Meningioma originates from meningothelial cells of the arachnoid and is usually attached to the dura. It accounts for approximately 13%~30% of primary intracranial tumor in adults. About 20%~30% of meningioma occurs in the skull base. Most are benign and slow-growing tumors, and immediate intervention is not often needed [1,2,3]. However, if there is a clear tumor progression or any progressive or newly developed clinical symptoms, treatment is indicated. The goal of meningioma treatment is to minimize tumor progression or recurrence with low treatment-associated morbidity. Although the mainstay of meningioma treatment is surgical resection, many patients with skull base meningioma often fail to achieve complete resection without significant neurologic deficit due to the frequent involvement of cavernous sinus or cranial nerve, or close proximity to optic nerve or chiasm[4,5,6,7]. The progression rate after incomplete resection of Simpson grade III or higher has been reported to be 30% at 5 years, 60% at 10 years, and 90% at 15 years [8,9,10]. Despite the recent advances in microsurgical technique, the morbidity and mortality after surgical resection of skull base meningioma is still high [11,12,13].

Radiotherapy (RT) is safe and effective as a primary treatment for inoperable meningioma or adjuvant treatment for recurrent tumor after surgical resection [14,15]. Conventional radiotherapy has shown a 10-year tumor control rate exceeding 80% in large residual tumors or progressive growing masses [16,17]. Fractionated stereotactic RT (FSRT) was developed to reduce the high radiation dose administered to the surrounding normal brain tissue. FSRT has a similar therapeutic outcome compared to conventional RT [18,19]. For smaller tumors, stereotactic radiosurgery (SRS) such as a linear accelerator or Gamma Knife radiosurgery (GKS), has equivalent local control rates and acceptable toxicity [20,21,22,23]. However, SRS is limited in effectiveness for tumors close to the critical structures or tumors having a large volume, because of the radiosensitivity of these structures to a single large radiation dose. Multi-session or fractionated radiosurgery can be attractive and noninvasive treatment options for large residual or recurrent, inoperable skull base meningiomas. Hypofractionated radiosurgery can reduce the risk of late side effects because it allows normal tissue repair between fractions while delivering high dose per fraction [24]. In addition, reoxygenation and reassortment between fractions can improve tumor control by increasing cell kill. Colombo et al. [25] reported their experience of hypofractionated radiosurgery for meningioma patients who were unable to have single-session SRS using a Cyberknife with up to five fractionations. The authors reported a satisfactory tumor volume control rate of approximately 96.5% during the median 30-month follow-up period. However, as far as we know, there are few reports of fractionated radiosurgery for meningioma using GKS. While the Cyberknife and other linear accelerator-based systems perform multisession radiosurgery with 80% prescription isodose, the GKS Extend can give a higher maximum and cumulative radiation dose to the treatment volume using 50% isodose line [26]. We present our experience on the feasibility, neurological outcome, tumor control, and complication rate of hypofractionated GKS (FGKS) in consecutive days with the same Leksell® frame for large-sized skull base meningioma.

The goal of SRS in meningioma is local tumor control and preservation of neurological function [27]. SRS has shown satisfactory outcome with ≥90% tumor growth control rates [25,28,29]. In a long-term study of GKS with mean marginal dose of 14 Gy for 972 patients (1,045 tumors), the 10-year local control rate was 91%, 50%, and 17% in WHO grade I, II, and III, respectively [30,31]. A Mayo Clinic follow-up study of 190 patients with 206 meningiomas treated by median prescription dose 16 Gy found the 5- and 7-year survival rate of 94% and 92%. In SRS for meningioma, the effect of local control highly depends on radiation dose, and single fraction dose ≤15 Gy is less effective [32,33].

GKS is a radiosurgery usually performed in a single session. However, lesions adjacent to radiation-sensitive critical structures, such as the optic pathway, increase the risk of traditional single-session GKS. Large-sized lesions also increase the risk [34]. Currently, the concept of radiosurgery has been extended up to five fractionations. More studies on fractionation have been recently done, reflecting the interest in avoiding unwanted radiation to adjacent radio-sensitive structures while giving high-dose radiation to the target [26,35,36,37,38,39]. Fractionation is a method of delivering higher cumulative radiation dose to target while minimizing damage to normal tissues. It is hypothesized that sublethal damage is rapidly repaired in normal tissue [34,40].

Hypofractionated radiosurgery has shown similar efficacy and treatment related toxicity, as reported in single-session SRS. Studies on FGKS have include the use of 20 Gy in three to five fractions [41] and 25 Gy in five fractions [42]. Both studies usually targeted benign neoplasms adjacent to the optic pathway, and neither had visual toxicity. Despite the fact that fractionation reduces unwanted radiation to surrounding tissue, higher doses are required to achieve the same dose effect due to DNS repair and cell repopulation between fractions [43]. While the Cyberknife and other linear accelerator-based systems perform multisession radiosurgery with 80% prescription isodose, the GKS Extend system can give a higher maximum and cumulative radiation dose to the treatment volume using 50% isodose line [26]. Previous studies indicated that higher maximum dose and dose heterogeneity of target may play an important role in a highly beneficial radiobiologic pathway, especially in late-responding tissue such as benign tumors, resulting in delayed vascular response [44,45]. The dose heterogeneity of multisession GKS with 50% isodose line may be beneficial in the treatment of solid neoplasm, unlike the linear-accelerator based system, which is 80%~90% isodose line [46]. FGKS will broaden the indication of intracranial radiosurgery that can be treated with GKS.

Skull base meningiomas have a poorer outcome of single-session GKS than meningiomas located in other sites. Studies published on long-term efficacy of radiosurgery for skull base meningioma have reported tumor control rates of 89% to 98% and acceptable complication rates of 4% to 14% [47,48,49,50,51]. Our group reported a long-term outcome of single-session GKS for skull base meningioma [52]. The 5-year actuarial tumor control rate was 90.2% and unfavorable outcome of cranial neuropathy occurred in 15.9%. The improvement of cranial neuropathy was 45.1%, especially, the meningioma located at cavernous sinus showed a high improvement rate even at low marginal dose of 12 Gy.

There are several reports of FSRT for large skull base meningiomas. Debus et al. [18] reported their experiences about FSRT for 189 patients with a mean tumor volume of 52.5 cm³. The median radiation dose was 56.8 Gy and the mean follow-up duration was 35 months. The actuarial tumor control rate of WHO grade I meningiomas was 97% at 5 years and 96% at 10 years. Clinical significant treatment-induced toxicity was 1.6%. Minniti et al. [19] reported obtained similar outcomes after FSRT for 52 large skull base meningiomas. The median gross tumor volume (GTV) was 35.4 cm³, and radiotherapy was performed in 30 daily fractions over 6 weeks to a total dose of 50 Gy. During the median follow-up period of 42 months, the progression-free survival (PFS) rate was 96% and 93% at 3 and 5 years, respectively. Clinically significant late neurological toxicity was reported in 5.5% of the patients.

Bria et al. [53] reported the results of hypofractionated radiosurgery using the CyberKnife for 73 meningiomas. Local failure occurred in 11 cases, and the 1-year survival rate was 95%, 71%, and 9% in WHO grade I, II, and III, respectively. Tumor-related symptoms improved in 60% of cases. Satisfactory outcome on tumor control with similar toxicity rates compared to single-session GKS were evident in this study and previously reported studies.

Starke et al. [54] reported their single-session GKS experiences for 75 large skull base meningiomas with a mean tumor volume of 14.1 cm³. The mean follow-up duration was 6.5 years, and the actuarial PFS rate was 90.3% (3-year), 88.6% (5-year), and 77.2% (10-year). The neurological function deteriorated in 17% of the patients. To overcome the limitations of single-session GKS, few authors have tried multi-session GKS for skull base meningiomas. Iwai et al. [55] performed two-stage GKS for large petroclival and cavernous sinus meningiomas with a median prescription dose of 9 Gy per session. The mean initial tumor volume was 16.8 cm³. After median follow-up duration of 39 months, 6 patients (86%) obtained local control, and 3 had symptom improvement. Tumor progression occurred in only one person. There was no toxicity associated with treatment. There was also a study of volume-staged GKS in large skull base meningiomas with mean volume of 13.2 cm³ [56]. The tumor margin dose at stage I and II was 13.5 Gy and 9 Gy, respectively. Although only 4 patients were included in the study, after the median follow-up period of 100.5 months, all 4 patients obtained tumor control and all neurological deficits that existed before GKS were improved.

The Stanford group reviewed the outcome of fractionated SRS using the Cyberknife for large benign skull base tumors, including 21 meningiomas [39]. For 34 large benign tumors with median tumor volume of 19.3 cm³, fractionated SRS with median prescription dose of 24 Gy was performed over two to five sessions. After 31 months of median follow-up period, fractionated SRS was effective and safe, with local control rate of 100% and symptom improvement rate of 21%. About 11.7% of patients required glucocorticoids treatment due to transient neurological worsening, but there was no permanent deficit.

To our knowledge, two reports included FGKS experiences for large skull base meningioma. In the published reports, FGKS was primarily considered for the tumors difficult to surgically access or tumors expected to have high complication rates after single GKS. Large meningiomas located in convexity, falx, or parasagittal sinus were included, because of the concern about the occurrence of extensive peritumoral edema after single GKS. Tumors adjacent to eloquent area or critical organs were also candidates for FGKS. Surgically inaccessible skull base meningiomas also became indications for FGKS. McTyre et al. [57] included 15 cases of meningioma ≥10 cc, attached to the optic pathway, or had previously undergone single-session GKS. Recently, a study was published on the comparison of single-session GKS (n=42) and FGKS (n=28) for meningiomas ≥10 cm³ [58]. The FGKS group also included 16 skull base meningiomas. The mean tumor volume of single-session GKS and FGKS was 15.2 cm³ and 21 cm³, respectively. The FGKS group showed a higher overall 5-year tumor control rate than the single-session GKS group, without statistical significance (92.9% vs 88.1%, p=0.389).

In this study, the overall tumor control rate of skull base meningioma over mean follow-up duration of 38 months was 100%. Although the mean follow-up duration was relatively short, FGKS revealed considerable tumor control rates compared to single-session radiosurgery or conventional radiotherapy. Our group reported on the long-term outcome and growth rate of subtotally resected petroclival meningiomas in 2000 [59]. A total of 38 cases were followed for a mean of 47.5 months. The 5-year PFS rate was 60% and the median PFS survival time was 66 months. Based on these results, we have proposed subtotal resection with or without radiation or radiosurgery for the treatment of skull base meningioma. However, with the development of the radiosurgery technique and the increase in safety and efficacy, we experienced better results after FGKS as an initial treatment rather than surgical resection for large skull base meningioma.

Single-session GKS or FGKS overcomes tumor cell redistribution or reoxygenation of hypoxic cells within the cell cycle. Dividing a single dose into fractions reduces damage to normal tissue by restoring sublethal damage between fractions and allows cell repopulation. However, FGKS should also be performed with consideration of normal tissue embedded within radiosurgical target. The effect of dose and fractionation on normal tissue can be assessed using a linear quadratic cell survival curve model. In this model, the α/β ratio reflects the cell response to changes in the radiation fraction size. Tissues with low α/β ratio, such as normal brain, are more sensitive to larger dose fractions. Benign tumors such as meningioma have a low α/β ratio ≤3, so there is little benefit from fractionation and a single or hypofractionated regimen is preferred. Single session GKS for WHO grade I tumors has achieved a tumor control rate ≥90% using a dose of 14 Gy at 50% isodose line. In the FKGS for large skull base meningioma, we have tried a 3 or 4 fraction with a lower prescription dose, considering that the lesions are adjacent to the surrounding normal eloquent brain tissue or cranial nerve. The treatment dose given per fraction was determined to obtain the same biologically equivalent dose as in single session GKS using a BED calculation algorithm.

Symptomatic peritumoral edema has been reported on an average of 5%~10% after radiosurgery or conventional radiotherapy [31,60,61,62]. Among the 23 patients who underwent FGKS, progression of the preexisting edema or newly developed edema was found in 2 patients, but there was no symptomatic edema. In previous studies, post-radiosurgical edema or necrosis was associated with tumor volume control [63], but we did not find any correlation between them in this study.

FKGS showed satisfactory results in clinical aspects, especially in facial pain. Two patients who had trigeminal neuralgia experienced a dramatic facial pain improvement after FGKS. This is consistent with previous findings that the fractionated approach is beneficial for tumor-associated trigeminal neuralgia [64,65,66,67]. After FGKS, there was no exacerbation of pre-existing cranial neuropathy, and 5 patients experienced newly developed cranial neuropathy but all of them was transient finding and improved spontaneously. We did not experience an occurrence of permanent neurologic deficit.

Our main concern was that whether the patients could tolerate the procedure well with the fixation of stereotactic frame for 3 or 4 consecutive days. All patients tolerated the pain and headache. Another concern about the movement of target in each fraction was resolved with the use of scout images. Since the introduction of ICON™ in March 2016, more patients have received FGKS using mask immobilization comfortably without pain. Considering the similar tumor control rate to single-session GKS and the satisfactory clinical outcome, FGKS is expected to become useful in large-sized skull base lesions including meningioma.

This study has some limitations resulting from its retrospective design and heterogeneous meningioma entities. We started the FGKS relatively recently and the follow-up duration is short. This study has no control group, and the comparison of efficacy and toxicity between single and fractionated GKS due to the small size of cohort. Another drawback is that there is no information on histology and proliferation indices, because radiosurgery was the initial treatment for meningioma diagnosed by imaging only. Very little is known about the optimal dose and fractionation regimen. FGKS using mask immobilization has been growing, and optimal treatment regimen would be clarified. Despite performed using frame, this result reporting FGKS would be some help in implementing FGKS in the future. Further study about FGKS with follow-up exceeding 10 years and prospective design is necessary to identify the long-term results and radiation-toxicity.

We analyzed the clinical results of FGKS performed as an initial treatment option for large skull base meningioma. FGKS produced satisfactory tumor control with functional preservation for large skull base meningiomas. FGKS could be an alternative option for large skull base lesions such as meningiomas, while avoiding high risks or surgical resection. Further prospective studies of large cohorts with long-term follow-up are required to clarify the efficacy in the tumor control and functional outcome as well as radiation toxicity.