Controversies in Radiotherapy for Meningioma

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Controversies in Radiotherapy for Meningioma J. Maclean *, N. Fersht *, S. Short y * Department y

of Radiotherapy, University College London Hospitals NHS Trust, London, UK Leeds Institute of Molecular Medicine, St James’ University Hospital, Leeds, UK

Received 17 April 2013; received in revised form 21 August 2013; accepted 2 October 2013

Abstract Meningiomas are the most common primary intracranial tumour. Although external beam radiotherapy and radiosurgery are well-established treatments, affording local control rates of 85e95% at 10 years, the evidence base is mainly limited to single institution case series. This has resulted in inconsistent practices. It is generally agreed that radiotherapy is an established primary therapy in patients requiring treatment for surgically inaccessible disease and postoperatively for grade 3 tumours. Controversy exists surrounding whether radiotherapy should be upfront or reserved for progression for incompletely excised and grade 2 tumours. External beam radiotherapy and radiosurgery have not been directly compared, but seem to offer comparable rates of control for benign disease. Target volume definition remains contentious, including the inclusion of hyperostotic bone, dural tail and surrounding brain, but pathological studies are shedding some light. Most agree that doses around 50e54 Gy are appropriate for benign meningiomas and ongoing European Organization for Research and Treatment of Cancer and Radiation Therapy Oncology Group studies are evaluating dose escalation for higher risk disease. Here we address the ‘who, when and how’ of radiotherapy for meningioma. Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Meningioma; radiosurgery; radiotherapy; review

Statement of Search Strategies Used and Sources of Information A comprehensive review of published studies and review articles pertaining to radiotherapy for meningioma was carried out using PubMed. As the evidence base is level IV or V, all publications, regardless of study design, were considered. Ongoing Radiation Therapy Oncology Group and European Organization for Research and Treatment of Cancer study protocols and the National Comprehensive Cancer Network guidelines related to meningioma were accessed via their respective websites.

Introduction Meningiomas are the most common primary intracranial tumour [1]. Between 70 and 80% are benign and active

Author for correspondence: J. Maclean, Department of Radiotherapy, University College London Hospitals, 235 Euston Rd, London NW1 2BU, UK. Tel: þ44-20-3447-9287; Fax: þ44-20-3447-9055. E-mail address: [email protected] (J. Maclean).

surveillance with serial magnetic resonance imaging (MRI) can be appropriate for those without significant symptoms. In the largest analysis of growth in observed meningiomas (244 patients, mean follow-up 3.8 years), 74% showed growth on volumetric criteria (>8.2%) and 44% using linear criteria (2 mm), with 26.3% requiring treatment in this period [2]. Nevertheless, depending on location and grade, meningiomas can be severely disabling and can limit life expectancy. Surgery is the mainstay of therapy, as this offers the potential of cure, but tumour location may preclude meaningful resection. Figure 1 depicts the difference in surgical accessibility between meningioma sites. The Simpson grading scale describes the extent of surgical meningioma resection (Table 1) and is an important predictor of recurrence/progression [3]. Most authors (including the Radiation Therapy Oncology Group [RTOG] and the European Organization for Research and Treatment of Cancer [EORTC]) classify a gross total resection (GTR) as Simpson grade 1e3 (abnormal bone may remain). Tumour location prevents GTR in about a third of cases (about 50% in the skull base) [4,5]. External beam radiotherapy (EBRT) and radiosurgery are well-established treatments for meningioma. However, the

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J. Maclean et al. / Clinical Oncology 26 (2014) 51e64

Fig 1. Tumour location and surgical potential. (a) Large convexity meningioma (gross total resection was possible); (b) smaller cavernous sinus meningioma (no meaningful resection possible due to proximity to vessels and nerves).

evidence base is limited to retrospective case series (usually single institution) that often analyse outcomes together regardless of treatment setting, technique or dose. Furthermore, many series have insufficient follow-up as progression/recurrence can occur even after 10 years. Local control rates 5e10 years after modern EBRT in benign tumours are generally >90% and recent radiosurgery series suggest similar results for local control [6]. Table 2 details outcomes for EBRT from series using exclusively modern radiotherapy techniques (not two-dimensional). Where possible, results are grouped for benign/non-benign tumours and according to treatment timing, but should be interpreted with caution in view of the small number of progressions and non-benign tumours in most series. Symptom control after radiation is not uniformly reported and analysis is clouded by high rates of previous surgery. However, some degree of clinical improvement is reported in 29.3e53.5% of patients after EBRT/radiosurgery, with symptom stabilisation in most others with radiological stable disease [16,22e26].

Table 1 Simpson grading: extent of meningioma resection Simpson grade

Description

1

Macroscopically complete tumour removal with excision of the dural attachment and any abnormal bone Macroscopically complete tumour removal with coagulation of its dural attachment Macroscopically complete removal of the intradural tumour without resection or coagulation of its dural attachment or extradural extensions Subtotal removal of the tumour Simple decompression of the tumour

2 3

4 5

Pathology Meningiomas are broadly categorised as grade 1 (benign) and grade 2 and 3 (non-benign), but there are a multitude of pathological subtypes and molecular features within each grade and considerable interobserver variability in grading. This complicates outcome analyses. Biopsy is usually unnecessary when tumours are adjacent to critical structures, as MRI is usually diagnostic. However, tumour grade cannot be reliably identified on imaging [27], which may have implications for radiotherapy and the interpretation of outcomes. That said, biopsy is unlikely to identify small high-grade regions or brain invasion, a feature that confers grade 2 status on meningiomas since the World Health Organization (WHO) 2007 classification revision. This revision may result in a stage migration in treatment outcomes in new studies (most series include patients diagnosed pre-2007). Therefore, although radiotherapy seems to be an effective treatment for meningioma, the poor evidence base means that many controversies exist, which we discuss in this review.

When Should Radiotherapy be Used? Primary Radiotherapy EBRT or radiosurgery is used in the primary setting in symptomatic patients when significant resection is not possible, usually because the meningioma involves critical structures [28]. Durable progression-free survival (PFS) is experienced by most patients, although older studies with longer follow-up periods usually show lower PFS rates [29]. It is unclear whether PFS after radiotherapy is influenced by previous surgery. Some studies report no difference between groups: Tanzler et al. [20] recently reported 5 and 10 year PFS of 99 and 97%, respectively, for patients with grade

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Table 2 Fractionated radiotherapy outcomes for meningioma (studies using solely three-dimensional conformal radiotherapy or intensitymodulated radiotherapy [IMRT]) Reference Patients Region Grade Primary Previous Planning (n) (where Tx (%) surgery (%) method known)

Median Median Local dose follow-up control by (Gy) (months) grade (%)

[7]*

189

SB

1 and 2

31

69

FSRT

56.8

35

[8]

41

All

1

36.6

63.4

FSRT

55

21

[9]

40

27.5

62.5

IMRT

50.4

30

[10]

20

All (no 1 ONS) SB 1

20

80

IMRT

57

36

[11]**

77

All

All

35

65

FSRT

48.4

24

[12]**

45

CS

1

36

64

FSRT

50.4

36

317

All

1 and 2

43

67

FSRT

57.6

67

[14]

35

All

54

IMRT

50.4

19.1

[15]y

224

All

1 (2 46 patients grade 2) All 42

58

FSRT (plus11 RS)

55.8

36

[16]*

94

All

All

28

72

IMRT

57.6

52

[17]y [18] [19] [20]

181 100 52 146

SB CS SB All

All NS 1 1

30 74 66 60

70 26 34 40

FSRT FSRT FSRT FSRT (threedimensional/ IMRT)

56 45 50 52.7

36 33 72 88

[21]*

85

All

2 and 3

91.7

FSRT (three- 57.6 dimensional), IMRT (carbon)

73

[13]*

8.3

Local control by timing (%)

Grade 1: 94 NS at 10 years Grade 2: 78 at 8 years 100 at 3 NS years 93 at 5 years NS

Late toxicity (%) 12

9.8 5

100 at 3 years Grade 1: 97.2 at median follow-up Grade 2: 60 at median follow-up 97.4 at 3 years Grade 1: 89 at 10 years Grade 2: 67 at 10 years

NS

0

NS

5.2

NS

0

Grade 1: 100 at 5 years Grade 2: 90 at 3 years Grade 3: 83 at 3 years Grade 1: 96.3 at 5 years Grade 2: 77.8 at 5 years 97 at 5 years 93 at 3 years 93 at 5 years 96 at 10 years

NS

0

NS

4

NS NS No difference Primary: 99 at 10 years Postoperative: 93 at 10 years No difference

8.2 0 5.5 6.8

Primary: 4.7 at 8.2 median followup Rec: 10 at median followup 97 at 3 years No difference 5

Grade 2: 50% at 5 years Grade 3: 13% at 5 years

0e1

(continued on next page)

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Table 2 (continued ) Reference Patients Region Grade Primary Previous Planning (n) (where Tx (%) surgery (%) method known)

Median Median Local dose follow-up control by (Gy) (months) grade (%)

Local control by timing (%)

[22]

72

All

All

64

36

FSRT

54

50

Grade 1: 95 at 3 years Grade 2: 40 at 3 years

[23]

30

All (vd) All

30

70

IMRT

50.4

28

SB

54.4

45.6

FSRT or IMRT 57.6

107

97 at median follow-up Overall: 88 at 10 years Grade 1: 91 at 10 years Grade 2/3: 53 at 10 years

Primary: 94 at 3 4.2 years Postoperative: 71 at 3 years Rec: 58 at 3 years No difference 3 for symptom improvement No difference NS

[24]*

507

All

Late toxicity (%)

Tx ONS, optic nerve sheath; FSRT, fractionated stereotactic radiotherapy (with three-dimensional conformal radiotherapy); vd, visual deficits; NS, not specified; SB, skull base; ND, no difference; Rec, treatment for recurrent disease; CS, cavernous sinus. Note: FSRT is threedimensional conformal radiotherapy with stereotactic set-up unless specified. Note: FSRT is three-dimensional conformal radiotherapy with stereotactic set-up unless specified. *, **, y: authors from the same institution and potentially patient cross-over between series.

1 meningioma treated with primary EBRT (96 and 93% for postoperative EBRT), but others show improved PFS in those without previous surgery, although residual bias is likely [25,26]. Symptomatic outcomes according to timing of radiotherapy have not been analysed. Optic nerve sheath meningiomas (ONSM) provide a considerable body of literature regarding outcomes after primary EBRT, as this is usually the treatment of choice due to high rates of blindness associated with optic nerve infarction during surgery [30]. Overall, reported data suggest that ONSM remained stable or reduced in size after primary EBRT in 93.3e100% of cases (20.4e91.3 months median follow-up). Clinical improvement figures vary as criteria differ, but 85% achieved stable disease in reported studies (Table 3). Primary radiosurgery outcomes for meningioma are also impressive and data are available for larger patient cohorts than EBRT. Santacroce et al. [25] reported 10 year PFS rates of 92.7% after radiosurgery in nearly 3000 patients with imaging-defined meningiomas (implying no previous surgery). Pollock et al. [46] found no difference in 7 year PFS rates between radiosurgery and GTR (>95% for both). Although some reduction in volume can occur, in general, meningiomas do not substantially shrink after radiotherapy and treatment should not be delayed waiting until symptoms become severe. Some patients can have symptom improvement without significant change in tumour dimensions [16,23,45], probably because only a very small change may be required to relieve nerve compression in certain regions or perhaps reflecting vascular changes. If the tumour is large, even if GTR is not possible, surgery to relieve mass effect followed by radiotherapy to the inoperable residual may be appropriate rather than radiotherapy alone.

Radiotherapy after Subtotal Resection Benign Subtotal resection (STR) is associated with inferior PFS [47]. This is improved by postoperative radiotherapy. In case series, PFS after STR plus EBRT seems to be comparable with GTR (Table 4). Radiosurgery rather than EBRT can treat the post-surgery remnant if size and location are appropriate. Although no studies directly compare the two, overall PFS rates after STR plus radiosurgery seem to be equivalent to GTR [6]. Unfortunately, a phase III EORTC study comparing observation with radiotherapy after STR in benign meningiomas closed due to low accrual (EORTC 26021-22021). The ongoing RTOG 0539 study, designed to assess dose escalation in non-benign meningiomas, incorporates an observational arm for grade 1 meningiomas after GTR or STR, so should provide prospective outcome data for those who are not irradiated. Most studies focus on PFS and do not address whether this affects overall survival. McCarthy et al. [55] analysed overall survival according to treatment in >8000 meningioma patients using the US National Cancer Database. They reported equivalent overall survival in patients with GTR or STR and poorer outcomes in those treated with radiotherapy. However, considerable bias was unaccounted for in the database and <5% of patients received radiotherapy. Soyuer et al. [54] reported no difference in overall survival among those with STR or STR plus upfront radiotherapy, suggesting it may be safe to delay radiotherapy until progression. In practice, STR of meningioma is usually in locations where tumour growth would cause symptoms. Hence, upfront radiotherapy may still be favoured in benign disease.

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Table 3 Outcomes after radiotherapy for optic nerve sheath meningioma Reference Patients Follow-up Radiotherapy method (n) months (mean/ median)

Total Dose dose (Gy) per fraction (Gy)

Vision improved (%)

Vision Vision Imaging Late stable (%) worse (%) stable/ toxicity (%) improved (%)

[31] [32] [33] [34] [35] [36] [37]

36 20.4 34.8 51.3 20 30 57

FSRT FSRT FSRT 3DCRT FSRT FSRT FSRT

45e54 50e54 54 50.4e56 45e54 43.4e45 50e54

1.8 1.8 1.8 1.8e2 1.8e2 1.67e1.75 1.7e1.8

80 30 6 35.7 72.7 100 85.7

20 63.3 94 50 22.7 0 0

0 6.7 0 14.3 4.6 0 14.3

100 100 100 100 100 100 100

0 10 10.3 14 4.6 0 0

[38] [39] [40] [41]

5 30 39 14 23 4 7 (eyes) 12 8 22 15

34 27 30 86.4

FSRT FSRT 3D or proton FSRT/3D/RS

55.7 45 45e59.4 50

1.8 1.8 1.8 1.8e2

40 62.5 32 92.3

0 0 4 6.7

100 100 95 93.3

3 0 0 6.7

[42] [43] [44] [45]

32 34 11 8

54 58 89.6 91.3

FSRT 3D/FSRT FSRT/3D/IMRT FSRT

54.9 45e54 45e54 50.4e54

1.8 1.8 1.8 1.8

60 37.5 64 0 (some slight improvements) 38 41 36 75

59 50 55 25

3 9 9 0

100 N/A 100 100

0 35 (mild) 18 12.5

FSRT, fractionated stereotactic radiotherapy; 3DCRT, three-dimensional conformal radiotherapy; RS, radiosurgery; IMRT, intensitymodulated radiotherapy. Note: FSRT delivered with 3DCRT.

Non-benign Overall survival does seem to be significantly shorter for patients with non-benign meningiomas who undergo STR as opposed to GTR [56,57]. As such, postoperative radiotherapy is commonly recommended after STR of non-benign meningiomas. This is usually EBRT, although some groups support radiosurgery in this setting [58,59]. Unfortunately, the literature tends to group grade 2 and grade 3 disease together. Radiotherapy after Gross Total Resection in Non-benign Meningiomas Five year PFS after GTR for grade 2 meningiomas is 40e50% [60,61]. Such patients are therefore commonly offered adjuvant irradiation. However, study results are

clouded by small patient numbers, combined outcomes for grade 2/3 tumours and significant variation in radiotherapy technique/doses. Komotar et al. [62] reported recurrences in 22% of grade 2 meningiomas after GTR (median 44 months’ follow-up): 8% versus 41% for those with or without postoperative radiotherapy. Likewise, Aghi et al. [63] described no recurrences in eight patients with atypical meningioma (out of 108) who had undergone GTR plus radiotherapy versus a 30% recurrence rate with GTR only (mean 3 year follow-up). However, modern imaging highly sensitive to early recurrences may permit a surveillance approach and in some locations repeat surgery in the event of regrowth may be preferable to radiotherapy. The largest study (n ¼ 114) found no benefit for postoperative radiotherapy in patients with grade 2 meningioma after GTR [59].

Table 4 Meningioma studies reporting outcomes after gross total resection (GTR), subtotal resection (STR) and GTR or STR plus radiotherapy 5 year progression-free survival after STR þ radiotherapy (%)

Reference

Patients (n)

Histology grade

5 year progressionfree survival after GTR (%)

5 year progressionfree survival after STR (%)

[48] [49]

114 135

90 96

45 60

82 80

[50] [51] [52] [53] [54]

132 115 86 246 92

1* No comment 1* 1* 1* 1* 1*

96 N/A N/A 95 77

43 48 52 53 38

85 88 100 86 91

* All studies included patients treated historically (e.g. from 1960s) so grading and treatment techniques do not necessarily apply to current practices.

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There is a clearer case for postoperative radiotherapy for grade 3 meningiomas regardless of the extent of resection. After GTR, 5 year PFS improved from 15% without radiation to 80% with adjuvant radiation [64]. Coke et al. [65] reported local disease progression in 65% of patients after surgery alone, versus 18% after surgery plus radiation. Stessin et al. [66] evaluated postoperative radiotherapy for grade 2/3 meningiomas using the SEER database. They concluded that adjuvant radiotherapy did not improve survival, but emphasised that the role of radiation remains uncertain due to selection bias, scant radiation and surgical detail and small patient numbers evaluable by the WHO 2007 criteria (n ¼ 82). Radiotherapy for Recurrence Recurrent meningiomas pursue a more aggressive course than newly diagnosed meningiomas (they are a group selected by their propensity to recur). Older studies suggest improved salvage rates with surgery plus radiation or radiation alone versus surgery alone [50,51,57]. PFS with immediate or delayed postoperative radiotherapy is similar in some reports [50,54], whereas others suggest that postponing radiation results in less effective tumour control [22,51,68]. No studies addressed overall survival. Again treatment decisions are individualised.

What Type of Radiotherapy Should be Used? External Beam Radiotherapy Modern planning techniques seem to have improved tumour control. Goldsmith et al. [69] reported a 22% improvement in PFS for meningioma patients treated with immobilisation devices and computed tomography or MRIbased target definition versus those treated without such techniques. In older EBRT series that included twodimensional planning, 10 year PFS rates for benign meningioma were often <80%, significantly lower than modern series [29], although the median follow-up was generally longer in older studies. Intensity-modulated radiotherapy (IMRT) will probably provide better coverage of meningiomas close to critical structures. This may improve local control and reduce toxicity, although the effects of the ‘low dose bath’ to normal brain and the additional radiation exposure associated with daily image-guided set-up with IMRT is unknown. No comparative studies of IMRT and other techniques exist. Some patients in fractionated stereotactic radiotherapy (FSRT) series had treatment delivered with IMRT, but IMRT is usually delivered without stereotactic immobilisation (with slightly larger planning target volume margins). Studies using solely IMRT report late toxicity rates of <5%, although the median follow-up is shorter than reports of older techniques (Tables 3 and 4). Any improved outcomes seen in the IMRT era will also relate to improved imaging techniques, treatment planning

systems, set-up verification, etc., as well as improved dose distributions. IMRT is a prerequisite of dose-escalation studies. Segmental, dynamic and arc-based IMRT techniques seem to produce equivalent target coverage and avoidance of critical structures, but treatment times are shorter and monitor units less with arc therapy [70e74]. Radiosurgery No randomised studies have compared EBRT with radiosurgery. Five and 10 year PFS for grade 1 meningioma after both seem to be similar: 86e100% with radiosurgery [6] and 89e97% with EBRT (Table 2). Han et al. [75] reported equivalent outcomes in patients treated with either modality. If patients are suitable for both EBRT and radiosurgery, radiosurgery is often favoured for patient convenience. Comparable outcomes are reported for linearaccelerator radiosurgery [76e78] and gamma knife radiosurgery [25,79e81]. In a retrospective multicentre analysis of 3768 patients with apparently benign meningiomas treated in 15 gamma knife centres [25] 5 and 10 year PFS rates were 95.2 and 88.6%, respectively, with a permanent morbidity of 6.6% (4.8%  moderate morbidity), which seems to be similar to EBRT. Symptomatic peritumoural oedema is rarely noted after EBRT, but is reported in 6e35% of patients up to 18 months after radiosurgery (associated with larger tumours and parasagittal/convexity locations where there is a greater parenchymal interface than in the skull base) [6,82,83]. As non-benign tumours are more likely to be infiltrative, subclinical disease may not be adequately treated by radiosurgery (usually no clinical target volume [CTV], see below), and many institutions reserve radiosurgery for benign meningiomas. Furthermore, there is a theoretical radiobiological advantage of the higher total dose delivered in EBRT. However, some outcomes have been reported for higher grade meningiomas treated with radiosurgery [84e86]. The largest study (n ¼ 50) reported 40% 5 year PFS rates [85], but many patients received radiosurgery after progression after EBRT [85]. In general, failing EBRT is a negative predictor of PFS after radiosurgery and complications are more likely [85,87], but treatment may be appropriate in the absence of other options. In view of the sensitivity of normal tissues to dose per fraction, EBRT is often preferred to single-fraction radiosurgery when the tumour is close to sensitive critical structures, particularly the anterior visual pathway. A meningioma size of >3.5 cm mean diameter, optic nerve/ chiasm compression or ONSM are cited as contraindications to single fraction radiosurgery [80]. Some groups have reported good short-term PFS rates and low toxicity after Cyberknife radiosurgery of two to five fractions for larger meningiomas [88,89]. Radiosurgery criteria are dependent on a centre’s experience, one centre even reported using single fraction radiosurgery to treat ONSM, although reported visual deterioration rates of 20% are higher than in most fractionated EBRT papers [90].

J. Maclean et al. / Clinical Oncology 26 (2014) 51e64

Protons and Heavy Ions Outcomes have been reported for about 200 patients treated with protons delivered as fractionated courses, large single fractions or as boosts after EBRT [91e97]. Local control seems to be comparable with photon studies, but in some cases toxicity rates seem higher [92,95]. A small modelling study indicated that proton therapy may half the risk of second malignancy (absolute reduction 2.8e1.3 per 10 000 patients per year) and reduce doses to neurocognitive and visual/auditory structures [98]. However, substantial uncertainties regarding proton dosimetry remain (e.g. range uncertainty of Bragg peaks) and whether the theoretical advantages are clinically significant compared with modern photon planning techniques in meningiomas remains unclear. A phase II study is currently evaluating a carbon ion boost after EBRT in patients with grade 2 meningiomas after STR/biopsy [99]. The same group reported a palliative benefit from re-irradiation with carbon therapy after failed EBRT in three patients [100].

What are the Long-term Risks of Radiotherapy? Long-term toxicity is a concern for meningioma patients, as they usually have long life expectancies. Overall permanent toxicity rates of 0e18% and 2.5e23% have been reported with modern EBRT and radiosurgery techniques [6]. However, the lack of prospective data necessitates caution in the interpretation of these figures. For EBRT, optic neuropathy and retinopathy are rare with doses 54 and 45 Gy, respectively (<2 Gy per fraction) [69,101e103] and rates of severe dry-eye syndrome, retinopathy and optic neuropathy increase steeply after doses of 40, 50 and 60 Gy to related organs, respectively [101,102,104]. Pituitary hormone insufficiency, seizures, hearing and other cranial nerve deficits and necrosis are occasionally reported [7,10,19,51]. Radiosurgery series rarely report doses to critical structures. Bloch et al. [6] cited increasing tumour size and supratentorial location to be associated with toxicity rather than prescribed dose. Likewise, Pollock et al. [79] reported increased tumour volume and a parasagittal/falx/convexity location as risk factors for permanent radiosurgery complications. Formal evaluation of cognitive toxicity in meningioma is limited. Steinvorth et al. [105] reported a transient memory decline after the first fraction of FSRT. However, this subsequently improved, associated with improved mood, and no changes were later noted (only 14 patients had 1 year of follow-up). Another group found that although meningioma patients exhibited long-term deficits in neurocognition, these seemed to be due to antiepileptic drugs and tumour location as there was no difference between the surgery only or surgery plus radiotherapy groups [106,107]. There are no meningioma-specific second malignancy data. The relative risk of second malignancy after EBRT for

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pituitary adenoma compared with the normal population was reported as 10.5, with 10 and 20 year absolute risks of 2.0 and 2.4% [108]. Long-term follow-up of IMRT patients is required to assess whether this historic data remain comparable in view of the larger volumes of normal tissue receiving low-dose radiation with IMRT. There are only a few reported cases of second malignancy after radiosurgery [109] and the largest study of almost 5000 patients showed no increase in second tumours compared with the general population, but no patient had 20 years of follow-up (364 patients had >15 years of follow-up) [110].

What Dose of Radiation Should be Prescribed? Standard treatment doses for EBRT are 50e60 Gy in 2 Gy per fraction. Data regarding whether a dose-response relationship exists are scarce and study quality is poor (retrospective case series, small numbers of heterogeneous patients, varying treatment schedules and combined results for tumour grades). Katz et al. [111] found no apparent improvement in local control for non-benign meningiomas after hyperfractionated treatment plus radiosurgery boost (about 60 Gy in twice daily fractions plus 10e17.5 Gy boost). Others report improved local control with doses >52e53 Gy in both benign and higher grade tumours [69], lower recurrence rates in patients who received >50 Gy (combined tumour grades) [112] and improved PFS and overall survival with 60 Gy in non-benign meningiomas [113]. The EORTC and RTOG are currently running nonrandomised studies investigating dose escalation in nonbenign meningioma (Table 5). The optimal radiosurgery dose is also debated. The median marginal dose in studies published since 2000 has been 11e18 Gy. Several groups have proposed a minimal marginal dose of 12e16 Gy [80,114,115], but others prefer 14e15 Gy [116]. Pollock et al. [116] highlighted that a 12 Gy single fraction only equates to 42 Gy of EBRT in 2 Gy fractions (alpha/beta ratio 2). However, they found no improvement in local control with increasing dose. The few reports of radiosurgery for non-benign meningiomas generally used higher median marginal doses (about 18 Gy) [85]. Attia et al. [86] reported improved PFS for atypical meningiomas treated with >14 Gy and some recommend doses >20 Gy in this setting [117]. Interestingly, non-benign meningiomas are more commonly reported in the convexity or parasagittal regions where there may be more scope to increase dose compared with other regions.

What is the Target Volume? The optimal meningioma target definition has not been prospectively addressed and there is a lack of evidence to make recommendations. In EBRT, reported planning target volumes include the gross tumour volume (GTV) plus 2 cm [60], GTV plus 1 cm [69], down to GTV plus 2 mm (FSRT) [7].

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Table 5 Current Radiation Therapy Oncology Group (RTOG) and European Organization for Research and Treatment of Cancer (EORTC) study target volume specifications Study

Groups

Margins

Dose

RTOG 0539 Observational (low risk) and phase II (non-low risk)

Low risk: Grade 1 post GTR or STR

No radiotherapy

No radiotherapy

Intermediate risk: Grade 1 recurrent disease Grade 2 post-GTR

GTV ¼ tumour bed, nodular dural enhancement, hyperostotic/directly invaded bone. Dural tail/oedema NOT included CTV54 ¼ GTVþ1 cm (reduce to 0.5 cm at natural barriers)

54 Gy in 30 fractions IMRT or protons

High risk: Grade 2 recurrent disease Grade 2 post STR Grade 3 any

GTV as above CTV54 ¼ GTVþ2 cm (reduce to 1 cm at natural barriers) CTV60 ¼ GTV þ 1 cm

60 Gy in 30 fractions IMRT only

Group 1: Grade 2 and 3 post GTR

GTV ¼ postoperative residual CTV60 ¼ GTV þ ‘subclinical microscopic tumour’ (may include preoperative tumour bed, peritumoral oedema, hyperostotic changes, preoperative dural enhancement/ thickening) þ 1 cm

60 Gy in 30 fractions

Group 2: Grade 2 and 3 post STR

GTV as above CTV60 as above CTV70 ¼ GTV þ 0.5 cm

70 Gy in 35 fractions

EORTC 22042e26042 Observational (group 1) and phase II (group 2)

GTR, gross total resection; STR, subtotal resection; GTV, gross tumour volume; IMRT, intensity-modulated radiotherapy.

In this latter report, no margin failures were reported, but a median follow-up was too short to draw conclusions (35 months). As non-benign meningiomas are more likely to be infiltrative, many authors have supported an increased CTV margin for non-benign tumours. Adeberg et al. [21] recommended a CTV of GTV þ 1e2 cm for grade 2 meningiomas and GTV þ 2e3 cm for grade 3. The same group reported using CTV margins of 1e3 mm for benign skull base meningiomas [24]. The current RTOG and EORTC study specifications are detailed in Table 5 (intermediate or highrisk tumours). Most radiosurgery series do not specify target definition, but the general radiosurgery principle is to target enhancing disease alone (no CTV). Information about where recurrences occur in relation to target volume is scare for meningioma. Askoxylakis et al. [118] reported the location of progression post-EBRT in 22 meningiomas: marginal in 50% (most commonly in benign tumours) and central in 50% (more common in non-benign tumours). This suggests that improvement in target delineation and dose escalation may be more important for benign and non-benign meningiomas, respectively.

invasion from meningioma is well documented [121], but ‘reactive’ bone expansion has also been shown. The few pathological correlation studies available frequently show meningioma cells in bone when hyperostosis is present on imaging, but not all cases of bone invasion are identified on imaging. Goyal et al. [120] identified hyperostosis on preoperative imaging in 75% of meningioma patients. Tumour cells were present in bone in 23.3% of all patients, of whom 88% had hyperostosis on preoperative imaging. Pieper et al. [121] reported that of the 51 patients with computed tomography hyperostosis, 26 had biopsyproven bone invasion, but 10 more had bone invasion without computed tomography hyperostosis [121]. The same group recently reported similar results: 13 of 14 patients with imaging-identified hyperostosis had meningioma in bone [123]. Most of these tumours were grade 1 with Ki67 <4%, indicating bone invasion does not itself indicate aggressive histology. Nakasu et al. [124] found that the association between bone invasion and recurrence disappeared when incomplete excision was considered. However, one group reported an association between poorer prognosis and bone invasion in atypical meningiomas [125].

Hyperostosis Dural Tail Hyperostosis (Figure 2a) is reported in association with meningioma in 25e75% of cases, most commonly in the convexities and sphenoid wing [119e122]. Direct bony

Figure 2b depicts a ‘dural tail’, commonly seen in meningioma. The clinical significance of the dural tail remains

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Fig 2. (a) Abnormal bone associated with meningioma; (b) dural tail.

unclear. The largest study of 179 patients with resected dural tails from convexity meningiomas found 88.3% contained tumour cells, of which 95% lay within 2.5 cm of the tumour base [126] (with no difference between benign/ non-benign tumours). This raises the question of whether margins required to pathologically clear disease differ from those required for radiotherapy as this extent of dural tail is often not included in radiotherapy target volumes and local control rates are excellent. In other series, about half of meningioma dural tails contained tumour and half were attributed to dural inflammation and vascular congestion (around 80 patients in total) [127e133]. The RTOG and EORTC studies specify GTV inclusion of only ‘nodular’ dural tails, although ‘smooth’ dural tails seem as likely to contain meningioma cells (but are associated with benign disease) [126]. DiBiase et al. [134] reported PFS rates of 96% versus 77.9% at 5 years for patients who did or did not have the dural tail included in the radiosurgery prescription isodose, respectively. However, this association did not remain statistically significant on multivariate analysis and some groups argue that recurrences are no more likely in the dural tail than in any other portion of dura next to the main tumour mass and that improved control with dural tail inclusion simply reflects larger target volumes [135]. Practice varies between centres and there is a need for prospective evaluation with quality assurance for contouring and dosimetry. Peritumoural Oedema Peritumoural oedema has been found to be an indicator of the likelihood of brain invasion (for each centimetre of oedema, the probability of brain invasion increased by 20%) [136] and has been shown to relate to tumour aggressiveness, correlating with a high meningioma MIB-1 index [137,138]. Most authors do not specifically include oedema within the target volume, although the current EORTC study states that it may be included in the CTV (non-benign disease).

What Imaging Should be Used to Define Target Volume? Accurate target delineation is essential with increased use of highly conformal radiotherapy techniques. Contrastenhanced MRI co-registered to planning computed tomography is the current standard imaging (meningioma out-with bone clearest on post-contrast T1-weighted MRI [139], bone clearest on computed tomography). Several groups have evaluated positron emission tomography (PET)/computed tomography using 68Ga DOTA-based tracers (bind to somatostatin receptors present on meningiomas) [140e143] or the amino acid tracer 11C-methionine [144]. Overall, most altered target volumes using PET (particularly bone). The high specificity of PET tracers justifies an increase in target volume (caution around the pituitary, which is also 68Ga-DOTA avid), but, although some groups also reduced volumes according to PET, clinical outcome or pathological-correlation data showing the safety of this approach are awaited (Figure 3).

Are There any Guidelines? Guidelines are relatively broad. The US National Comprehensive Cancer Network guidelines [28] state that radiotherapy can be used as a primary treatment and they recommend postoperative radiotherapy for grade 3 disease or after STR in grade 2 disease (and grade 1 if tumour initially >3 cm). They recommend that grade 1 or 2 meningiomas be treated with 45e54 Gy (EBRT) or radiosurgery at 12e14 Gy (grade 1 only), whereas grade 3 tumours should receive 54e60 Gy to the GTV plus 2e3 cm.

Conclusion Radiotherapy has an important role in the treatment of meningiomas with extremely good control rates for benign

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Fig 3. Abnormal area of bone shown on: (a) computed tomography (not clear whether disease or reactive); (b) magnetic resonance imaging (soft tissue disease seen, bone unclear); (c) 68Ga-DOTA positron emission tomography/magnetic resonance imaging (‘hot’ in soft tissue only). Whether it is safe to exclude this region of bone from the target volume is unclear.

tumours and improved PFS in non-benign disease. EBRT and radiosurgery seem to be equivalent for benign disease, although tumour location and size can limit suitability for radiosurgery. Although meningiomas are relatively common, most patients do not require radiotherapy and the lack of evidence beyond retrospective case series means that debate persists regarding optimal patient selection, treatment timing and delivery. Randomised studies have proved challenging to carry out and research strategies similar to those undertaken in other rare tumours should be adopted. The current RTOG/EORTC studies offer a non-randomised approach for prospective data collection and registries could be extended. Multidisciplinary teamworking between radiotherapists and surgeons is important to allow each to better understand the possibilities and limitations of different treatment options and to permit tailoring of management plans to individual patient’s circumstances within broadly agreed network treatment guidelines.

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