrent meningioma is sometimes accompanied by dedifferentiation into a more aggressive histology,33 and previous articles focusing on surgical cohorts have shown that 2% to 29% of benign meningiomas transform into higher grade meningiomas at the recurrence.34-37 Therefore, there is a possibility that they might acquire a certain level of radioresistance or aggressiveness by nature. The probability of radiation-induced malignant transformation of benign meningiomas remains unclear, but Iwai and colleagues reported that approximately 6% of cases in their GKRS cohort underwent malignant transformation.19 In our cohort, the rate of anaplastic change after GKRS was 3%, which is comparable to if not better than previous studies. We believe the anaplastic progression in our cohort can be explained by the latent aggressive nature of the diseases themselves. Further studies are desirable to unveil the relationship between radiosurgery and malignant transformation. Secondary Treatment In the cases with marginal or remote progression, secondary treatment was feasible, providing favorable tumor control at a median of 27 mo (range, 4-114 mo) follow-up without adverse events. Theoretically, marginal and remote progression results from insufficient irradiation or suboptimal tumor coverage; thus, it would be reasonable to treat these tumors with additional optimal irradiation. Therefore, if the repeated radiosurgery was taken into consideration, the actual tumor control rate using “solo” radiosurgery will be better than the results of “single” radiosurgery. A similar tendency toward salvage treatment for out-of-field recurrence can be seen in a previous study.21 On the contrary, in intrafield progression cases, we have to seriously discuss the choice of additional treatments considering the time course and the pattern of recurrence, because these tumors may become radioresistant or develop into anaplastic lesions.19 We performed salvage surgery for 3 patients with intrafield progression, finding that 2 of them harbored malignant progression (Table 3). In those cases, SRS may have contributed only to delay their radical treatments. However, considering that they were recurrent cases after previous surgery, indication and the timing of initial SRS was considered reasonable. Peritumoral Edema and Neurological Complications One of the novel aspects of the current study was the analysis of the deterioration of mRS. For elderly patients, the most important thing is to pass the expected life span uneventfully, and in this respect, not only achievement of definitive tumor control but also growth retardation of the tumor for 10 yr has significant meaning. Our results revealed that deterioration of mRS was found in only 6.0% of the patients after SRS, which was estimated 13% at 10 yr and was acceptable as therapeutic outcomes considering the present patient population included more than 40% cases of failed tumor control after surgery. Some previous studies have reported that parasagittal tumor location is one of the risk factors for peritumoral edema.14,16,38 On the other hand, Kuhn et al39 found no association between parasagittal location and peritumoral edema. They concluded that parasagittal meningiomas tend to be larger in volume, leading to a higher risk of treatment-related toxicity than those in other locations. The results of the present study support Kuhn's results, although we could not reach a definitive conclusion because of the small sample size and retrospective nature of the present study. Optimal Radiosurgical Dose The optimal radiosurgical dose remains controversial, with a balance that needs to be achieved between tumor control and adverse events. Shin et al17 reported that a margin dose of 10 to 12 Gy produced a 20% recurrence rate, whereas no recurrences were observed with a margin dose of 14 Gy. Kollova et al18 found that a margin dose ≥16 Gy is a risk factor for complications. Most prior studies have adopted a median margin dose of 13 to 15 Gy.13,18,20,22,40,41 In the present study, we prescribed a relatively high radiosurgical dose (≥16 Gy) aiming to obtain definitive tumor control. We particularly aimed to control skull base lesions, as these lesions are in close proximity to key anatomic structures, and further growth often makes surgery or GKRS more challenging. However, we also found that margin dose >16 Gy was significantly associated with adverse events (P = .041) by univariate analysis, as with some previous studies.18,21,24,42 High dose irradiation can lead to undesirable complications that could affect day-to-day functions in elderly patients. Therefore, we believe that the dose ideally should be reduced to 13 to 15 Gy, though the optimal dose should be further discussed. Limitations The first limitation of our study is that our data are based on a retrospective review of patients from a single institution; thus, potential selection bias cannot be excluded. Second, the lack of an untreated control group restricts our ability to assess the full benefit of SRS. Third, because most meningiomas are slowly progressing tumors, the mean follow-up of 62.1 mo in our cohort may not exclude the possibility of underestimating tumor recurrence after 5 to 10 yr. Considering the median age in the present cohort was 71 yr and the life expectancy in most developed countries is 80 yr, the ideal follow-up would be at least 10 yr to measure the outcomes over the patient's residual life. However, our follow-up period is comparable to that of other studies regarding radiotherapy for benign meningiomas (20-70 mo).18,20-22,30,39,43-45 Additionally, some previous studies suggested that the rates of tumor control at 5 to 10 yr are nearly stable after radiotherapy for WHO grade-1 meningiomas.22,44 Although a longer follow-up is desirable, we believe that the current follow-up period is sufficient to provide reliable results. Enrolling more cases with a longer follow-up would be invaluable to further evaluate long-term efficacy and safety. CONCLUSION SRS is a safe and effective treatment modality for intracranial meningioma in the elderly population. Previous surgery and falcine/parasagittal tumor location are predictive factors for failed LTC. Early detection of recurrent tumors can neutralize this risk, because secondary treatment for out-of-field recurrence is feasible. To achieve both favorable LTC and a decreased complication rate, peripheral dose should be less than 16 Gy; however, the optimal dose should be further defined. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Sacko O, Sesay M, Roux FE et al.   Intracranial meningioma surgery in the ninth decade of life. Neurosurgery . 2007; 61( 5): 950- 954; discussion 955. Google Scholar CrossRef Search ADS PubMed  2. Elia-Pasquet S, Provost D, Jaffré A et al.   Incidence of central nervous system tumors in Gironde, France. Neuroepidemiology . 2004; 23( 3): 110- 117. Google Scholar CrossRef Search ADS PubMed  3. Cahill KS, Claus EB. 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Kondziolka D, Levy EI, Niranjan A, Flickinger JC, Lunsford LD. Long-term outcomes after meningioma radiosurgery: physician and patient perspectives. J Neurosurg . 1999; 91( 1): 44- 50. Google Scholar CrossRef Search ADS PubMed  16. Singh VP, Kansai S, Vaishya S, Julka PK, Mehta VS. Early complications following gamma knife radiosurgery for intracranial meningiomas. J Neurosurg . 2000; 93( suppl 3): 57- 61. Google Scholar PubMed  17. Shin M, Kurita H, Sasaki T et al.   Analysis of treatment outcome after stereotactic radiosurgery for cavernous sinus meningiomas. J Neurosurg . 2001; 95( 3): 435- 439. Google Scholar CrossRef Search ADS PubMed  18. Kollová A, Liscák R, Novotný J, Vladyka V, Simonová G, Janousková L. Gamma Knife surgery for benign meningioma. J Neurosurg . 2007; 107( 2): 325- 336. Google Scholar CrossRef Search ADS PubMed  19. Iwai Y, Yamanaka K, Ikeda H. Gamma Knife radiosurgery for skull base meningioma: long-term results of low-dose treatment. J Neurosurg . 2008; 109( 5): 804- 810. Google Scholar CrossRef Search ADS PubMed  20. Patil CG, Hoang S, Borchers DJ et al.   Predictors of peritumoral edema after stereotactic radiosurgery of supratentorial meningiomas. Neurosurgery . 2008; 63( 3): 435- 440; discussion 440-432. Google Scholar CrossRef Search ADS PubMed  21. Hasegawa T, Kida Y, Yoshimoto M, Iizuka H, Ishii D, Yoshida K. Gamma knife surgery for convexity, parasagittal, and falcine meningiomas. J Neurosurg . 2011; 114( 5): 1392- 1398. Google Scholar CrossRef Search ADS PubMed  22. Pollock BE, Stafford SL, Link MJ, Brown PD, Garces YI, Foote RL. Single-fraction radiosurgery of benign intracranial meningiomas. Neurosurgery . 2012; 71( 3): 604- 612; discussion 613. Google Scholar CrossRef Search ADS PubMed  23. Perry A, Stafford SL, Scheithauer BW, Suman VJ, Lohse CM. The prognostic significance of MIB-1, p53, and DNA flow cytometry in completely resected primary meningiomas. Cancer . 1998; 82( 11): 2262- 2269. Google Scholar CrossRef Search ADS PubMed  24. Sheehan JP, Lee CC, Xu Z, Przybylowski CJ, Melmer PD, Schlesinger D. Edema following Gamma Knife radiosurgery for parasagittal and parafalcine meningiomas. J Neurosurg . 2015; 123( 5): 1287- 1293. Google Scholar CrossRef Search ADS PubMed  25. Koga T, Shin M, Saito N. Treatment with high marginal dose is mandatory to achieve long-term control of skull base chordomas and chondrosarcomas by means of stereotactic radiosurgery. J Neurooncol . 2010; 98( 2): 233- 238. Google Scholar CrossRef Search ADS PubMed  26. Maruyama K, Kawahara N, Shin M et al.   The risk of hemorrhage after radiosurgery for cerebral arteriovenous malformations. N Engl J Med . 2005; 352( 2): 146- 153. Google Scholar CrossRef Search ADS PubMed  27. Shin M, Kawahara N, Maruyama K, Tago M, Ueki K, Kirino T. Risk of hemorrhage from an arteriovenous malformation confirmed to have been obliterated on angiography after stereotactic radiosurgery. J Neurosurg . 2005; 102( 5): 842- 846. Google Scholar CrossRef Search ADS PubMed  28. Kano H, Sheehan J, Sneed PK et al.   Skull base chondrosarcoma radiosurgery: report of the North American Gamma Knife Consortium. J Neurosurg . 2015; 123( 5): 1268- 1275. Google Scholar CrossRef Search ADS PubMed  29. van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJ, van Gijn J. Interobserver agreement for the assessment of handicap in stroke patients. Stroke . 1988; 19( 5): 604- 607. Google Scholar CrossRef Search ADS PubMed  30. Starke RM, Williams BJ, Hiles C, Nguyen JH, Elsharkawy MY, Sheehan JP. Gamma knife surgery for skull base meningiomas. J Neurosurg . 2012; 116( 3): 588- 597. Google Scholar CrossRef Search ADS PubMed  31. Santacroce A, Walier M, Régis J et al.   Long-term tumor control of benign intracranial meningiomas after radiosurgery in a series of 4565 patients. Neurosurgery . 2012; 70( 1): 32- 39; discussion 39. Google Scholar CrossRef Search ADS PubMed  32. Soldà F, Wharram B, De Ieso PB, Bonner J, Ashley S, Brada M. Long-term efficacy of fractionated radiotherapy for benign meningiomas. Radiother Oncol . 2013; 109( 2): 330- 334. Google Scholar CrossRef Search ADS PubMed  33. Rohringer M, Sutherland GR, Louw DF, Sima AA. Incidence and clinicopathological features of meningioma. J Neurosurg . 1989; 71( 5 pt 1): 665- 672. Google Scholar CrossRef Search ADS PubMed  34. Jellinger K, Slowik F. Histological subtypes and prognostic problems in meningiomas. J Neurol . 1975; 208( 4): 279- 298. Google Scholar CrossRef Search ADS PubMed  35. McGovern SL, Aldape KD, Munsell MF, Mahajan A, DeMonte F, Woo SY. A comparison of World Health Organization tumor grades at recurrence in patients with non-skull base and skull base meningiomas. J Neurosurg . 2010; 112( 5): 925- 933. Google Scholar CrossRef Search ADS PubMed  36. Al-Mefty O, Kadri PA, Pravdenkova S, Sawyer JR, Stangeby C, Husain M. Malignant progression in meningioma: documentation of a series and analysis of cytogenetic findings. J Neurosurg . 2004; 101( 2): 210- 218. Google Scholar CrossRef Search ADS PubMed  37. Adegbite AB, Khan MI, Paine KW, Tan LK. The recurrence of intracranial meningiomas after surgical treatment. J Neurosurg . 1983; 58( 1): 51- 56. Google Scholar CrossRef Search ADS PubMed  38. Chang JH, Chang JW, Choi JY, Park YG, Chung SS. Complications after gamma knife radiosurgery for benign meningiomas. J Neurol Neurosurg Psychiatry . 2003; 74( 2): 226- 230. Google Scholar CrossRef Search ADS PubMed  39. Kuhn EN, Taksler GB, Dayton O et al.   Is there a tumor volume threshold for postradiosurgical symptoms? A single-institution analysis. Neurosurgery . 2014; 75( 5): 536- 545; discussion 544-535; quiz 545. Google Scholar CrossRef Search ADS PubMed  40. Lee JY, Niranjan A, McInerney J, Kondziolka D, Flickinger JC, Lunsford LD. Stereotactic radiosurgery providing long-term tumor control of cavernous sinus meningiomas. J Neurosurg . 2002; 97( 1): 65- 72. Google Scholar CrossRef Search ADS PubMed  41. Park SH, Kano H, Niranjan A, Flickinger JC, Lunsford LD. Stereotactic radiosurgery for cerebellopontine angle meningiomas. J Neurosurg . 2014; 120( 3): 708- 715. Google Scholar CrossRef Search ADS PubMed  42. Leber KA, Berglöff J, Pendl G. Dose-response tolerance of the visual pathways and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neurosurg . 1998; 88( 1): 43- 50. Google Scholar CrossRef Search ADS PubMed  43. Fokas E, Henzel M, Surber G, Hamm K, Engenhart-Cabillic R. Stereotactic radiation therapy for benign meningioma: long-term outcome in 318 patients. Int J Radiat Oncol Biol Phys . 2014; 89( 3): 569- 575. Google Scholar CrossRef Search ADS PubMed  44. Fokas E, Henzel M, Surber G, Hamm K, Engenhart-Cabillic R. Stereotactic radiotherapy of benign meningioma in the elderly: clinical outcome and toxicity in 121 patients. Radiother Oncol . 2014; 111( 3): 457- 462. Google Scholar CrossRef Search ADS PubMed  45. Starke R, Kano H, Ding D et al.   Stereotactic radiosurgery of petroclival meningiomas: a multicenter study. J Neurooncol . 2014; 119( 1): 169- 176. Google Scholar CrossRef Search ADS PubMed  COMMENT The population of elderly patients is growing worldwide. This trend is rapidly advancing especially in Japan and other European and Asian countries. Thus, geriatric neurosurgical care is very important for health care in these countries. As the authors of this article describe, the management of meningiomas, which are very common in the elderly population, is important for these patients to maintain a high level of daily activity. This article provides good evidence to support the usefulness and validity of single-fraction radiosurgery to manage meningiomas in this population. The authors clarify that age itself did not affect the control rate or risk of adverse events, specifically malignant transformation after radiosurgery, which has been a somewhat controversial issue. They also show that the parasagittal/falcine location and previous surgery are risk factors for poor control. We often encounter large meningiomas and other tumors at parasagittal or falcine locations that present with progressive neurological deficits and require surgical excision. Further studies are necessary to determine the best mode of treatment for such lesions by comparing fractionated and single-fraction radiosurgery, or other modes of treatment, to control such lesions. Akio Morita Tokyo, Japan Copyright © 2017 by the Congress of Neurological Surgeons http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Operative Neurosurgery Oxford University Press

Single-Fractionated Stereotactic Radiosurgery for Intracranial Meningioma in Elderly Patients: 25-Year Experience at a Single Institution

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Copyright © 2017 by the Congress of Neurological Surgeons
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2332-4252
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Abstract

Abstract BACKGROUND Stereotactic radiosurgery (SRS) has been accepted as a therapeutic option for intracranial meningiomas; however, the detailed data on outcomes in elderly patients remain unclear. OBJECTIVE To delineate the efficacy of SRS for meningiomas in elderly patients. METHODS The outcomes of 67 patients aged ≥65 yr who underwent SRS for benign intracranial meningioma (World Health Organization grade I) between 1990 and 2014 at our institution were retrospectively analyzed. The median age was 71 yr (range, 65-83 yr), and the mean and median follow-up were 62 and 52 mo (range, 7-195 mo), respectively. Tumor margins were irradiated with a median dose of 16 Gy, and the median tumor volume was 4.9 cm3 (range, 0.7-22.9 cm3). RESULTS Actuarial local tumor control rates at 3, 5, and 10 yr after SRS were 92%, 86%, and 72%, respectively. Previous surgery and parasagittal/falcine location were statistically significant predictive factors for failed tumor control. Mild or moderate adverse events were noted in 9 patients. No severe adverse event was observed. A higher margin dose was significantly associated with adverse events by univariate analysis. CONCLUSION SRS is one of the standard therapies for meningiomas in elderly patients, providing both favorable tumor control and a low risk of adverse events under minimum invasiveness. Intracranial meningioma, Stereotactic radiosurgery, Elderly population ABBREVIATIONS ABBREVIATIONS CT computed tomography DFS disease-free survival GKRS gamma knife radiosurgery LTC local tumor control MRI magnetic resonance imaging SRS stereotactic radiosurgery Currently, we are facing a worldwide trend of an aging society. In the early 1980s, the average life expectancy of the global population was approximately 62 yr. Today, it is estimated to be 71 yr, based on a World Health Organization (WHO) report from 2013. The investigators who authored Profiles of Ageing by the United Nations predict that this number will be over 77 yr in about 30 yr. Meningiomas are the most common benign intracranial tumors, and their incidence increases with age.1,2 Considering the aging of the global population, one would easily expect that the number of elderly patients who require treatment for meningiomas is increasing. Surgery is the standard treatment3,4; however, it is not always ideal for elderly patients for a variety of reasons, including multiple comorbidities, decreased organ function, etc. It is widely accepted that elderly patients tend toward higher surgery-associated mortality and complication rates than younger patients; the 1-yr mortality rate after surgery among the elderly population is estimated as 7% to 16%.1,5-7 Thus, radiotherapies play more and more important roles in elderly patients. Among the radiotherapies, stereotactic radiosurgery (SRS) is minimally invasive and is open to elderly patients.8-11 Its efficacy for meningiomas in adult patients has been gradually elucidated since the 1990s.12-22 Nevertheless, to our knowledge, the detailed outcomes in elderly patients have not been determined yet. The goal of this study is to determine the efficacy of SRS in elderly patients by directly analyzing the outcomes of this special subpopulation in detail. METHODS Patient Selection We retrospectively reviewed 374 consecutive treatment records for 297 patients who suffered from intracranial meningioma treated with SRS between 1990 and 2014 at our institution. The following cases were excluded from this study: WHO grade II/III meningiomas or meningiomas with histologically confirmed brain invasion,23 neurofibromatosis type II-related meningiomas, follow-up periods of less than 6 mo without a significant clinical indication, multiple meningiomas arising separately at the initial SRS, and radiation-induced meningiomas. We defined the beginning of elderly as the chronological age of 65 yr. Therefore, 67 patients at a median age of 71 yr (range, 65-83 yr) were included in the study. Written informed consent was obtained from all patients according to the ethical principles for medical research involving human subjects as defined by the World Medical Association-Helsinki Declaration. The review board of our institute approved the study protocol. Decisions about each patient's treatment were meticulously made during a neurosurgical conference among radiation oncologists. Basically, incidentally revealed asymptomatic tumors were first observed and followed by serial imaging studies. Tumors increasing in size, symptomatic tumors, and postoperative residual tumors were considered candidates for treatment. The mean and median follow-up were 62.1 and 52.0 mo (range, 7-195 mo), respectively. Among them, 29 patients (43.3%) were followed for ≥5 yr, and 11 patients (16.4%) were followed for ≥10 yr. A meningioma diagnosis was made by histopathological analysis (n = 28) or by clinical course combined with computed tomography (CT) and magnetic resonance imaging (MRI) analysis (n = 39). Detailed tumor locations are shown in Table 1. Tumors located in the falcine and the parasagittal regions were considered as inhabiting 1 location, because tumors in these 2 regions are sometimes difficult to distinguish, and because numerous prior studies have revealed unique characteristics of these 2 groups.20,21,24 Significant comorbidities were defined as coexistence of diseases that might lead to a hesitation in aggressive surgery or general anesthesia: cardiac ischemia and arrhythmias (n = 6), diabetes mellitus (n = 6), decreased renal function (n = 2), systemic autoimmune diseases (n = 2), chronic liver disease (n = 1), and bronchial asthma (n = 1). Basic characteristics of the patients are summarized in Table 2. TABLE 1. Locations of Treated Meningioma Locationa  No. (%)  Nonskull base  21 (31)   Convexity  12 (18)    Frontal  6 (9)    Temporal  1 (1)    Parietal  3 (4)    Occipital  2 (3)   Parasagittal region  4 (6)   Falcine region  4 (6)   Intraventricle  1 (1)  Skull base  46 (69)   Anterior fossa  2 (3)   Orbit  1 (1)   Cavernous sinus  12 (18)   Sphenoid ridge  1 (1)   Tentorial region  4 (6)   Petroclival region  10 (15)   Cerebellopontine angle  13 (19)   Cerebellar region  2 (3)   Jugular foramen  1 (1)  Total  67 (100)  Locationa  No. (%)  Nonskull base  21 (31)   Convexity  12 (18)    Frontal  6 (9)    Temporal  1 (1)    Parietal  3 (4)    Occipital  2 (3)   Parasagittal region  4 (6)   Falcine region  4 (6)   Intraventricle  1 (1)  Skull base  46 (69)   Anterior fossa  2 (3)   Orbit  1 (1)   Cavernous sinus  12 (18)   Sphenoid ridge  1 (1)   Tentorial region  4 (6)   Petroclival region  10 (15)   Cerebellopontine angle  13 (19)   Cerebellar region  2 (3)   Jugular foramen  1 (1)  Total  67 (100)  aTumor location was determined by the location of its main mass if the tumor spreads over more than 1 anatomic location. View Large TABLE 2. Baseline Characteristics of the Patients Variables  Value (median)  Median age (range), years  71 (65-83)  Male, no. (%)  20 (30)  History of significant comorbidities, no. (%)  13 (19)  History of previous surgery, no. (%)  28 (42)  Median tumor volume (range), cm3  4.9 (0.7-22.9)  Median V12 volume (range), cm3  12.1 (1.01-31.96)  Median maximum diameter (range), mm  26 (12-52)  Median margin dose (range), Gy  16 (12-18)  Median follow-up periods (range), months  52 (7-195)  Variables  Value (median)  Median age (range), years  71 (65-83)  Male, no. (%)  20 (30)  History of significant comorbidities, no. (%)  13 (19)  History of previous surgery, no. (%)  28 (42)  Median tumor volume (range), cm3  4.9 (0.7-22.9)  Median V12 volume (range), cm3  12.1 (1.01-31.96)  Median maximum diameter (range), mm  26 (12-52)  Median margin dose (range), Gy  16 (12-18)  Median follow-up periods (range), months  52 (7-195)  View Large Radiosurgical Techniques The radiosurgical treatment was performed using Leksell Gamma Knife (Elekta Instruments, Inc, Stockholm, Sweden). The techniques used in the present study were previously reported.25-27 Briefly, after head fixation using a Leksell frame (Elekta Instruments, Inc., Stockholm, Sweden), stereotactic imaging (CT before July 1996, MRI thereafter) was performed to obtain precise data on the shape, volume, and 3D coordinates of the tumors. Dedicated neurosurgeons and radiation oncologists used commercially available software to plan treatments (KULA planning system until 1998, Leksell Gamma Plan thereafter; Elekta Instruments, Inc., Stockholm, Sweden). Because we did not usually set a margin for setup uncertainty, the target volume was simply the same as the tumor volume defined by imaging studies. Volume irradiated with ≥12 Gy, known as V12, was retrospectively calculated in each patient using Leksell Gamma Plan. In the present cohort, V12 was calculable in 57 patients. The dosimetry data are summarized in Table 2. Follow-up, Definition of Tumor Progression, and Adverse Events After SRS, patients were evaluated at regular intervals by the attending physicians at our institution or its associated hospitals. MRIs were obtained at 6-mo intervals for the first 3 yr and annually thereafter. A tumor was considered progressive if the diameter increased in size by a minimum of 2 mm in any direction, and was considered controlled otherwise.22 Tumor progression was further classified into 3 groups: intrafield tumor progression, which was defined as tumor regrowth within the target volume; marginal tumor progression, which was defined as tumor regrowth adjacent to the target volume but within the 20% isodose volume; and remote tumor progression, which was defined as tumor growth beyond the 20% isodose volume (Figure 1).28 FIGURE 1. View largeDownload slide A schematic drawing of the types of tumor progression. FIGURE 1. View largeDownload slide A schematic drawing of the types of tumor progression. The patient's functional status was fully recorded at each clinical visit, and the mRS was assigned based on this data; functional outcomes were classified as dependent (mRS 3-5) or independent (mRS 0-2).29 Adverse events were prospectively recorded at each visit, and the severity were assessed using the National Cancer Institute's Common Terminology Criteria for Adverse Events v4.0. Neurological deterioration due to tumor progression was not considered an adverse event. To assess the true risk of deterioration of disability or dependence in the daily activities after SRS, the risk of deteriorated mRS was evaluated. Failure was defined as deterioration of mRS related to tumor progression, additional treatment, or radiation side effects; deterioration of mRS due to events unrelated to meningiomas, including senility and other coexisting diseases, was not included in the failure. Statistical Analysis Kaplan–Meier curves to determine local tumor control (LTC), disease-free survival (DFS), and risk of deterioration in mRS were plotted using the following: the dates of gamma knife radiosurgery (GKRS), clinical and radiographical follow-up, and the state of tumor progression. Tumor-related death, intrafield progression, and marginal progression were considered failed LTC. DFS was defined as survival without tumor progression. Factors potentially affecting LTC and DFS were evaluated using log-rank test for univariate analysis and Cox proportional hazard model for multivariate analysis. Factors potentially affecting adverse events were evaluated by logistic regression analysis. A history of previous surgery, significant comorbidities, biological sex, and tumor locations were used as categorical variables; age, tumor volume, maximum diameter, and radiosurgical dose were used as continuous variables or binary variables in a dichotomous manner using the median values. All analyses were performed using JMP Pro 11 software (SAS Institute Inc, North Carolina). RESULTS Tumor Control Six intrafield, 7 marginal, and 3 remote progressions were observed in 11 patients after a median interval of 59 mo (range, 19-190 mo; Table 3) from initial GKRS; thus, LTC was achieved in 81% of the patients at the time of analysis. Actuarial LTC rates were 92%, 86%, and 72% at 3, 5, and 10 yr after GKRS, respectively. In 2 patients with intrafield progressions, after certain periods of tumor control, the tumors showed rapid growth. They underwent surgical resection, which disclosed anaplastic progression of the histology (cases 2 and 9 in Table 3). TABLE 3. Detailed Data of the Patients Showing Tumor Progression After SRS       Interval from first  Current tumor status,  WHO  Last visit  Final    Max diameter  Vol  Margin  No  Age, sex  Progression  GKRS (month)  additional treatment  gra  (month)  mRS  Location  (mm)  (cm3)  dose (Gy)  1  67, M  ITP  148  Observed due to senility    151  2b  Cavernous  29  6.7  14  2  75, F  ITP  19  Anaplastic meningioma was confirmed and controlled after additional salvage surgery + adjuvant EBRT  III  52  2c  Orbit  23  4.8  16  3  75, F  ITP  37  Controlled after surgical resection  I  38  2b  Parasagittal  31  10.1  16  4  81, M  ITP  23  Observed due to senility    30  5d  Parasagittal  21  8.6  16  5  66, M  MTP  106  Controlled after 2nd GKRS    169  2b  Petroclival  25  3.7  18  6  69, M  MTP  59  Controlled after 2nd GKRS    84  0  CP angle  12  0.7  16  7  65, F  MTP  95  Controlled after 2nd GKRS    122  0  Cavernous  28  3.7  16  8  72, M  MTP + MTP + MTP  23, 47, 57  Controlled after additional 3 sessions of GKRS for repeated MTP    61  1b  Occipital convexity  12  1.6  16  9  66, F  MTP + ITP + ITP  35, 60, 77  Active tumor after additional 2 sessions of GKRS, and anaplastic meningioma was confirmed after salvage surgery  III  109  5d  Parasagittal  40  12.7  12  10  67, F  RTP  92  Observed due to asymptomatic tumor    141  1b  Falcine  29  12.9  16  11  69, F  RTP + RTP  87, 190  Controlled after additional GKRS    201  1b  CP angle  20  3.2  16        Interval from first  Current tumor status,  WHO  Last visit  Final    Max diameter  Vol  Margin  No  Age, sex  Progression  GKRS (month)  additional treatment  gra  (month)  mRS  Location  (mm)  (cm3)  dose (Gy)  1  67, M  ITP  148  Observed due to senility    151  2b  Cavernous  29  6.7  14  2  75, F  ITP  19  Anaplastic meningioma was confirmed and controlled after additional salvage surgery + adjuvant EBRT  III  52  2c  Orbit  23  4.8  16  3  75, F  ITP  37  Controlled after surgical resection  I  38  2b  Parasagittal  31  10.1  16  4  81, M  ITP  23  Observed due to senility    30  5d  Parasagittal  21  8.6  16  5  66, M  MTP  106  Controlled after 2nd GKRS    169  2b  Petroclival  25  3.7  18  6  69, M  MTP  59  Controlled after 2nd GKRS    84  0  CP angle  12  0.7  16  7  65, F  MTP  95  Controlled after 2nd GKRS    122  0  Cavernous  28  3.7  16  8  72, M  MTP + MTP + MTP  23, 47, 57  Controlled after additional 3 sessions of GKRS for repeated MTP    61  1b  Occipital convexity  12  1.6  16  9  66, F  MTP + ITP + ITP  35, 60, 77  Active tumor after additional 2 sessions of GKRS, and anaplastic meningioma was confirmed after salvage surgery  III  109  5d  Parasagittal  40  12.7  12  10  67, F  RTP  92  Observed due to asymptomatic tumor    141  1b  Falcine  29  12.9  16  11  69, F  RTP + RTP  87, 190  Controlled after additional GKRS    201  1b  CP angle  20  3.2  16  CP: cerebellopontine, EBRT: external beam radiation therapy, SRS: stereotactic radiosurgery, ITP: intra-field tumor progression, mRS: modified Rankin Scale, MTP: marginal tumor progression, RTP: remote tumor progression aWHO grade confirmed by salvage surgery after progression bdue to senility cdue to senility and disturbed visual acuity after the initial surgery ddue to progressive tumor View Large History of previous surgery and falcine/parasagittal tumor location were significantly associated with failed LTC as determined by multivariate analysis, though the latter did not quite achieve statistical significance via univariate analysis (Figure 2; Table 4). Falcine/parasagittal tumor location was also a significant negative predictive factor for DFS, as determined by both univariate and multivariate analyses. We did not identify any significant association between age and tumor control (Table 4). FIGURE 2. View largeDownload slide The Kaplan–Meyer curves for actuarial rates of LTC, DFS, and risk of deterioration of mRS are shown A. History of previous surgery and falcine/parasagittal locations were significantly associated with failed LTC B and C, whereas the latter was also a significant risk factor for DFS D and E. LTC = local tumor control, DFS = disease-free survival, mRS = modified Rankin Scale. FIGURE 2. View largeDownload slide The Kaplan–Meyer curves for actuarial rates of LTC, DFS, and risk of deterioration of mRS are shown A. History of previous surgery and falcine/parasagittal locations were significantly associated with failed LTC B and C, whereas the latter was also a significant risk factor for DFS D and E. LTC = local tumor control, DFS = disease-free survival, mRS = modified Rankin Scale. TABLE 4. The Result of Univariate and Multivariate Analysis for LTC and DFS Analysis for LTC  Univariate analysis  Multivariate analysis  Factors  P value  Factors  P value  HR (95% CI)  Age > 71  .59  Age  .38  1.1 (0.90-1.3)  Falcine/parasagittal location  .036*  Falcine/parasagittal location  .14  3.9 (0.6-23)  Male sex  .23  Male sex  .70  1.4 (0.27-6.6)  Maximum diameter > 25 mm  .75  Maximum diameter  NT  NT  Planned tumor volume > 5 cm3  .79  Planned tumor volume  .87  0.87 (0.69-1.1)  Margin dose > 16 Gy  .17  Margin dose  .18  0.71 (0.43-1.2)  History of surgery  .0047*  History of surgery  .013*  11 (1.6-220)  Analysis for LTC  Univariate analysis  Multivariate analysis  Factors  P value  Factors  P value  HR (95% CI)  Age > 71  .59  Age  .38  1.1 (0.90-1.3)  Falcine/parasagittal location  .036*  Falcine/parasagittal location  .14  3.9 (0.6-23)  Male sex  .23  Male sex  .70  1.4 (0.27-6.6)  Maximum diameter > 25 mm  .75  Maximum diameter  NT  NT  Planned tumor volume > 5 cm3  .79  Planned tumor volume  .87  0.87 (0.69-1.1)  Margin dose > 16 Gy  .17  Margin dose  .18  0.71 (0.43-1.2)  History of surgery  .0047*  History of surgery  .013*  11 (1.6-220)  Analysis for DFS  Univariate analysis  Multivariate analysis  Factors  P value  Factors  P value  HR (95% CI)  Age > 71  .84  Age  .66  1.0 (0.88-1.2)  Falcine/parasagittal location  .0060*  Falcine/parasagittal location  .029*  5.7 (1.2-28)  Male sex  .72  Male sex  .89  0.90 (0.19-3.8)  Maximum diameter > 25 mm  .74  Maximum diameter  NT  NT  Planned tumor volume > 5 cm3  .71  Planned tumor volume  .35  0.92 (0.75-1.1)  Margin dose >16 Gy  .059  Margin dose  .18  0.75 (0.48-1.1)  History of surgery  .060  History of surgery  .14  2.9 (0.70-15)  Analysis for DFS  Univariate analysis  Multivariate analysis  Factors  P value  Factors  P value  HR (95% CI)  Age > 71  .84  Age  .66  1.0 (0.88-1.2)  Falcine/parasagittal location  .0060*  Falcine/parasagittal location  .029*  5.7 (1.2-28)  Male sex  .72  Male sex  .89  0.90 (0.19-3.8)  Maximum diameter > 25 mm  .74  Maximum diameter  NT  NT  Planned tumor volume > 5 cm3  .71  Planned tumor volume  .35  0.92 (0.75-1.1)  Margin dose >16 Gy  .059  Margin dose  .18  0.75 (0.48-1.1)  History of surgery  .060  History of surgery  .14  2.9 (0.70-15)  CI: confident interval; DFS: disease-free survival; HR: hazard ratio; LTC: local tumor control; NT: not tested. *P value < .05 is considered significant. View Large Additional Treatments Ten sessions of GKRS were performed for recurrent tumors (Table 3). Among them, 9 tumors (90%), including 7 marginal and 2 remote progressions, were controlled successfully. One intrafield progression tumor (patient number 9) again showed intrafield progression at 17 mo, which was subsequently confirmed as anaplastic meningioma after salvage surgery (Figure 3). Salvage surgery was performed in 3 cases with intrafield progression. FIGURE 3. View largeDownload slide A detailed case report of patient no. 9 was shown. This patient was first referred to us because of progressive recurrence 5 yr after the first near-total resection of the parasagittal meningioma. During the second surgery at our institution, a small portion of the tumor could not be resected due to its location adjacent to the intact superior sagittal sinus, and was subsequently treated with SRS A. Three years after SRS, a follow-up MRI showed marginal progression at the falcine region B, which was then treated with a secondary SRS C. Two years after the secondary SRS, intrafield progression of the initially treated tumor was observed D. This was treated with a third SRS E. The initial tumor again regrew 17 mo after the third SRS F, and a histopathological diagnosis of anaplastic meningioma (World Health Organization grade III) was confirmed at surgical resection. Finally, the patient's family chose to decline further intervention, and she was referred to an extended care hospital. FIGURE 3. View largeDownload slide A detailed case report of patient no. 9 was shown. This patient was first referred to us because of progressive recurrence 5 yr after the first near-total resection of the parasagittal meningioma. During the second surgery at our institution, a small portion of the tumor could not be resected due to its location adjacent to the intact superior sagittal sinus, and was subsequently treated with SRS A. Three years after SRS, a follow-up MRI showed marginal progression at the falcine region B, which was then treated with a secondary SRS C. Two years after the secondary SRS, intrafield progression of the initially treated tumor was observed D. This was treated with a third SRS E. The initial tumor again regrew 17 mo after the third SRS F, and a histopathological diagnosis of anaplastic meningioma (World Health Organization grade III) was confirmed at surgical resection. Finally, the patient's family chose to decline further intervention, and she was referred to an extended care hospital. Adverse Events and Post-Treatment Edema Ten patients (15%) developed peritumoral edema at 4 to 15 mo (median 7 mo) after GKRS. Only 3 (4%) of them were symptomatic, with 1 patient presenting with mild hemiparesis, 1 with mild sensory disturbance, and 1 with new onset seizures. No significant association was found between post-treatment edema and the following factors: age, tumor volume, maximum diameter, tumor location (falcine/parasagittal vs the other), margin dose, and previous surgical history (Table 5). TABLE 5. Potential Risk Factors for Peritumoral Edema and Symptomatic AEs   Peritumoral edema  Symptomatic AEs    P value  P value  Factors  Univariate analysis  Multivariate analysis  Univariate analysis  Multivariate analysis  Age  .87  .84  .12  .16  Parasagittal/falcine locations  .41  .31  .95  .85  Male sex  .47  .99  .60  .40  Maximum diameter  .82  NT  .79  NT  Planned tumor volume  .56  NT  .84  .32  V12 volume  .25  .39  .97  NT  Margin dose  .66  .60  .042*  .055  History of surgery  .43  .21  .20  .18    Peritumoral edema  Symptomatic AEs    P value  P value  Factors  Univariate analysis  Multivariate analysis  Univariate analysis  Multivariate analysis  Age  .87  .84  .12  .16  Parasagittal/falcine locations  .41  .31  .95  .85  Male sex  .47  .99  .60  .40  Maximum diameter  .82  NT  .79  NT  Planned tumor volume  .56  NT  .84  .32  V12 volume  .25  .39  .97  NT  Margin dose  .66  .60  .042*  .055  History of surgery  .43  .21  .20  .18  AE: adverse event; NT: not tested. *P value < .05 is considered significant. View Large After GKRS, 9 patients (13%) developed Common Terminology Criteria for Adverse Events grade 1 to 2 adverse events (Table 6). The median interval between the onset of adverse events and GKRS was 9 mo (range, 3-30 mo). These adverse events were basically managed with oral corticosteroids. A higher margin dose was a significant risk factor by univariate analysis (P = .042), whereas no factor was significant by multivariate analysis (Table 5). We did not observe any acute complications, including dizziness, headache, memory impairment, or alopecia. TABLE 6. Summary of AEs After SRS Age,  Interval from first    CTCAE  Final    Max diameter  Vol  Margin dose  sex  GKRS (month)  Symptoms of AEs  grade  mRS  Location  (mm)  (cm3)  (Gy)  66, M  12  Mild unilateral motor weakness  2  3  Petroclival  25  3.7  18  68, M  14  Slight weakness in lower extremity  1  2  Falx  44  8.9  16  65, F  5  Sensory disturbance  1  1  Frontal  18  1.5  18  65, F  3  Sensory disturbance  1  1  JF  30  11.9  18  65, F  4  Trigeminal neuralgia  2  1  Petroclival  25  2.8  18  69, F  6  Trigeminal neuralgia  2  1  Petroclival  15  1.2  16  68, F  23  Sensory disturbance  1  1  Tentorial  31  14.9  14  78, F  30  Trigeminal neuralgia  2  1  Tentorial  17  2.9  16  83, F  5  Generalized seizure  2  1  Frontal  29  13.3  14  Age,  Interval from first    CTCAE  Final    Max diameter  Vol  Margin dose  sex  GKRS (month)  Symptoms of AEs  grade  mRS  Location  (mm)  (cm3)  (Gy)  66, M  12  Mild unilateral motor weakness  2  3  Petroclival  25  3.7  18  68, M  14  Slight weakness in lower extremity  1  2  Falx  44  8.9  16  65, F  5  Sensory disturbance  1  1  Frontal  18  1.5  18  65, F  3  Sensory disturbance  1  1  JF  30  11.9  18  65, F  4  Trigeminal neuralgia  2  1  Petroclival  25  2.8  18  69, F  6  Trigeminal neuralgia  2  1  Petroclival  15  1.2  16  68, F  23  Sensory disturbance  1  1  Tentorial  31  14.9  14  78, F  30  Trigeminal neuralgia  2  1  Tentorial  17  2.9  16  83, F  5  Generalized seizure  2  1  Frontal  29  13.3  14  AE: adverse event; CTCAE: Common Terminology Criteria for Adverse Events ver. 4.0; SRS: stereotactic radiosurgery; JF: jugular foramen; mRS: modified Rankin Scale. View Large Deterioration of mRS after SRS Four of 67 patients (6%) showed deterioration of mRS, 2 because of adverse events (12 and 14 mo after SRS, Table 6), 1 because of complication after additional surgical resection for tumor progression (97 mo after SRS, case 9 in Table 3), and 1 because of tumor progression itself (23 mo after SRS, case 4 in Table 3). The Kaplan–Meier analysis revealed that the actuarial risks of deterioration in mRS after SRS were 5% at 3 and 5 yr, and 13% at 10 yr (Figure 2). Two patients died of unrelated causes (1 case of massive intestinal bleeding due to ulcerative colitis and 1 case of myelodysplastic syndrome); thus, 62 (93%) patients could maintain independence at the final follow-up examination. DISCUSSION Tumor Control It is not yet well understood how increasing age affects the treatment outcomes. There were some studies that suggested increasing age was one of the risk factors for failed tumor control based on the outcomes of all-ages cohorts,22,30 whereas a previous study reported that age did not significantly affect the clinical outcomes.31 However, these studies lacked detailed and direct analysis of the actual outcomes of elderly patients, which is essential to determine the real usefulness of SRS. In the present study, we directly analyzed the outcomes of elderly patients and found that SRS is a safe and effective treatment modality, providing 86% LTC at 5 yr. Long-term tumor control is also favorable, with actuarial 10-yr LTC reaching 72%. As far as we know, this may be the first report describing detailed outcomes of SRS for meningioma in this subpopulation. We found that previous surgery and falcine/parasagittal location were associated with failed LTC. In particular, falcine/parasagittal location was also a risk factor for failed DFS. These findings were similar to those of previous reports describing meningiomas in all ages.22 One of the advantages of GKRS is its very sharp fall-off of radiosurgical dose. This advantage, however, requires an accurate definition of tumor contour. In cases of falcine/parasagittal meningiomas, it is sometimes difficult to differentiate the tumor margin from normal anatomic structures including dural tissue, the superior sagittal sinus, and cortical veins, which may lead to relatively lower tumor control rates. In theory, fractionated radiotherapy such as cyber knife could effectively cover the tumor margin, leading to better tumor control. However, a previous study revealed that even fractionated radiotherapy failed to show sufficient tumor control in falcine meningiomas.32 In our opinion, close serial follow-up should be mandatory to manage this type of failure, but it is still controversial whether we should include originally involved sinus, falx, and dural attachment in the treatment volume. Another issue that we need to emphasize herein is an association between recurrence and previous surgery. In the present study, all intrafield/marginal progression meningiomas were recurrent tumors after surgery. As with falcine/parasagittal meningiomas, postoperative scar tissues can appear enhanced on MRI, becoming indistinguishable from tumor tissue in the treatment of postoperative tumors. This may result in decrease in LTC. Additionally, recurrent meningioma is sometimes accompanied by dedifferentiation into a more aggressive histology,33 and previous articles focusing on surgical cohorts have shown that 2% to 29% of benign meningiomas transform into higher grade meningiomas at the recurrence.34-37 Therefore, there is a possibility that they might acquire a certain level of radioresistance or aggressiveness by nature. The probability of radiation-induced malignant transformation of benign meningiomas remains unclear, but Iwai and colleagues reported that approximately 6% of cases in their GKRS cohort underwent malignant transformation.19 In our cohort, the rate of anaplastic change after GKRS was 3%, which is comparable to if not better than previous studies. We believe the anaplastic progression in our cohort can be explained by the latent aggressive nature of the diseases themselves. Further studies are desirable to unveil the relationship between radiosurgery and malignant transformation. Secondary Treatment In the cases with marginal or remote progression, secondary treatment was feasible, providing favorable tumor control at a median of 27 mo (range, 4-114 mo) follow-up without adverse events. Theoretically, marginal and remote progression results from insufficient irradiation or suboptimal tumor coverage; thus, it would be reasonable to treat these tumors with additional optimal irradiation. Therefore, if the repeated radiosurgery was taken into consideration, the actual tumor control rate using “solo” radiosurgery will be better than the results of “single” radiosurgery. A similar tendency toward salvage treatment for out-of-field recurrence can be seen in a previous study.21 On the contrary, in intrafield progression cases, we have to seriously discuss the choice of additional treatments considering the time course and the pattern of recurrence, because these tumors may become radioresistant or develop into anaplastic lesions.19 We performed salvage surgery for 3 patients with intrafield progression, finding that 2 of them harbored malignant progression (Table 3). In those cases, SRS may have contributed only to delay their radical treatments. However, considering that they were recurrent cases after previous surgery, indication and the timing of initial SRS was considered reasonable. Peritumoral Edema and Neurological Complications One of the novel aspects of the current study was the analysis of the deterioration of mRS. For elderly patients, the most important thing is to pass the expected life span uneventfully, and in this respect, not only achievement of definitive tumor control but also growth retardation of the tumor for 10 yr has significant meaning. Our results revealed that deterioration of mRS was found in only 6.0% of the patients after SRS, which was estimated 13% at 10 yr and was acceptable as therapeutic outcomes considering the present patient population included more than 40% cases of failed tumor control after surgery. Some previous studies have reported that parasagittal tumor location is one of the risk factors for peritumoral edema.14,16,38 On the other hand, Kuhn et al39 found no association between parasagittal location and peritumoral edema. They concluded that parasagittal meningiomas tend to be larger in volume, leading to a higher risk of treatment-related toxicity than those in other locations. The results of the present study support Kuhn's results, although we could not reach a definitive conclusion because of the small sample size and retrospective nature of the present study. Optimal Radiosurgical Dose The optimal radiosurgical dose remains controversial, with a balance that needs to be achieved between tumor control and adverse events. Shin et al17 reported that a margin dose of 10 to 12 Gy produced a 20% recurrence rate, whereas no recurrences were observed with a margin dose of 14 Gy. Kollova et al18 found that a margin dose ≥16 Gy is a risk factor for complications. Most prior studies have adopted a median margin dose of 13 to 15 Gy.13,18,20,22,40,41 In the present study, we prescribed a relatively high radiosurgical dose (≥16 Gy) aiming to obtain definitive tumor control. We particularly aimed to control skull base lesions, as these lesions are in close proximity to key anatomic structures, and further growth often makes surgery or GKRS more challenging. However, we also found that margin dose >16 Gy was significantly associated with adverse events (P = .041) by univariate analysis, as with some previous studies.18,21,24,42 High dose irradiation can lead to undesirable complications that could affect day-to-day functions in elderly patients. Therefore, we believe that the dose ideally should be reduced to 13 to 15 Gy, though the optimal dose should be further discussed. Limitations The first limitation of our study is that our data are based on a retrospective review of patients from a single institution; thus, potential selection bias cannot be excluded. Second, the lack of an untreated control group restricts our ability to assess the full benefit of SRS. Third, because most meningiomas are slowly progressing tumors, the mean follow-up of 62.1 mo in our cohort may not exclude the possibility of underestimating tumor recurrence after 5 to 10 yr. Considering the median age in the present cohort was 71 yr and the life expectancy in most developed countries is 80 yr, the ideal follow-up would be at least 10 yr to measure the outcomes over the patient's residual life. However, our follow-up period is comparable to that of other studies regarding radiotherapy for benign meningiomas (20-70 mo).18,20-22,30,39,43-45 Additionally, some previous studies suggested that the rates of tumor control at 5 to 10 yr are nearly stable after radiotherapy for WHO grade-1 meningiomas.22,44 Although a longer follow-up is desirable, we believe that the current follow-up period is sufficient to provide reliable results. Enrolling more cases with a longer follow-up would be invaluable to further evaluate long-term efficacy and safety. CONCLUSION SRS is a safe and effective treatment modality for intracranial meningioma in the elderly population. Previous surgery and falcine/parasagittal tumor location are predictive factors for failed LTC. 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Stereotactic radiotherapy of benign meningioma in the elderly: clinical outcome and toxicity in 121 patients. Radiother Oncol . 2014; 111( 3): 457- 462. Google Scholar CrossRef Search ADS PubMed  45. Starke R, Kano H, Ding D et al.   Stereotactic radiosurgery of petroclival meningiomas: a multicenter study. J Neurooncol . 2014; 119( 1): 169- 176. Google Scholar CrossRef Search ADS PubMed  COMMENT The population of elderly patients is growing worldwide. This trend is rapidly advancing especially in Japan and other European and Asian countries. Thus, geriatric neurosurgical care is very important for health care in these countries. As the authors of this article describe, the management of meningiomas, which are very common in the elderly population, is important for these patients to maintain a high level of daily activity. This article provides good evidence to support the usefulness and validity of single-fraction radiosurgery to manage meningiomas in this population. The authors clarify that age itself did not affect the control rate or risk of adverse events, specifically malignant transformation after radiosurgery, which has been a somewhat controversial issue. They also show that the parasagittal/falcine location and previous surgery are risk factors for poor control. We often encounter large meningiomas and other tumors at parasagittal or falcine locations that present with progressive neurological deficits and require surgical excision. Further studies are necessary to determine the best mode of treatment for such lesions by comparing fractionated and single-fraction radiosurgery, or other modes of treatment, to control such lesions. Akio Morita Tokyo, Japan Copyright © 2017 by the Congress of Neurological Surgeons

Journal

Operative NeurosurgeryOxford University Press

Published: Apr 1, 2018

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