Fractionated stereotactic conformal radiotherapy for large benign skull base meningiomas

Purpose to assess the safety and efficacy of fractionated stereotactic radiotherapy (FSRT) for large skull base meningiomas. Methods and Materials Fifty-two patients with large skull base meningiomas aged 34-74 years (median age 56 years) were treated with FSRT between June 2004 and August 2009. All patients received FSRT for residual or progressive meningiomas more than 4 centimeters in greatest dimension. The median GTV was 35.4 cm3 (range 24.1-94.9 cm3), and the median PTV was 47.6 cm3 (range 33.5-142.7 cm3). Treatment volumes were achieved with 5-8 noncoplanar beams shaped using a micromultileaf collimator (MLC). Treatment was delivered in 30 daily fractions over 6 weeks to a total dose of 50 Gy using 6 MV photons. Outcome was assessed prospectively. Results At a median follow-up of 42 months (range 9-72 months) the 3-year and 5-year progression-free survival (PFS) rates were 96% and 93%, respectively, and survival was 100%. Three patients required further debulking surgery for progressive disease. Hypopituitarism was the most commonly reported late complication, with a new hormone pituitary deficit occurring in 10 (19%) of patients. Clinically significant late neurological toxicity was observed in 3 (5.5%) patients consisting of worsening of pre-existing cranial deficits. Conclusion FSRT as a high-precision technique of localized RT is suitable for the treatment of large skull base meningiomas. The local control is comparable to that reported following conventional external beam RT. Longer follow-up is required to assess long term efficacy and toxicity, particularly in terms of potential reduction of treatment-related late toxicity.


Introduction
The optimal management of large benign meningiomas of the skull base is challenging. Surgery remains the standard treatment and following apparently complete removal the reported control rates are in the region of 95% at 5 years and 90% at 10 years [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. However, a significant subset of meningiomas, especially large tumors involving the cavernous sinus, the petroclival region, and the brainstem cannot be completely resected for the risk of significant morbidity [1,[3][4][5][6]9]. In such patients incomplete removal of tumor with preservation of the involved cranial nerves may result in improved neurological function and temporary local control, although progression on long-term follow-up is reported in up to 80% of patients [2,8,13].
Local control following partial resection of benign meningiomas and at the time of recurrence can be improved with conventional fractionated external beam radiotherapy (RT), with a reported 10-year progressionfree survival in the region of 75-90% [15][16][17]. More recently, stereotactic radiation techniques in form of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) have been developed as accurate techniques that can deliver more localized irradiation with a steeper dose gradient between the tumor and the surrounding normal tissue, and consequently reducing the volume of normal brain irradiated to high radiation doses. Both techniques have been reported as an effective treatment in several benign skull base tumors including pituitary adenomas [18,19], acoustic neuromas [20,21], craniopharyngiomas [22,23] and meningiomas [24].
Although in many centers SRS is the preferred treatment option for patients with small to moderate recurrent or enlarging skull base meningiomas, fractionated RT is often performed for larger tumors close to critical structures because of the radiobiological advantage of dose fractionation in reducing the risk of post-radiation long-term complications. In this study, we report the experience with FSRT at our center for patients with large residual or progressive skull base meningiomas.

Patients and Methods
Between June 2004 and August 2009, fifty-two patients with benign skull base meningiomas more than 4 centimeters in greatest dimension were treated with FSRT. Characteristics of patients are shown in Table 1. There were 17 males and 35 females. Median age was 56 years, ranging from 34 to 74 years. All patients had a KPS ≥ 60. Eighteen received FSRT following surgery for a macroscopic tumor remnant and the other 34 patients had FSRT at tumor regrowth. Twenty-one patients had more than one surgical procedure. Histology confirmed the presence of a benign meningioma in all cases.
Cranial nerve deficits were present in 43 patients, mainly consisting of visual field defects in 22 and/or impaired ocular motility in 19 (Table 2). Endocrine deficits were present in 7 patients. The median time from resection to FSRT was 39 months. None of patients had received previous radiotherapy.

SCRT technique and dose prescription
The FSRT technical details and procedure using the BrainLab stereotactic mask fixation system have been previously reported [25]. The gross tumor volume (GTV) was delineated on the basis of the contrastenhancing tumor demonstrated on T1-weighted MRI fused with the simulation CT images. CTV was considered the same as GTV. The planning target volume (PTV) was generated by the geometric expansion of GTV plus 2-3 mm. For the last 18 patients the 3-D margin was reduced to 2 mm. The median GTV was 35.4 cm 3 (range 24.1-94.9 cm 3 ). The PTV was 47.6 cm 3 (range 33.5-142.7 cm 3 ). Treatment volumes were achieved with 5-8 noncoplanar beams shaped using a micromultileaf collimator (MLC). Plans were prescribed at the isocentre according to ICRU 50 criteria with PTV covered by the 95% isodose in 3-D. To assess the accuracy of relocation, the isocentre position was verified with a second CT scan performed just prior to the start of treatment. The tolerance of relocation had to be < 1.5 mm in any direction. Daily portal images acquired at 0 and 90°through the isocenter were obtained for each patient during the treatment. All patients were treated on a 6-MV LINAC with a 120 leaf MLC (Varian Clinac 600 DBX) and received a dose of 50 Gy in 30 fractions over 6 weeks.

Follow-up and data analysis
A clinical assessment of neurological status and tolerance to treatment was performed every six months. An MRI scan was performed every 6 months for the first 2 years and thereafter every 12 months. Tumor control

Tumor control and survival
Fifty-two patients with large benign skull base meningioma were treated with FSRT. At the time of analysis in December 2010, three patients had tumor progression 18, 30 and 42 months after FSRT and required surgery. After a median follow-up of 42 months (range from 12 months to 72 months), the actuarial tumor control was 96% at 3 years and 93% at 5 years, and respective survival 100% (Figure 1). Local control was similar for patients treated with FSRT as a part of their primary treatment or at the time of recurrence. MRI showed on serial imaging no changes in 37 (71%) and reduction in tumor size in 12 patients (23%), however without reaching conventional partial response criteria. Univariate analysis showed no significant tumor control between 23 meningiomas larger than 40 cm 3 and 29 meningiomas smaller than or equal to 40 cm 3 (P = 0.16) (Figure 2). Similarly, tumor location, sex, and age were not correlated with tumor control.

Neurological function
Neurological deficits were present in 43 (82%) patients. After FSRT 11 (20%) patients had a clinical improvement of neurological deficits (Table 2). Vision improved in 7 patients and cranial nerve function in 5 patients.
The optic chiasm was included in the PTV of the majority of patients (n = 36) and received the prescribed dose of 50 Gy. Three patients deteriorated without evidence of tumor progression on imaging. One patient had a slight worsening of vision and two progressive hearing loss. Seven patients had a transient mild visual deterioration (n = 4) and a worsening of pre-existing 7 th (n = 1) and 5 th (n = 2) nerve palsy during or shortly after treatment, with full recovery after a short course of corticosteroids.    [15,28,29]. Connell et al [29] reported a 5-year control of 93% for 54 patients with skull base meningiomas less than 5 centimeters in greatest dimension and 40% for tumors more than 5 centimeters, and similar findings have been reported by others [15,28]. Although a clear limitation of the study is represented by the relatively short followup, neverthless our results and data from literature suggest that FSRT is an appropriate treatment option for patients with large recurrent or enlarging skull base meningiomas with a 5-year control similar or even better than conventional RT. The external beam radiation dose for meningioma that represents the best balance of tumor control and a low complication rate has not been defined. Most of published series show no significant difference on tumor control with the use of doses ranging between 50 and 60 Gy, however a dose < 50 Gy has been associated with higher recurrence rates [15,27,33]. The present results, with a tumor control of 90% at 5 years, suggest that a dose of 50 Gy in 30 fractions may achieve a good local tumor control with acceptable toxicity in large skull base meningiomas. SRS represents an effective and safe alternative treatment option for patients with skull base meningiomas. At doses of 12-16 Gy the reported actuarial 5-year and 10-year tumor local control rates are in the range of 90-95% and 80-85%, as shown in some recent large series [46][47][48][49][50][51][52][53][54][55][56][57][58]; however, larger tumors are associated with worse long-term local control and increased toxicity [49,54,55]. DiBiase et al [49] reported a significant higher 5-year tumor control in patients with meningiomas < 10 ml than those with larger tumors (92% vs 68%, p = 0.038). In a large series of 972 patients with meningioma treated with Gamma Knife SRS using a median dose to the tumor margin of 13 Gy local control was negatively correlated with increasing volume (p = 0.01), and a similar trend was observed with disease-specific survival (p = 0.11) [54]. In a retrospective review of 116 patients treated with SRS for meningiomas > 10 cm 3 in volume at a dose of 15 Gy, Bledsoe et al [55] reported a local control of 92% at 7 years, although complications occurred in 18% of patients with skull base tumors. Interestingly, Iwai et al [53] using a median marginal dose ranging from 8 to 12 Gy showed a progression-free survival of 93% and 83% at 5 and 10 years in 108 patients with skull base meningiomas treated with Gamma Knife SRS; permanent neurological deficits occurred in 6% of patients. Although the use of radiosurgical doses less than 12 Gy may represent a promising approach in patients with large meningiomas, the reported favourable outcome needs to be confirmed in future studies. Currently, results from published series suggest that FSRT is a better treatment option in such patients based on its proven efficacy and safety.

Acute and late toxicity
Hypopituitarism was the most commonly reported late complication. A new pituitary hormone deficit requiring hormone replacement occurred in 19% of patients. Late neurological toxicity was observed in 7% of patients and consisted of worsening of pre-existing cranial deficits in 3 patients and mild neurocognitive dysfunction in one patient. A neurological improvement was observed in 19% of patients; vision remained stable in 46 patients and improved in 7 patients with visual impairment. Since the late effects of radiotherapy in terms of normal tissue damage expressed as radiation optic neuropathy occur usually within 1-5 years of treatment, the low incidence of radiation-induced optic neuropathy and others cranial nerve deficits at a median follow-up of 42 months provide some reassurance about the safety of the present dose and technique for large skull base meningiomas. The present and some other recent series on FSRT [34][35][36][37][38][39][40][41][42][43][44][45] and conformal RT [15,17] definitely contradict the historical perception of unresponsiveness of meningiomas as well as the considerably concern of high late morbidity following the radiation treatment for benign brain tumors, which was primarily based on old reports where radiation was delivered with orthovoltage machines.
We conclude that FSRT is a high precise and safe treatment for the majority of large skull base meningiomas, with a control of tumor growth at 5 years comparable to that seen following conventional fractionated radiotherapy. For patients with large skull base meningiomas a combination of conservative surgery and postoperative irradiation should always be considered when an attempt to complete resection carries unacceptable risks of neurological deficits. The use of 2-3 mm margin from GTV to generate PTV with FSRT permits a more localized irradiation compared with conventional radiotherapy. Minimizing the radiation dose to normal brain FSRT may reduce the risk of developing late radiationinduced toxicity; however, the potential benefit in reducing long term treatment complications while maintaining a high efficacy will require longer follow-up of a large cohort of patients.