Spot-scanning proton radiation therapy for recurrent, residual or untreated intracranial meningiomas

Radiotherapy and Oncology 71 (2004) 251–258 www.elsevier.com/locate/radonline

Spot-scanning proton radiation therapy for recurrent, residual or untreated intracranial meningiomas Damien C. Webera,b,*, Antony J. Lomaxa, Hans Peter Rutza, Otto Stadelmanna, Emmanuel Eggera, Beate Timmermanna, Eros S. Pedronia, Jorn Verweya, Raymond Miralbellb, Gudrun Goiteina, The Swiss Proton Users Group a

Department of Radiation Medicine, Proton Therapy Program, Paul Scherrer Institute, Villigen-PSI CH-5232, Switzerland b Department of Radiation Oncology, Geneva University Hospital, CH-1211 Geneva 14, Switzerland Received 9 September 2003; received in revised form 26 January 2004; accepted 6 February 2004

Abstract Background and purpose: To assess the safety and efficacy of spot scanning proton beam radiation therapy (PRT) in the treatment of intracranial meningiomas. Patients and methods: Sixteen patients with intracranial meningioma (histopathologically proven in 13/16 cases) were treated with PRT between July 1997 and July 2002. Eight patients had skull base lesions. Thirteen patients received PRT after surgery either as adjuvant therapy for incomplete resection (eight patients) or for recurrence (five patients). Three patients received radical PRT after presumptive diagnosis based on imaging. The median prescribed dose was 56 CGE (range, 52.2– 64, CGE ¼ proton Gy X 1.1) at 1.8 – 2.0 CGE (median, 2.0) per fraction. Gross tumor volume and planning target volume ranged from 0.8 to 87.6 cc (median, 17.5) and 4.6 –208.1 cc (median 107.7), respectively. Late ophthalmologic and non-ophthalmologic toxicity was assessed using the Subjective, Objective, Management and Analytic scale (SOMA) of the Late Effects of Normal Tissue scoring system and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, v3.0) grading system, respectively. The median follow-up time was 34.1 months (range, 6.5– 67.8). Results: Cumulative 3-year local control, progression-free survival and overall survival were 91.7, 91.7 and 92.7%, respectively. No patient died from recurrent meningioma. One patient progressed locally after PRT. Radiographic follow-up (median, 34 months) revealed an objective response in three patients and stable disease in 12 patients. Cumulative 3-year toxicity free survival was 76.2%. One patient presented with radiation induced optic neuropathy (SOMA Grade 3) and retinopathy (SOMA Grade 2) 8.8 and 30.4 months after treatment, respectively. These patients with ophthalmologic toxicity received doses higher than those allowed for the optic/ocular structures. Another patient developed a symptomatic brain necrosis (CTCAE Grade 4) 7.2 months after treatment. No radiation-induced hypothalamic/pituitary dysfunction was observed. Conclusions: Spot-scanning PRT is an effective treatment for patient with untreated, recurrent or incompletely resected intracranial meningiomas. It offers highly conformal irradiation for complex-shaped intracranial meningiomas, while delivering minimal non-target dose. Observed ophthalmologic toxicity is dose-related. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Central nervous system; Intracranial meningioma; Radiation therapy; Proton beam therapy; Spot scanning proton beam radiation therapy; Bragg peak; Active beam delivery

1. Introduction Meningiomas are extra-axial, slow-growing tumors that arise from the arachnoid cap cells of the central nervous system. They constitute between 13 and 26% of all primary intracranial tumors [24] and are the most common non-glial * Corresponding author. 0167-8140/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.radonc.2004.02.011

brain tumors. Most meningiomas are benign (World Health Organization (WHO) Grade I), while atypical (WHO Grade II) or anaplastic (malignant, WHO Grade III) are uncommon subtypes, accounting for 4.7 –7.2% and 1.0 –2.8% of all resected meningiomas, respectively [28,29,44]. If the tumor is resectable, complete surgical excision is the standard therapy and results in excellent (68 – 92%) longterm tumor control for benign meningiomas [6,33,58].

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Subtotal excision of these tumors, however, results in lower rates of tumor control and cause-specific survival [6] and numerous retrospective series have shown that local recurrence rates can be decreased from 50 – 60% to 12 – 23% at 8 –10 years [5,14,15,32] with photon irradiation. As a result, subtotal excision of these tumors should be routinely followed by adjuvant radiotherapy [10,30]. If the tumor is not resectable, or if there are contraindications to surgery, radical radiotherapy can be delivered with 5-year local tumor control rates of 80– 86% [6,47]. Atypical and malignant meningiomas are undisputedly at high risk for local failure after surgery [17]. As such, radiotherapy is often recommended in atypical or malignant meningioma to decrease the probability of local recurrence [10,30]. Meningioma patients can be adjuvantely or radically treated by conventional external beam photon radiotherapy [6], 3D conformal radiation therapy [34], stereotactic radiosurgery [25,35,46,53], stereotactic fractionated radiotherapy [1,3,4,42], or intensity modulated radiotherapy [45], with the former treatment modality administrating substantial dose to non-target tissue. Proton beam radiation therapy (PRT) can also be used to precisely deliver dose to the tumor volume while sparing normal brain and other organs at risk (OARs), such as the optic apparatus, brainstem and pituitary gland. Protons hence have the advantage of being simultaneously often more conformal and homogenous as compared to photon radiotherapy [8]. PRT offers superior dose distributional qualities as compared to X- or gamma rays, as the dose deposition occurs in a modulated narrow zone called the Bragg peak. Traditionally, PRT has been administered through a delivery system (apertures, range shifter wheel) that conforms, both laterally and in depth, the delivered dose distribution to the target volume (passive scattering). Proton dose distribution can however also be achieved with spatial refinement using proton pencils beams with a near mono-energetic Bragg peak (‘spot’ of dose), superposition of which constitutes the treated volume. It is possible to dynamically position such Bragg peaks, by mechanical and magnetic means, in three dimensions throughout the target volume (active scanning). At the Swiss National Paul Scherrer Institute (PSI), active scanning for PRT has been pioneered using a spot scanning approach [43]. The goals of the present study were to analyze the tumor control results, radiological tumor response and evaluate the treatment-related sequelae after active scanning PRT. This is the first published report of clinical results using the PSI spot scanning PRT delivery technique.

2. Materials and methods 2.1. Patient population Between July 1997 and July 2002, 13 and three (total 16) patients with pathologically proven and presumed intracranial

meningiomas, respectively, were treated at the PSI using dynamic scanning PRT. The patient characteristics are detailed in Table 1. Tumors were classified by site as either skull base or non-skull base meningiomas. Skull base lesions were defined as lesion located in the sphenoid wing, clivus, cavernous sinus or foramen magnum. Skull base lesions were present in eight (50%) patients (Table 1). Surgical excision was classified by Simpson’s classification [55] based on the operative report and postoperative radiological imaging. Eleven and two patients had a histological diagnosis of meningioma WHO Grade I and II, respectively, made at the time of craniotomy 1.8– 123.4 (median, 34.8) months before PRT. Simpson stages were III and IV for four and nine patients, respectively. Eight patients were treated in an adjuvant/postoperative setting after macroscopic subtotal resection (Simpson III and IV). Another five patients were irradiated for recurrence after initial surgical resection. Overall, eight, four and one patient had one, two and three craniotomies before PRT, respectively. One of these patients underwent gamma-knife radiosurgery, 73.8 months before PRT. Chemotherapy with hydroxyurea was also administered (and stopped at the initiation of PRT) to this patient. No other patient had systemic chemo- or hormonal therapy. In three cases, in which the risk of biopsy or surgery was deemed unacceptably high, a clinical and radiographic diagnosis was made and the patients were subsequently referred for PRT. For non-adjuvant irradiation, indications for PRT were radiological tumor progression (verified with MRI) associated with the onset of new symptoms and/or the deterioration in neurologic condition. After a multidisciplinary decision, all tumor progressions were considered not amendable to surgery, or that the patient’s condition did not support a Table 1 Patient characteristics ðn ¼ 16) Characteristics Gender Female/male Age (years) Median Range Histology ðn ¼ 13Þ Benign (WHO I) Atypical (WHO II) GTV (cc) Median Range Tumor location Sphenoid wing Petroclival and Cavernous sinus Foramen magnum Optic canal and nerve Orbitary cavity Olfactive groove Falx cerebri Multiple GTV, gross tumor volume.

No. of patients (%)

13 (81)/3 (19) 45.6 7.2 –64.8 11 (85) 2 (15) 17.5 (0.8– 87.6) 1 6 1 3 1 1 2 1

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surgical intervention. Tumor volumes were also considered too large for radiosurgery in all cases. All tumors were complex in shape and situated in vicinity of, or enveloped, organs at risk (OARs). The tumor locations are listed in Table 1. Written, informed consent was obtained from all patients (or child’s legal guardian). The median duration of follow-up was 34.1 months (range, 6.5 –67.8). All patients had a follow-up of at least 6-months, and 14 (88%) patients had a follow-up of at least 1-year. No patient was lost to follow-up. 2.2. Proton beam radiation therapy planning and delivery Proton dose calculation was computed using a 3-D dosecalculation algorithm, developed at the PSI [51]. This in-house treatment planning system is based on the superposition of 3-D pencil beam kernels, oriented in the beam coordinate system and precalculated in water-equivalent space. Spot-scanning technique enables the proton pencil beams to be scanned within the tumor volume in two dimensions using a magnetic sweeping of the beam and a mechanical table (1-D) motion. Furthermore, to variate the Bragg peak position in depth (third dimension), sequential poly-carbonate sheet absorbers (range shifters) are interposed into the beam. To obtain a homogeneous dose across the target volume from each incident field direction, the individual weights of the Bragg peak are calculated using a dose based optimization scheme [43]. Typically, each pencil beam has a lateral full width at half maximum of about 8 mm in air and about 14 mm after 10 cm of tissue, due to multiple Coulomb scattering (MCS). The effects of MCS depend not only on the total amount of material crossed by the beam but also on its source location and propagation distance. Bragg peaks are deposited on a regular grid with a spacing of 5 mm along each axis (direction of irradiation). The grid spacing is determined by the requirement that a sufficient overlap exist between the dose distributions delivered by adjacent pencils beams, to allow for construction of smooth dose distributions. The gross tumor volume (GTV) was defined as the macroscopic tumor, including the hyperostotic changes, seen on the planning CT and MRI (axial, post-Gadolinium T1W images) brain study. The clinical target volume (CTV) included the GTV plus regions of suspected microscopic spread (0 –10 mm). The planning target volume (PTV) encompassed the CTV plus a 4 – 6 mm margin. The PTV was defined taking into account the presence of natural anatomic barriers in adding the margins and efforts were made to spare portions of OARs. All atypical meningioma patients received 64 CGE. Prescribed dose for benign meningiomas was tailored according to prognostic factors: age, tumor volume, gender and extent of the surgical excision when applicable. Patients with favourable, intermediate and unfavourable prognostic factors received 52.2, 54 and 56 CGE, respectively. One benign meningioma patient was, however, administered 64 CGE, as a result of a

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rapid clinical deterioration and radiological progression, respectively. Dose constraints to the surrounding OARs were set based on published data and our clinical experience: maximum dose of 54 and 63 CGE to the centre and surface of the brainstem, respectively [9]; 56 CGE to the optic chiasm and optic nerve; 56 CGE to the pituitary gland [41], 32 CGE to the lacrimal gland, 50 CGE to the retina [11] and 10 CGE to the lens [11]. If clinically indicated, the treating physician had the option to relax the OAR-dose constraints. Treatment plans were optimised as to maximize the coverage of the GTV, whilst obeying the OAR’s dose constraints. All plans were normalized to the mean dose of the PTV. A relative biologic effectiveness factor for protons of 1.1 (relative to 60Co) was employed and proton doses were expressed in terms of Cobalt Gray Equivalent (CGE ¼ proton Gy X 1.1) [40]. 2.3. Follow-up evaluation Follow-up was obtained by office visit in the author’s clinic (DCW), correspondence with the referring physician or by direct telephone contact with the patient or guardian. Serial brain imaging studies (MRI or contrast enhanced CT) were requested at 6 months and 1 year after PRT, annually for the next 2 years and one once every second year thereafter. Radiological criteria for tumor progression and regression were a 25% increase and decrease, respectively, in CT/MRI tumor volume. Clinical tumor control was defined as the absence of tumor growth requiring salvage treatment. Acute toxicities were defined as those adverse events that occur from the first day of the treatment through day 90 after treatment. All side effects seen after 90 days from the end of PRT were considered late complications. Ocular/optic late complications were graded according to the objective portion of the Somatic, Objective, Management and Analytic (SOMA) scale of the Late Effects of Normal Tissue scoring system [16]. Other late complications were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v3.0 grading system (http://www.ctep. cancer.gov). 2.4. Statistics Overall, progression-free and complication-free survival times were determined from the date of the first day of PRT. Survival rates were calculated using the actuarial method of Kaplan –Meier [21]. Observations were censored on death or end of follow-up for survival and tumor control endpoints. To assess variables influencing late toxicity, univariate analyses were performed to evaluate age, treatment date, gender, delivered dose, tumor margins, tumor localization (skull base vs. non-skull base), number of surgery and length of follow-up. To further verify the results of univariate analyses, Cox proportional hazards multivariate analyses were conducted adjusting for age, treatment

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Table 2 Median radiation doses, in CGE, to the tumor and OARs

Target GTV PTV OAR Brainstem Optic nerve Optic chiasm Retina Pituitary gland Lacrimal gland

Median volume (cc)

Dose, Max. (CGE) (range)

Dose, Mean (CGE) (range)

Volume (cc) receiving .50% dose

Volume (cc) receiving .80% dose

Volume (cc) receiving .95% dose

17.5 107.7

59.4 (53.5– 67.8) 60.5 (53.5– 68.7)

55.8 (51.9–65.5) 54.5 (50–61.9)

17.5 93.2

17.5 93.2

17.5 77.6

54.2 (0–62.9) 56.1 (0–66.8) 54.7 (0–65.5) 45.7 (0–55.9) 50.5 (0–54.4) 18.5 (0–31.3)

8.5 (0–32.5) 47.4 (0–58.7) 32.0 (0–63.8) 14.8 (0–36.3) 25.5 (0–51.1) 8.1 (0–19.1)

2.8 0.7 0.4 2.4 0.3 0.1

1.2 0.5 0.2 0.1 0.1 0.1

0.4 0.2 0.1 0.0 0.0 0.1

22.8 0.9 0.7 10.0 0.3 0.4

CGE, cobalt Gray Equivalent; OAR, organ at risk.

date, gender, delivered dose and tumor margins [7]. The statistical analysis was performed on SPSS 7.5 system (http://www.spss.com).

but three cases (maximum dose, optic nerve, 66.8 CGE; maximum dose, retina, 55.9 CGE, maximum dose optic chiasm 65.5 CGE, Table 2).

3. Results

3.2. Progression-free survival (PFS) and overall survival (OS)

3.1. Treatment delivery Two to three noncoplanar (median, 3) beams were used for treatment. An actual treatment plan of an orbital meningioma is shown in Fig. 1. The prescribed dose ranged from 52.2 to 64 CGE with a median prescribed dose of 56 CGE, and median daily fraction of 2 CGE (range, 1.8– 2.0). The GTV (Table 1) and PTV ranged from 0.8 to 87.6 cc (median, 17.5) and 4.6 –208.1 cc (median, 107.7), respectively. The mean dose delivered to the GTV and PTV ranged from 51.9 to 65.5 CGE (median, 55.8) and 50 – 59.5 CGE (median, 54.5), respectively (Table 2). Maximum and mean doses delivered to the target volumes are detailed in Table 2. The OAR’s dose constraints were respected in all

One patient presented a clinical and radiological progression. This patient was 65 years old at the time of treatment and presented with an orbital WHO Grade I meningioma en plaque, involving the greater wing of the sphenoid bone and ipsilateral optic canal/nerve. Due to the tumor progression localization (Zynn’s annulus), no salvage surgical treatment could be proposed and the patient was legally blind 36 months after treatment. She is currently free of any additional tumor related symptoms 37.2 months after treatment. Two patients died in our series, neither from disease progression or treatment complication. One patient was 62 years old at the time of treatment and had multiple medical problems. She died from pneumonia 15.9 months after completing treatment. She had follow-up imaging, which showed no progression of disease (multiple WHO Grade II meningioma), but did experience late side effects (brain necrosis), which will be detailed below. The other was 63 years old at the time of treatment for a sphenoid sinus WHO Grade I meningioma. She died 37.6 months after completing PRT of an unrelated ischiemic vascular event. Follow-up imaging for this patient showed also no disease progression. Overall, 3-year cumulative PFS and OS were 91.7% and 92.9%, respectively. 3.3. Radiological response and clinical tumor control

Fig. 1. Dose distribution of a typical treatment plan superimposed on axial CT images of the orbital meningioma of a patient receiving 52.2 CGE from three directions (three portals). The isodose contours are represented by different colours (corresponding values are displayed on the right border of the figure). Note the rapid dose decline between tumor and brain/retina.

Follow-up imaging studies of the brain were available in all patients. Median radiographic follow-up was 34 months (range, 13.1– 54.7). By MRI, 12 patients had stable disease, whereas three patients had a regression, 13 – 32 months after treatment. Two patients with radiological response experienced significant improvement of pre-existing neurologic

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symptoms. These improvements were clinically verified months 13.3 and 14.4 after treatment, respectively. Noteworthy, no major (. 50%) radiological or complete response was observed. One patient presented with a radiological progression 24.2 months after treatment. Four patients developed asymptomatic adjacent parenchymal changes on post-treatment T2-weighted MRI, 5.4 –18.3 months (median, 7.5) after treatment. For skull base tumors, no brainstem oedema or parenchymal radiological changes was observed. Overall, all but one patient (orbital meningioma) was controlled clinically. Cumulative 3-year local control was 91.7%. No patient failed distantly. 3.4. Acute and late complications The most common transient acute side effect was focal alopecia and skin erythema. Other acute side effects included mild headache (four (25%) patients), which was controlled with pain medication or steroids, nausea (three (19%) patients), fatigue (two (13%) patients) and serous tympanitis (one (6.5%) patient). Of note, no conjunctivitis or increased tearing was observed for the optic or orbitary tumors. Five (31%) patients presented with discrete gum lesions after mechanical positioning of the vacuum-bite block. Topic treatment allowed improved comfort in all cases. Late side effects were seen in three (19%) patients. One patient with an optic nerve sheath meningioma presented with sudden visual field deterioration of the ipsilateral eye, 30.4 months after irradiation (56 CGE). Cotton wool spots with macular exsudation were visualized. No retinal detachment was seen (SOMA Grade 2). Argon retinal photocoagulation has resulted in a significant regression of these lesions with a stabilization of the visual field loss. For this patient, maximum and mean retinal dose were 55.9 and 36.3 CGE, respectively (Table 2). Dose– volume analysis, demonstrated that 4.8, 2.0 and 0.5 cc of the retinal volume (total, 11.4 cc) received 27.5, 44 and 52.3 CGE, respectively. The second patient, with an extensive left sphenoid sinus meningioma, encasing the ipsilateral optic nerve, showed deterioration of her vision (central scotoma), 8.8 months after PRT (64 CGE). At this time, the appearance of the optic nerve was edematous, with no associated peripapillary exudates or subretinal fluid (SOMA Grade 3). Last ophthalmologic evaluation revealed no optic disc pallor. Clinically, the central scotoma had significantly regressed and the loss of central vision had no consequence on daily living activities. For this patient, maximum and mean optic nerve dose were 66.8 and 58.7 CGE, respectively (Table 2). Dose –volume analysis, demonstrated that 1.1, 0.84 and 0.6 cc of the optic nerve volume (total, 1.18 cc) received 32, 51.2 and 60.8 CGE, respectively. Finally, the third patient with multiple WHO Grade II meningiomas experienced a left-side hemiparesis, 7.2 months after treatment (64 CGE). Serial brain MRIs revealed a right frontal Gadolinium enhanced lesion associated with severe edema (CTCAE

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Grade 4). This frontal lesion was in the high-dose portion of the irradiated volume. A frontal craniotomy was performed 11.7 months after PRT, and partial removal of tumor was accomplished (Simpson IV). Pathologic examination revealed a soft tissue mass composed of necrotic material and atypical (WHO Grade II) meningioma. Subsequently, the patient died 15.9 months after irradiation of respiratory insufficiency secondary to pneumonia. An autopsy was performed and necrosis with viable WHO grade II tumor cells, with reactive gliosis, was identified in the irradiated volume. An assay of intrinsic radiosensitivity based on apoptosis in CD4 and CD8 T-lymphocytes was negative for this patient. Overall, 3-years complication-free survival was 76.2% for the entire group of patients. Eleven (69%) patients had a pre-treatment endocrinologic work-up. One of them presented with postoperative partial insufficiency of the pituitary gland before irradiation. At a median follow-up of 39.6 months (range, 6.6 –60.7), no new endocrinologic deficit was observed after PRT. Likewise, 13 (81.3%) patients had a pre-treatment neuroophthalmologic evaluation. Of these 13 patients, 11 had post-treatment visual field testing, and all were tested for visual acuity. At a median follow-up of 35.8 months (range, 13.2 – 71.6), 7 (63.6%) patients had stable visual fields and acuity, whereas two (18.2%) patients had improved visual fields, while two (18.2%) patients presented a retinitis and radiation optic neuropathy, respectively, and one (9.1%) patient had a worsening visual acuity 24.2 months after PRT secondary to tumor progression and was legally blind (visual acuity , 0.05) 36 months after treatment. Several variables have been suggested as predictors of late toxicity for intracranial meningiomas [38]. We performed univariate analyses to evaluate whether these variables are associated with late toxicity, followed by multivariate analyses to adjust for age, treatment date, gender, delivered dose or tumor margins. Univariate and multivariate analyses indicated no association of radiationinduced late toxicity and treatment (treatment date, P ¼ 0.98; delivered dose, P ¼ 0.72; margins, P ¼ 0.96)/ patients (age, P ¼ 0.98; gender, P ¼ 0.93)-related factors.

4. Discussion 4.1. Proton beam radiation therapy (PRT) and meningiomas The cumulative 3-year local control (LC), complicationfree survival and overall survival (OS) rates of 91.7, 76.2 and 92.9%, respectively, compares favorably with other large proton or combined photon –proton radiation therapy series, although the median follow-up is only 34.1 months. Wenkel et al. [57] reported 3-year recurrence-free survival and OS of 100 and 92%, respectively, in a population of 46 patients with incompletely resected or recurrent histologically confirmed benign meningioma, treated between 1981 and 1996 with combined proton and photon radiotherapy.

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After a median follow-up of 53 months, 17% (8/46) patients developed severe long-term toxicity in the Boston series, with a 3-year actuarial complication-free toxicity of 80%. All patients with ophthalmologic complications received $ 56.4 CGE (maximum dose, 63.2– 67.5) to the optic structures. As a result, dose constraints to the optic apparatus have been decreased from initially 62 (1981) to 56.4 CGE (1996), with no observed additional toxicity. Dose to the optic structures were however further constrained to 54 CGE after March 1997. Vernimmen et al. [56] reported on 23 skull-base (15 histologically confirmed) meningiomas treated with conventionally fractionated (five patients) or hypofractionated (18 patients) stereotactic radiotherapy with protons. After a mean followup of 40 months, LC was achieved in 88% of patients (two marginal failures). These patients were salvaged with repeated radiation therapy or surgery. Interestingly, a complete radiological response was achieved in a substantial number of patients (23%) with hypofractionated stereotactic PRT (31.5 CGE in three fractions). Two (11%) and one (20%) patients treated with hypofractionated and conventionally fractionated PRT developed late toxicity. Noel et al. [37] reported on 17 (five atypical or malignant) histologically confirmed patients treated with proton and photon radiation therapy to a median dose of 61 CGE. With a median follow-up of 37 months, the 4-year LC and OS were 87.5 and 88.9%, respectively. One patient failed within the clinical tumor volume. Objective radiological partial response was observed in five (29%) patients, whereas 12 (71%) were stable. No late toxicity data was reported. Hug et al. [20] reported on 15 and 16 atypical—malignant meningioma patient treated with photon and combined proton and photon radiotherapy to a mean dose of 58 – 62 CGE, respectively. Mean follow-up was 59 months. Fiveyear LC was significantly higher improved with proton/ photon when compared to photon only radiotherapy (80% vs. 17%, P ¼ 0.003). Moreover, 5-year OS rate for malignant meningioma was also significantly improved by the use of protons over photons only and radiation dose of . 60 CGE. Three (10%) patients developed symptomatic late complications. Finally, Gudjonsson et al. reported on 19 patients with unresectable skull-base meningioma (target volume, 2– 53 cm3) treated with stereotactic PRT [18]. Twenty-four CGE were administered in four consecutive factions using the 180 MeV cyclotron in Uppsala. With a minimum follow-up of 36 months, all patients were locally controlled. One (5.3%) objective radiological response was observed. Symptomatic brain edema was observed in two (10.5%) patients, 6 months after treatment. Stabilization of their clinical status however was observed 24 months after stereotactic irradiation. Passive scattering, which is the most mature method for delivering proton therapy, has been used for all the series of meningioma patients. This is the first outcome report of patients treated with an active scanning technology. This scanning system positions the Bragg peak of a pencil beam

target - voxel to deliver desired incremental dose at that grid point by a fully automated and computer-controlled process. Each voxel is irradiated to the planned dose, and the beam is switched off while moving to the adjacent voxel. This process enables these dose-spots to conform precisely (‘paint’) the dose to the target volume as required [43]. Our preliminary results are encouraging, with only one patient presenting a local failure. This failure could be either the result of a too lower dose delivered to the tumor, as a consequence of the optic nerve (56 CGE) and chiasm doseconstraints (56 CGE), which did not allow us to apply a sufficiently high-dose, or, more probably, be the consequence of the target delineation of a meningioma en plaque, which is difficult with the current radiological modalities, and thus should be considered a true marginal failure. Radiation-induced toxicity has been reported to range between 2% [14] and 30% [12] after photon radiotherapy. The majority of these treated meningiomas were however in favorable parasagittal or cortical sites, and the administered doses delivered with fractionated radiotherapy were substantially lower (50 – 55 Gy). One optic neuropathy and one retinopathy were observed in our study. Part of the optic nerve was encompassed in the GTV in both (optic nerve sheath and sphenoid sinus meningioma) cases, which were treated with 56 and 64 CGE, respectively. Thus, the observed toxicity results from the tumor location, as the majority of meningiomas (. 87%) in our series was situated either in the skull base or the orbit and was therefore adjacent to or encased the optical apparatus. Interestingly, one patient received a maximum and mean optic chiasm dose of 65.5 and 63.8 CGE, respectively, with no observed visual complication (Table 2). When compared to other unfavorable location meningioma treated with PRT, the reported visual toxicity is comparable [57]. Noteworthy, no pituitary dysfunction has been yet (median endocrinologic follow-up, 39.6 months) observed, possibly as a result of the pituitary gland lower irradiation after PRT when compared to photon radiation therapy for non-skull base lesions [2,39]. 4.2. Proton beam radiation therapy (PRT) and integral dose Intensity modulated radiotherapy using photons (IMRT) offers highly conformal irradiation and has recently been shown to be both safe and effective for the treatment of complex-shaped skull-base meningiomas [45]. A body of literature predicts however that the use of protons decrease the integral non-target dose when compared to 3Dconformal radiation therapy [8,26] or IMRT [27,31]. This observed integral dose decrement is consequential to the physical advantage of protons for single beams, which extends to multibeam treatments, including IMRT. The magnitude of this nontarget-integral dose reduction is typically by a factor of 2 –5. Whether or not this decreased integral dose resulting from PRT will translate in an improved therapeutic ratio remains to be demonstrated. Radiation induced tumors represent a documented long-term

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complication of radiotherapy for brain tumors [36] in general and meningioma in particular [13,59]. Moreover, treating skull-base meningioma requires substantial volume of bone irradiation in the low- to high-dose range. Knowing the long latent period for radiation-induced bone-sarcomas (median, 11 years) [23], this complication could well be under-reported in radiotherapy series. Historical data have demonstrated that low-dose radiation therapy, in the order of 1 – 2 Gy, can induce a life-long risk for occurrence of this complication [22,48,54]. Conversely, epidemiological cancer data have shown that the probability of radiationinduced oncogenesis increases with dose (8%/Gy), with no threshold (stochastic effect) among atomic bomb survivors [19]. The relationship of this oncogenic risk to radiation dose and volume is however complex, due to the competing processes of cell killing, transformation, repair processes and the uncertainty tissue-weighting factors. Animal studies have shown however that low-dose irradiation may elicit radiation-induced oncogenesis and that this risk may be paradoxically high due to cellular sub-lethal dose [50]. Thus, although it remains debatable, it is prudent to assume that no dose is safe and limiting the non-target integral dose should be of paramount importance. Protons have the potential to deliver highly conformal treatment to the target, while reducing the integral dose to non-target structures, thus, in principle decreasing the carcinogenic risk associated with low- to medium- non-target dose [49,52]. In conclusion, high local control was achieved after PRT for intracranial meningioma, with acceptable radiationinduced toxicity. Spot scanning PRT offers highly conformal irradiation for complex-shaped intracranial meningiomas, while delivering minimal non-target (integral) dose. Observed ophthalmologic toxicity is dose-related. No endocrinologic toxicity was observed. Our present treatment policy is to deliver 54 and 60 CGE for WHO Grade I and II – III, respectively. As a result of the observed ophthalmologic toxicity, dose constraints to the optic apparatus have been decreased from initially 56– 54 CGE.

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