Radiotherapy and Oncology 109 (2013) 330–334
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Benign meningiomas
Long-term efficacy of fractionated radiotherapy for benign meningiomas Francesca Soldà a,1, Beverley Wharram a,2, Paul B. De Ieso a,3, Jacob Bonner a,2, Sue Ashley a, Michael Brada a,b,⇑ a
Neuro-oncology Unit, The Royal Marsden NHS Foundation Trust; and b Academic Unit of Radiotherapy and Oncology, The Institute of Cancer Research, London, UK
a r t i c l e
i n f o
Article history: Received 19 April 2013 Received in revised form 13 September 2013 Accepted 13 October 2013 Available online 31 October 2013 Keywords: Skull base Intracranial Meningioma Fractionated stereotactic radiotherapy
a b s t r a c t Purpose: To assess long term efficacy of fractionated stereotactic radiotherapy (fSRT) in the treatment of benign intracranial meningiomas. Materials and methods: Retrospective study of 222 patients with histologically confirmed (58%) and unverified presumed (42%) grade I intracranial meningioma treated with fSRT in a single institution to doses of 50–55 Gy in 30–33 fractions. Results: At a median follow-up of 43 months (range 3–144) the 5 and 10 years local control (LC) were 93% and 86%. Patients with tumors involving the optic nerve (42 patients) and patients with cavernous sinus/parasellar region meningiomas (78 patients) had 5 and 10 years LC of 100%. The 5 and 10 years survival probabilities were 93% and 84%. On multivariate analysis gender and tumor site were independent predictors of LC. Worsening of pre-existing cranial nerve deficit occurred in 8 (3.5%) and onset of new deficit in 1 (0.5%) patient. Two patients with optic nerve sheath meningioma (1%) developed radiation retinopathy. There were no cases of radiation necrosis or second brain tumors. Conclusion: fSRT achieves excellent medium and long term tumor control with minimal morbidity particularly in patients with benign meningiomas involving the parasellar region and the optic nerves and questions the role of other treatment modalities for tumors at these locations. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 109 (2013) 330–334
Intracranial meningiomas account for 13–26% of intracranial tumors [1] with surgical excision considered the treatment of choice for accessible benign meningiomas. In patients with inoperable, recurrent or residual benign meningiomas not accessible to surgery, conventional fractionated radiotherapy (RT) has been used successfully to achieve long term tumor control [2,3] with a progression-free survival in the region of 90% at 5 years and 80–90% at 10 years [4–8]. Fractionated stereotactic radiotherapy (fSRT) and single fraction radiosurgery (SRS) as more focused techniques of irradiation have largely replaced conventional radiotherapy with 5 and 10 years control rate in the region of 90–95% [9–12]. We provide an update on medium and long term efficacy and toxicity outcome of a cohort of patients with intracranial meningioma treated with fractionated stereotactic radiotherapy (fSRT) reported previously [13,14] and in the light of the present results suggest future strategies.
⇑ Corresponding author. Present address: LOC Leaders in Oncology Care, 95 Harley Street, W1G 6AF London, UK. E-mail address: [email protected] (M. Brada). 1 Present address: Harley Street at University College Hospital, London, UK. 2 Present address: Department of Paediatric Oncology, The Royal Marsden NHS Foundation Trust, Sutton, UK. 3 Present address: NTRO, Alan Walker Cancer Centre, Rocklands Drive Tiwi 0810 NT, UK. 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.10.006
Materials and methods We retrospectively reviewed the outcome of all patients with benign intracranial meningioma treated at the Royal Marsden Hospital between January 1995 and April 2010 with fSRT. Patients with atypical (grade II) and malignant (grade III) meningiomas and patients who received previous radiotherapy were excluded. Two hundred and twenty two patients with either histologically verified (128 patients – 58%) or unverified (94 patients – 42%), presumed WHO grade I meningioma were treated. Fifty-two patients were male (23%) and 170 female (77%) with a median age of 52 years (range 27–77). One hundred and forty five patients (65%) had skull base (of whom 78 patients (35%) cavernous sinus/parasellar), 42 (19%) optic nerve sheath, 20 (9%) suprasellar/sellar, 14 (6%) falx/parasagittal and 1 pineal region meningioma. Patients were generally treated at the time of progressive disease with or without prior surgery and in the presence of neurological deficit. One hundred and forty one patients received fSRT as part of primary treatment for residual tumor. Nine had a surgical biopsy, 38 had incomplete surgical excision, and 94 were not histologically verified. Eighty one patients received fSRT for recurrent meningioma following primary surgery. Forty eight were treated at first recurrence, 33 for recurrence or residual disease following second or subsequent surgery.
F. Soldà et al. / Radiotherapy and Oncology 109 (2013) 330–334
fSRT technique and dose prescription Technical details have been reported previously [14–17]. Briefly, patients were immobilized in a Gill–Thomas–Cosman (GCT) frame. High-resolution planning CT scan (2 or 3 mm slice thickness) was used early in the study to outline the gross tumor volume (GTV) (35 patients). Subsequently all patients had a planning gadolinium enhanced MRI fused with a planning CT scan. Three dimensional (3D) volume growing algorithm was used to expand the GTV initially by 5 mm (3 mm for optic nerve sheath meningiomas) to generate a planning target volume (PTV). In later stages of the accrual the margin was reduced to 3–4 mm based on relocation accuracy data [18]. Critical structures including the eyes, pituitary gland, optic nerves and optic chiasm were also outlined. All patients were treated with 4 (204 patients) or 3 (18 patients) static non-coplanar conformal fixed fields based on the class solution reported previously [19]. Initially beam shaping was achieved with customized lead blocks (35 patients) and subsequently with a multileaf collimator with variable leaf width (187 patients). To assess the accuracy of relocation, the isocentre position was verified with a second CT scan prior to the start of treatment. One hundred thirty one patients with tumor lying in close proximity or involving the optic apparatus were treated to a dose of 50 Gy in 30–33 daily fractions; 91 patients with tumors not involving the optic apparatus received a dose of 55 Gy in 33 daily fractions. All were treated on a 6 MV linear accelerator. Doses were prescribed at the isocentre according to ICRU 50 criteria with PTV covered by the 95% isodose in 3D. Gross tumor volume (GTV) and planning target volume (PTV) were available for 209 patients with a median GTV of 12.0 cm3 (range 0.4–183 cm3) and median PTV of 34.8 cm3 (range 2– 496 cm3).
Follow-up and data analysis Patients were reviewed weekly during radiotherapy and then at 1, 3 and 12 months after the completion of treatment and subsequently annually. Follow up MRI scan was performed at 3 months after the end of radiotherapy and then annually. Patients with skull base and sellar/parasellar tumors had annual endocrine assessment in an endocrine clinic. Tumor control was defined as the absence of radiological progression of meningioma (any increase in size = progression). The effect of treatment on vision was assessed by clinical and/or formal ophthalmological examination usually at the referring institution. Clinical improvement in neurological symptoms was defined as a resolution or improvement in neurological deficit or tumor related symptoms. Toxicities were documented according to the Common Toxicity Criteria (CTC) Version 2.0. Overall survival and local control were measured from the date of starting fSRT until death from any cause (overall survival) or recurrence in the irradiated site (local control) and were calculated using the Kaplan–Meier method [20]. Differences between groups were assessed by means of the logrank statistic. A Cox proportional hazards model was used to determine independent factors predictive of local control. A step-down method was employed. A 5% level of significance was used in all analyses. Results Survival The median follow up of the cohort was 43 months (range 2– 144 months). Overall actuarial survivals at 3, 5 and 10 years were 97%, 93% and 84%, respectively (Table 1, Fig. 1). During the follow-up period 15 patients (7%) died. The cause of death was pro-
331
gressive meningioma (5), cardiac (2), systemic malignancy (3), respiratory (1) and unknown (4 patients). Local control The local control rates at 3, 5 and 10 years were 96%, 93% and 86%, respectively (Table 2, Fig. 1). At the time of analysis, 12 patients (5%) had tumor progression; of these 2 (1%) underwent reoperation, 1 (0.5%) had stereotactic radiosurgery, 1 (0.5%) was under observation and 3 (1%) were lost to follow up. On univariate analysis the predictors of local control included gender, previous surgery and tumor location (Fig. 2). Patients with optic nerve sheath (42 patients, 19%), cavernous sinus/parasellar region (78 patients, 35%) and sellar/suprasellar region (20 patients, 9%) meningiomas all had 100% LC at 5 and 10 years. On multivariate analysis gender and tumor site were independent predictors of tumor control (Table 2). Neurological function Of the 222 patients, 145 (65%) presented with a deficit of which 117 had visual impairment and 73 impaired ocular mobility; 22 patients had trigeminal deficit (Table 3). After fSRT 39 patients (27%) had clinical improvement in one or more neurological deficits; 20 (14%) had improvement in vision, 14 (10%) in diplopia, 6 (4%) in pre-existing trigeminal neuralgia, and 2 (1%) improvement in balance. Proptosis regressed in 3 patients (2%). Acute and late toxicity Treatment was associated with mild transient acute toxicity. All patients noted transient localized alopecia at the beam entrance with full recovery of hair growth. Eight patients (4%) had transient worsening of headache and 3 (1%) a transient mild visual deterioration during or shortly after treatment, with full recovery. Deterioration of preexisting clinical features without evidence of tumor progression on imaging was observed in 8 patients (3.5%) all of whom had worsening vision. One patient (0.5%) with a left cavernous sinus meningioma developed a new trigeminal neuralgia 13 months after fSRT. Two patients (1%) with optic nerve sheath (ONS) meningioma developed radiation retinopathy. One patient with a left ONS meningioma involving the chiasm with blind left eye developed right retinal artery occlusion of embolic origin leading to complete blindness 10 years after treatment. Two patients (1%) had a suggestion of cognitive impairment at the time of clinical review. Two patients (1%) (with petrous apex and a sphenoid wing meningioma), developed a cerebrovascular accident 59 and 73 months after fSTR; one patient with a left cavernous sinus meningioma had a transient ischemic attack 27 months after fSRT. No brain necrosis was recorded. None of the patients developed a second brain tumor after fSRT. Discussion The management of benign meningiomas has evolved largely in the absence of grade I evidence with the options of surgery, surveillance and radiotherapy/radiosurgery used at varying frequencies based on the perception of the efficacy and toxicity of the different approaches. While high precision radiotherapy approaches are a relative newcomer, conventional fractionated radiotherapy has been used for some decades with mature results. While the majority of patients are appropriately treated with attempt at complete surgical excision, surveillance is considered appropriate in asymptomatic patients with small and slowly progressive tumors [21] with radiotherapy reserved for tumors in
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Table 1 Univariate analysis of overall survival. N All patients Gender Male Female Age 55 Previous surgery None Yes Tumor location Skull base Suprasellar Optic nerve Falx
3 years (%)
5 years (%)
10 years (%)
Significance
222
97
93
84
52 170
98 97
93 93
74 85
p = 0.5
31 107 84
100 99 93
99 97 92
93 86 75
p = 0.04
103 119
100 94
93 93
93 75
p = 0.1
145 20 42 14
97 100 100 80
93 100 91 80
82
p = 0.02
91 80
Fig. 1. Actuarial survival and local control (progression free survival) after fSRT in 222 patients with benign meningioma.
surgically challenging locations, although this is to some extent a subjective assessment. Nevertheless, complete tumor resection is the benchmark against which other treatment strategies should be compared. Regardless of the perception of operability, the results reported here suggest that fractionated high precision radiotherapy, using modern imaging and focused treatment, achieves excellent tumor control with low morbidity. The mature data on meningiomas in skull base location treated in a center with long experience in the use of stereotactic radiotherapy, managed within a multidisciplinary team suggest excellent results with 100% control rate for tumors in sellar, parasellar and cavernous locations without recourse to surgery. Overall the results compare favorably with the outcome of conventional radiotherapy and single fraction radiosurgery [4,7,8,14,22–31]. While comparisons are difficult in the absence of randomized studies, assuming that only small meningiomas are treated with SRS, the results of fSRT for meningiomas of all sizes in skull base location can be considered superior. The excellent local control in patients with optic nerve sheath, suprasellar/parasellar/cavernous meningiomas suggest more indolent disease characteristics with little justification for more invasive treatment methods. While patients receiving fSRT after previous surgery had worse local control than patients who received fSRT as the initial treatment (89% vs 99% at 5 years, p = 0.04) this is likely to represent a
selection bias where tumors requiring radiotherapy after surgery are likely to represent the more aggressive end of the spectrum of grade I meningiomas. Similar findings have been reported by others both following fSRT [22,32] and SRS [27,33]. The apparently better local control seen in women has been reported previously following fSRT and SRS [28,32,34] and the reason for this observation is not clear. The transient acute toxicity of fSRT is generally mild and may include fatigue, skin erythema, and patchy alopecia. Transient headache, nausea, or exacerbation of previous neurological deficits can occur during radiotherapy and has been ascribed to radiation induced swelling although this has not been demonstrated on imaging. Although many lesions are localized in close proximity to structures at risk, the onset of clinically significant new neurological deficit without preexisting dysfunction is low after fSRT [22,35]. It is difficult to ascribe the occurrence of late effects to radiotherapy, surgery or to the tumor itself and to distinguish these from the consequences of the normal aging process, particularly in older patients with meningiomas. Although this study is limited by the retrospective nature of the analysis, the 4% incidence of neurological deterioration in the absence of tumor progression, assumed to represent radiation induced side effects, was low; in 3.5% it occurred as worsening of pre-existing symptoms and in 0.5% as the development of a new deficit. This is at the lower end of the range of 2–13% reported by others [36,37]. We did not perform prospective neuropsychological testing and
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F. Soldà et al. / Radiotherapy and Oncology 109 (2013) 330–334 Table 2 Univariate and multivariate analysis of local control. N
Univariate analysis 5 years (%)
All patients Gender Male Female Age 55 Previous surgery None Yes Tumor location Skull base Suprasellar Optic nerve Falx Skull base location Cavernous sinus/parasellar Other skull base
Multivariate analysis 10 years (%)
Significance
Relative risk of recurrence (95% CI)
Significance
84 88
p = 0.04
1.0 0.2 (0.04;0.6)
p = 0.006
92 95 90
46 95 84
p = 0.2
103 119
99 89
94 81
p = 0.04
145 20 42 14
94 100 100 54
89
p < 0.0001
78 67
100 88
222
93
86
52 170
84 95
31 107 84
100
1.0 44 (12;166) p < 0.0001
100 81
p = 0.02
Fig. 2. Local control after fSRT in 222 patients with benign meningioma by site of disease; (a) all locations, (b) skull base location (145 patients).
the frequency of treatment induced deficit cannot be assessed, although mild neurocognitive dysfunction was recorded in two patients. Retinal injury has been reported following eye doses >50 Gy [38,39]. In patients with extension of the ONS meningioma right up to the eye globe, the posterior part of the retina will have received the full radiation dose and the retinopathy noted in 2 patients is likely, at least in part, radiation induced. However, contribution from the longstanding mechanical compression cannot be excluded. While cerebrovascular accidents have been described after RT for pituitary and head and neck tumors [40,41] the 3 cases reported here (1.3%) do not fall outside the expected range for the older patient population with meningioma. Currently it is not possible to assess whether fSRT contributes to the risk. Although the follow up of this cohort has not reached two decades, it is encouraging to note that no cases of second tumor have been seen to date. While the terms ‘‘safe and effective’’ are overused, in the presence of 100% or near 100% control rate in patients with both histologically verified and unverified meningiomas in some skull base locations it is not an overstatement of efficacy. The apparent 5–10% improvement over series reporting the results of conventional radiotherapy are likely to represent primarily improvement in imaging of meningiomas in locations where they were difficult
Table 3 Clinical features at presentation.*
*
Clinical features
No. of patients
Visual impairment Ophthalmoplegia Hearing impairment Trigeminal neuropathy VII nerve paresis Exophthalmos Seizures Cognitive problems Accessory nerve palsy Cerebellar deficits
177 73 16 22 4 15 17 12 1 3
Some patients had more than one feature at presentation.
to visualize prior to the MRI era. The dose fractionation schemes of fSRT are not dissimilar to those used with conventional radiotherapy and it is unlikely that the technique of delivery is responsible for the improvement. However, such excellent results in the face of the complexity of target definition, the need for precise treatment delivery founded on intensive quality assurance programmes and staff expertise would argue for such treatment to be carried out by experienced teams. In other tumor types where efficacy reaches 90–100% levels the next stage should be an attempt at reducing the treatment
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intensity either as lower doses or even an increased use of surveillance. These would have to be carried out with considerable caution not to compromise the excellent results and should ideally be in the form of randomized trials although such studies would require investment in very long term follow up not in general use in oncology.
[13] [14]
[15]
Authors’ details and contribution [16]
FS: study investigator, participated in treating patients, undertook the data collection and interpretation and drafted the manuscript. PDI: participated in treating patients, undertook the data collection and helped to draft the manuscript. BW and JB: study coordinators and data managers. SA: performed the statistical analysis. MB: principal clinician in developing the therapy and treating patients, conceived the study, participated in its design and coordination, drafted and critically reviewed the manuscript. All authors read and approved the final manuscript.
[17]
[18] [19]
[20] [21] [22]
Conflict of interest statement None. Acknowledgements The work of the Neuro-oncology Unit was supported by the Neuro-oncology Research Fund of the Royal Marsden NHS Foundation Trust. The Neuro-oncology Unit also received funding from the Cancer Research UK and the Royal Marsden NHS Foundation Trust. UK hospitals receive a proportion of their funding from the NHS Executive; the views expressed are those of the authors and not necessarily those of the NHS Executive.
[23]
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[25]
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[28]
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Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Benign meningiomas
Long-term efficacy of fractionated radiotherapy for benign meningiomas Francesca Soldà a,1, Beverley Wharram a,2, Paul B. De Ieso a,3, Jacob Bonner a,2, Sue Ashley a, Michael Brada a,b,⇑ a
Neuro-oncology Unit, The Royal Marsden NHS Foundation Trust; and b Academic Unit of Radiotherapy and Oncology, The Institute of Cancer Research, London, UK
a r t i c l e
i n f o
Article history: Received 19 April 2013 Received in revised form 13 September 2013 Accepted 13 October 2013 Available online 31 October 2013 Keywords: Skull base Intracranial Meningioma Fractionated stereotactic radiotherapy
a b s t r a c t Purpose: To assess long term efficacy of fractionated stereotactic radiotherapy (fSRT) in the treatment of benign intracranial meningiomas. Materials and methods: Retrospective study of 222 patients with histologically confirmed (58%) and unverified presumed (42%) grade I intracranial meningioma treated with fSRT in a single institution to doses of 50–55 Gy in 30–33 fractions. Results: At a median follow-up of 43 months (range 3–144) the 5 and 10 years local control (LC) were 93% and 86%. Patients with tumors involving the optic nerve (42 patients) and patients with cavernous sinus/parasellar region meningiomas (78 patients) had 5 and 10 years LC of 100%. The 5 and 10 years survival probabilities were 93% and 84%. On multivariate analysis gender and tumor site were independent predictors of LC. Worsening of pre-existing cranial nerve deficit occurred in 8 (3.5%) and onset of new deficit in 1 (0.5%) patient. Two patients with optic nerve sheath meningioma (1%) developed radiation retinopathy. There were no cases of radiation necrosis or second brain tumors. Conclusion: fSRT achieves excellent medium and long term tumor control with minimal morbidity particularly in patients with benign meningiomas involving the parasellar region and the optic nerves and questions the role of other treatment modalities for tumors at these locations. Ó 2013 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 109 (2013) 330–334
Intracranial meningiomas account for 13–26% of intracranial tumors [1] with surgical excision considered the treatment of choice for accessible benign meningiomas. In patients with inoperable, recurrent or residual benign meningiomas not accessible to surgery, conventional fractionated radiotherapy (RT) has been used successfully to achieve long term tumor control [2,3] with a progression-free survival in the region of 90% at 5 years and 80–90% at 10 years [4–8]. Fractionated stereotactic radiotherapy (fSRT) and single fraction radiosurgery (SRS) as more focused techniques of irradiation have largely replaced conventional radiotherapy with 5 and 10 years control rate in the region of 90–95% [9–12]. We provide an update on medium and long term efficacy and toxicity outcome of a cohort of patients with intracranial meningioma treated with fractionated stereotactic radiotherapy (fSRT) reported previously [13,14] and in the light of the present results suggest future strategies.
⇑ Corresponding author. Present address: LOC Leaders in Oncology Care, 95 Harley Street, W1G 6AF London, UK. E-mail address: [email protected] (M. Brada). 1 Present address: Harley Street at University College Hospital, London, UK. 2 Present address: Department of Paediatric Oncology, The Royal Marsden NHS Foundation Trust, Sutton, UK. 3 Present address: NTRO, Alan Walker Cancer Centre, Rocklands Drive Tiwi 0810 NT, UK. 0167-8140/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.radonc.2013.10.006
Materials and methods We retrospectively reviewed the outcome of all patients with benign intracranial meningioma treated at the Royal Marsden Hospital between January 1995 and April 2010 with fSRT. Patients with atypical (grade II) and malignant (grade III) meningiomas and patients who received previous radiotherapy were excluded. Two hundred and twenty two patients with either histologically verified (128 patients – 58%) or unverified (94 patients – 42%), presumed WHO grade I meningioma were treated. Fifty-two patients were male (23%) and 170 female (77%) with a median age of 52 years (range 27–77). One hundred and forty five patients (65%) had skull base (of whom 78 patients (35%) cavernous sinus/parasellar), 42 (19%) optic nerve sheath, 20 (9%) suprasellar/sellar, 14 (6%) falx/parasagittal and 1 pineal region meningioma. Patients were generally treated at the time of progressive disease with or without prior surgery and in the presence of neurological deficit. One hundred and forty one patients received fSRT as part of primary treatment for residual tumor. Nine had a surgical biopsy, 38 had incomplete surgical excision, and 94 were not histologically verified. Eighty one patients received fSRT for recurrent meningioma following primary surgery. Forty eight were treated at first recurrence, 33 for recurrence or residual disease following second or subsequent surgery.
F. Soldà et al. / Radiotherapy and Oncology 109 (2013) 330–334
fSRT technique and dose prescription Technical details have been reported previously [14–17]. Briefly, patients were immobilized in a Gill–Thomas–Cosman (GCT) frame. High-resolution planning CT scan (2 or 3 mm slice thickness) was used early in the study to outline the gross tumor volume (GTV) (35 patients). Subsequently all patients had a planning gadolinium enhanced MRI fused with a planning CT scan. Three dimensional (3D) volume growing algorithm was used to expand the GTV initially by 5 mm (3 mm for optic nerve sheath meningiomas) to generate a planning target volume (PTV). In later stages of the accrual the margin was reduced to 3–4 mm based on relocation accuracy data [18]. Critical structures including the eyes, pituitary gland, optic nerves and optic chiasm were also outlined. All patients were treated with 4 (204 patients) or 3 (18 patients) static non-coplanar conformal fixed fields based on the class solution reported previously [19]. Initially beam shaping was achieved with customized lead blocks (35 patients) and subsequently with a multileaf collimator with variable leaf width (187 patients). To assess the accuracy of relocation, the isocentre position was verified with a second CT scan prior to the start of treatment. One hundred thirty one patients with tumor lying in close proximity or involving the optic apparatus were treated to a dose of 50 Gy in 30–33 daily fractions; 91 patients with tumors not involving the optic apparatus received a dose of 55 Gy in 33 daily fractions. All were treated on a 6 MV linear accelerator. Doses were prescribed at the isocentre according to ICRU 50 criteria with PTV covered by the 95% isodose in 3D. Gross tumor volume (GTV) and planning target volume (PTV) were available for 209 patients with a median GTV of 12.0 cm3 (range 0.4–183 cm3) and median PTV of 34.8 cm3 (range 2– 496 cm3).
Follow-up and data analysis Patients were reviewed weekly during radiotherapy and then at 1, 3 and 12 months after the completion of treatment and subsequently annually. Follow up MRI scan was performed at 3 months after the end of radiotherapy and then annually. Patients with skull base and sellar/parasellar tumors had annual endocrine assessment in an endocrine clinic. Tumor control was defined as the absence of radiological progression of meningioma (any increase in size = progression). The effect of treatment on vision was assessed by clinical and/or formal ophthalmological examination usually at the referring institution. Clinical improvement in neurological symptoms was defined as a resolution or improvement in neurological deficit or tumor related symptoms. Toxicities were documented according to the Common Toxicity Criteria (CTC) Version 2.0. Overall survival and local control were measured from the date of starting fSRT until death from any cause (overall survival) or recurrence in the irradiated site (local control) and were calculated using the Kaplan–Meier method [20]. Differences between groups were assessed by means of the logrank statistic. A Cox proportional hazards model was used to determine independent factors predictive of local control. A step-down method was employed. A 5% level of significance was used in all analyses. Results Survival The median follow up of the cohort was 43 months (range 2– 144 months). Overall actuarial survivals at 3, 5 and 10 years were 97%, 93% and 84%, respectively (Table 1, Fig. 1). During the follow-up period 15 patients (7%) died. The cause of death was pro-
331
gressive meningioma (5), cardiac (2), systemic malignancy (3), respiratory (1) and unknown (4 patients). Local control The local control rates at 3, 5 and 10 years were 96%, 93% and 86%, respectively (Table 2, Fig. 1). At the time of analysis, 12 patients (5%) had tumor progression; of these 2 (1%) underwent reoperation, 1 (0.5%) had stereotactic radiosurgery, 1 (0.5%) was under observation and 3 (1%) were lost to follow up. On univariate analysis the predictors of local control included gender, previous surgery and tumor location (Fig. 2). Patients with optic nerve sheath (42 patients, 19%), cavernous sinus/parasellar region (78 patients, 35%) and sellar/suprasellar region (20 patients, 9%) meningiomas all had 100% LC at 5 and 10 years. On multivariate analysis gender and tumor site were independent predictors of tumor control (Table 2). Neurological function Of the 222 patients, 145 (65%) presented with a deficit of which 117 had visual impairment and 73 impaired ocular mobility; 22 patients had trigeminal deficit (Table 3). After fSRT 39 patients (27%) had clinical improvement in one or more neurological deficits; 20 (14%) had improvement in vision, 14 (10%) in diplopia, 6 (4%) in pre-existing trigeminal neuralgia, and 2 (1%) improvement in balance. Proptosis regressed in 3 patients (2%). Acute and late toxicity Treatment was associated with mild transient acute toxicity. All patients noted transient localized alopecia at the beam entrance with full recovery of hair growth. Eight patients (4%) had transient worsening of headache and 3 (1%) a transient mild visual deterioration during or shortly after treatment, with full recovery. Deterioration of preexisting clinical features without evidence of tumor progression on imaging was observed in 8 patients (3.5%) all of whom had worsening vision. One patient (0.5%) with a left cavernous sinus meningioma developed a new trigeminal neuralgia 13 months after fSRT. Two patients (1%) with optic nerve sheath (ONS) meningioma developed radiation retinopathy. One patient with a left ONS meningioma involving the chiasm with blind left eye developed right retinal artery occlusion of embolic origin leading to complete blindness 10 years after treatment. Two patients (1%) had a suggestion of cognitive impairment at the time of clinical review. Two patients (1%) (with petrous apex and a sphenoid wing meningioma), developed a cerebrovascular accident 59 and 73 months after fSTR; one patient with a left cavernous sinus meningioma had a transient ischemic attack 27 months after fSRT. No brain necrosis was recorded. None of the patients developed a second brain tumor after fSRT. Discussion The management of benign meningiomas has evolved largely in the absence of grade I evidence with the options of surgery, surveillance and radiotherapy/radiosurgery used at varying frequencies based on the perception of the efficacy and toxicity of the different approaches. While high precision radiotherapy approaches are a relative newcomer, conventional fractionated radiotherapy has been used for some decades with mature results. While the majority of patients are appropriately treated with attempt at complete surgical excision, surveillance is considered appropriate in asymptomatic patients with small and slowly progressive tumors [21] with radiotherapy reserved for tumors in
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Table 1 Univariate analysis of overall survival. N All patients Gender Male Female Age 55 Previous surgery None Yes Tumor location Skull base Suprasellar Optic nerve Falx
3 years (%)
5 years (%)
10 years (%)
Significance
222
97
93
84
52 170
98 97
93 93
74 85
p = 0.5
31 107 84
100 99 93
99 97 92
93 86 75
p = 0.04
103 119
100 94
93 93
93 75
p = 0.1
145 20 42 14
97 100 100 80
93 100 91 80
82
p = 0.02
91 80
Fig. 1. Actuarial survival and local control (progression free survival) after fSRT in 222 patients with benign meningioma.
surgically challenging locations, although this is to some extent a subjective assessment. Nevertheless, complete tumor resection is the benchmark against which other treatment strategies should be compared. Regardless of the perception of operability, the results reported here suggest that fractionated high precision radiotherapy, using modern imaging and focused treatment, achieves excellent tumor control with low morbidity. The mature data on meningiomas in skull base location treated in a center with long experience in the use of stereotactic radiotherapy, managed within a multidisciplinary team suggest excellent results with 100% control rate for tumors in sellar, parasellar and cavernous locations without recourse to surgery. Overall the results compare favorably with the outcome of conventional radiotherapy and single fraction radiosurgery [4,7,8,14,22–31]. While comparisons are difficult in the absence of randomized studies, assuming that only small meningiomas are treated with SRS, the results of fSRT for meningiomas of all sizes in skull base location can be considered superior. The excellent local control in patients with optic nerve sheath, suprasellar/parasellar/cavernous meningiomas suggest more indolent disease characteristics with little justification for more invasive treatment methods. While patients receiving fSRT after previous surgery had worse local control than patients who received fSRT as the initial treatment (89% vs 99% at 5 years, p = 0.04) this is likely to represent a
selection bias where tumors requiring radiotherapy after surgery are likely to represent the more aggressive end of the spectrum of grade I meningiomas. Similar findings have been reported by others both following fSRT [22,32] and SRS [27,33]. The apparently better local control seen in women has been reported previously following fSRT and SRS [28,32,34] and the reason for this observation is not clear. The transient acute toxicity of fSRT is generally mild and may include fatigue, skin erythema, and patchy alopecia. Transient headache, nausea, or exacerbation of previous neurological deficits can occur during radiotherapy and has been ascribed to radiation induced swelling although this has not been demonstrated on imaging. Although many lesions are localized in close proximity to structures at risk, the onset of clinically significant new neurological deficit without preexisting dysfunction is low after fSRT [22,35]. It is difficult to ascribe the occurrence of late effects to radiotherapy, surgery or to the tumor itself and to distinguish these from the consequences of the normal aging process, particularly in older patients with meningiomas. Although this study is limited by the retrospective nature of the analysis, the 4% incidence of neurological deterioration in the absence of tumor progression, assumed to represent radiation induced side effects, was low; in 3.5% it occurred as worsening of pre-existing symptoms and in 0.5% as the development of a new deficit. This is at the lower end of the range of 2–13% reported by others [36,37]. We did not perform prospective neuropsychological testing and
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F. Soldà et al. / Radiotherapy and Oncology 109 (2013) 330–334 Table 2 Univariate and multivariate analysis of local control. N
Univariate analysis 5 years (%)
All patients Gender Male Female Age 55 Previous surgery None Yes Tumor location Skull base Suprasellar Optic nerve Falx Skull base location Cavernous sinus/parasellar Other skull base
Multivariate analysis 10 years (%)
Significance
Relative risk of recurrence (95% CI)
Significance
84 88
p = 0.04
1.0 0.2 (0.04;0.6)
p = 0.006
92 95 90
46 95 84
p = 0.2
103 119
99 89
94 81
p = 0.04
145 20 42 14
94 100 100 54
89
p < 0.0001
78 67
100 88
222
93
86
52 170
84 95
31 107 84
100
1.0 44 (12;166) p < 0.0001
100 81
p = 0.02
Fig. 2. Local control after fSRT in 222 patients with benign meningioma by site of disease; (a) all locations, (b) skull base location (145 patients).
the frequency of treatment induced deficit cannot be assessed, although mild neurocognitive dysfunction was recorded in two patients. Retinal injury has been reported following eye doses >50 Gy [38,39]. In patients with extension of the ONS meningioma right up to the eye globe, the posterior part of the retina will have received the full radiation dose and the retinopathy noted in 2 patients is likely, at least in part, radiation induced. However, contribution from the longstanding mechanical compression cannot be excluded. While cerebrovascular accidents have been described after RT for pituitary and head and neck tumors [40,41] the 3 cases reported here (1.3%) do not fall outside the expected range for the older patient population with meningioma. Currently it is not possible to assess whether fSRT contributes to the risk. Although the follow up of this cohort has not reached two decades, it is encouraging to note that no cases of second tumor have been seen to date. While the terms ‘‘safe and effective’’ are overused, in the presence of 100% or near 100% control rate in patients with both histologically verified and unverified meningiomas in some skull base locations it is not an overstatement of efficacy. The apparent 5–10% improvement over series reporting the results of conventional radiotherapy are likely to represent primarily improvement in imaging of meningiomas in locations where they were difficult
Table 3 Clinical features at presentation.*
*
Clinical features
No. of patients
Visual impairment Ophthalmoplegia Hearing impairment Trigeminal neuropathy VII nerve paresis Exophthalmos Seizures Cognitive problems Accessory nerve palsy Cerebellar deficits
177 73 16 22 4 15 17 12 1 3
Some patients had more than one feature at presentation.
to visualize prior to the MRI era. The dose fractionation schemes of fSRT are not dissimilar to those used with conventional radiotherapy and it is unlikely that the technique of delivery is responsible for the improvement. However, such excellent results in the face of the complexity of target definition, the need for precise treatment delivery founded on intensive quality assurance programmes and staff expertise would argue for such treatment to be carried out by experienced teams. In other tumor types where efficacy reaches 90–100% levels the next stage should be an attempt at reducing the treatment
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intensity either as lower doses or even an increased use of surveillance. These would have to be carried out with considerable caution not to compromise the excellent results and should ideally be in the form of randomized trials although such studies would require investment in very long term follow up not in general use in oncology.
[13] [14]
[15]
Authors’ details and contribution [16]
FS: study investigator, participated in treating patients, undertook the data collection and interpretation and drafted the manuscript. PDI: participated in treating patients, undertook the data collection and helped to draft the manuscript. BW and JB: study coordinators and data managers. SA: performed the statistical analysis. MB: principal clinician in developing the therapy and treating patients, conceived the study, participated in its design and coordination, drafted and critically reviewed the manuscript. All authors read and approved the final manuscript.
[17]
[18] [19]
[20] [21] [22]
Conflict of interest statement None. Acknowledgements The work of the Neuro-oncology Unit was supported by the Neuro-oncology Research Fund of the Royal Marsden NHS Foundation Trust. The Neuro-oncology Unit also received funding from the Cancer Research UK and the Royal Marsden NHS Foundation Trust. UK hospitals receive a proportion of their funding from the NHS Executive; the views expressed are those of the authors and not necessarily those of the NHS Executive.
[23]
[24]
[25]
[26] [27]
[28]
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