Proton Stereotactic Radiosurgery for the Treatment of Benign Meningiomas

Int. J. Radiation Oncology Biol. Phys., Vol. 81, No. 5, pp. 1428–1435, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter

doi:10.1016/j.ijrobp.2010.07.1991

CLINICAL INVESTIGATION

Brain

PROTON STEREOTACTIC RADIOSURGERY FOR THE TREATMENT OF BENIGN MENINGIOMAS LIA M. HALASZ, M.D.,*x MARC R. BUSSIE`RE, M.SC.,y ELIZABETH R. DENNIS, M.SC.,y ANDRZEJ NIEMIERKO, PH.D.,y PAUL H. CHAPMAN, M.D.,yyx JAY S. LOEFFLER, M.D.,yx yx AND HELEN A. SHIH, M.D., M.P.H. *Harvard Radiation Oncology Program, Boston, Massachusetts; yDepartment of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts; yyDepartment of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts; and xHarvard Medical School, Boston, Massachusetts Purpose: Given the excellent prognosis for patients with benign meningiomas, treatment strategies to minimize late effects are important. One strategy is proton radiation therapy (RT), which allows less integral dose to normal tissue and greater homogeneity than photon RT. Here, we report the first series of proton stereotactic radiosurgery (SRS) used for the treatment of meningiomas. Methods and Materials: We identified 50 patients with 51 histologically proven or image- defined, presumedbenign meningiomas treated at our institution between 1996 and 2007. Tumors of <4 cm in diameter and located $2 mm from the optic apparatus were eligible for treatment. Indications included primary treatment (n = 32), residual tumor following surgery (n = 8), and recurrent tumor following surgery (n = 10). The median dose delivered was 13 Gray radiobiologic equivalent (Gy[RBE]) (range, 10.0-15.5 Gy[RBE]) prescribed to the 90% isodose line. Results: Median follow-up was 32 months (range, 6-133 months). Magnetic resonance imaging at the most recent follow-up or time of progression revealed 33 meningiomas with stable sizes, 13 meningiomas with decreased size, and 5 meningiomas with increased size. The 3-year actuarial tumor control rate was 94% (95% confidence interval, 77%-98%). Symptoms were improved in 47% (16/ 34) of patients, unchanged in 44% (15/34) of patients, and worse in 9% (3/34) of patients. The rate of potential permanent adverse effects after SRS was 5.9% (3/51 patients). Conclusions: Proton SRS is an effective therapy for small benign meningiomas, with a potentially lower rate of long-term treatment-related morbidity. Longer follow-up is needed to assess durability of tumor control and late effects. Ó 2011 Elsevier Inc. Benign meningioma, Stereotactic radiosurgery, Proton radiation, Radiation therapy.

meningiomas. A number of studies performed in the past decade have reported SRS results with 5-year local tumor control rates of 86% to 98% (4–20). The development of radiosurgery has primarily involved linear accelerator (LINAC)-based or cobalt-60 delivery systems, largely because of the ease with which photon radiation can be generated and manipulated. However, with the more widespread availability of proton RT, there is increasing interest in proton SRS, which was pioneered in the 1950s and 1960s by Lawrence at the University of California Berkley Cyclotron facility (21) and by Kjellberg at the Harvard Cyclotron Laboratory (22). Proton RT deposits the majority of its dose at the modulated narrow zone called the Bragg peak and is ideal for dose conformation to target volumes

INTRODUCTION Between 90% and 95% of meningiomas are benign, with indolent growth patterns and without potential for metastatic spread. Surgical resection remains the preferred treatment whenever complete resection can be accomplished with acceptable morbidity (1). However, radiation therapy (RT) is an effective alternative treatment when surgery is not possible or when patients are not suitable surgical candidates. Additionally, RT is often used adjuvantly when benign meningiomas are felt to be at risk for symptomatic tumor progression after subtotal resection (STR) or as a salvage treatment following gross total resection (2, 3). Since the 1990s, stereotactic radiosurgery (SRS) has been used for both primary and adjuvant treatment of benign Reprint requests to: Lia M. Halasz, M.D., Harvard Radiation Oncology Program, Massachusetts General Hospital, Department of Radiation Oncology, 100 Blossom St., Cox 3, Boston, MA 02114. Tel: (617) 726-8650; Fax: 617-726-3603; E-mail: [email protected] Presented at the 50th Annual Meeting of the American Society for Radiation Oncology, Boston, MA, September 24-28, 2008.

Conflict of interest: none. Acknowledgment—We thank Anat Stemmer-Rachamimov, M.D., Department of Pathology, Massachusetts General Hospital, Boston, MA, for expert assistance. Received April 20, 2010, and in revised form July 23, 2010. Accepted for publication July 26, 2010. 1428

Proton radiosurgery for meningiomas d L. M. HALASZ et al.

Table 1. Tumor locations Location Total number Posterior fossa Petroclival Cerebellopontine angle Middle fossa Cavernous sinus Meckel’s cave Parasellar/medial sphenoid wing Convexity Other Falx/sagittal sinus Tentorium Intraventricular

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Table 2. Patient characteristics

No. of tumors % of total 51

100

4 8

8 16

16 5 2 3

31 10 4 6

8 3 2

16 6 4

that may be in close proximity to sensitive normal structures. Bolsi et al. (23) showed that for small intracranial targets, proton techniques, including passive scattering and spot scanning, have the advantage of simultaneously increased homogeneity, better sparing of organs at risk, and lower normal tissue integral dose than photon techniques, including three-dimensional conformal RT, stereotactic arc therapy, and intensity-modulated radiation therapy (IMRT) (23). Since the majority of benign meningiomas are amenable to cure with surgery and/or RT, strategies to spare radiation late effects are of the utmost importance. One such strategy is the use of proton SRS, which can be used for small, intracranial targets. In this study, we present a retrospective review of our experience determining tumor control rates and treatment-related morbidity in a study of 50 patients with 51 benign meningiomas after proton SRS. METHODS AND MATERIALS Patient population We identified 66 patients treated with proton SRS for benign meningiomas at the Harvard Cyclotron Laboratory between 1996 and 2001 and at the Francis H. Burr Proton Therapy Center, Massachusetts General Hospital, between 2002 and 2007. Clinical, imaging, treatment, and follow-up information was obtained through retrospective reviews of patients’ medical records. The institutional review boards approved all aspects of this study. Patients were generally eligible for proton SRS if they had tumors of <4 cm in diameter and were located $2 mm from the optic nerves and chiasm. The following study inclusion criteria were used: (1) patients had diagnoses of benign meningioma based on histology or imaging characteristics; (2) patients were treated with curative intent; (3) treatment consisted of one fraction; and (4) at a minimum, patients underwent one follow-up imaging study at least 6 months after treatment. Two patients with meningiomas >4 cm in diameter were excluded because they were treated with palliative intent, and the contoured tumor volume encompassed less than half of the tumor volume visible on imaging. The first patient refused recommended fractionated treatment, which would have permitted comprehensive treatment of the whole tumor. The second patient had previously received RT, which limited the volume of tumor that could be reirradiated due to neighboring critical structure dose constraints. One patient was excluded because treatment over two fractions was received. Thirteen patients did not

Characteristic

No. of patients

% of total

Total number Median age (range), years Gender Female Male No symptoms Presenting symptoms* Cranial neuropathy Seizures Dizziness Headaches Sensory deficit Motor deficit Other Unknown Diagnostic modality Imaging alone Imaging and histology Histology Benign Benign with atypical features Prior surgery None Subtotal resection Gross total resection Prior radiation therapy None Fractionated

50 60 (33–85)

100

35 15 3

70 30 6

29 6 5 4 2 2 1 3

58 12 10 8 4 4 2 6

32 18

64 36

12 6

24 12

32 14 4

64 28 8

48 2

96 4

* Some patients presented with multiple symptoms. have adequate follow-up. In total, 50 patients with 51 meningiomas treated with proton SRS were eligible for the study. Tumor locations are displayed in Table 1. While tumor locations were varied, most tumors were located at the cavernous sinus (n = 16), cerebellopontine angle (n = 8), or falx/sagittal sinus (n = 8). Of note, 75% (n = 38 tumors) were located at the cranial base, in areas that were difficult to access surgically. Patient characteristics are displayed in Table 2. The median age for the entire cohort was 60 years (range, 33-85 years). There were 35 females (70%) and 15 males (30%). Fifty-eight percent (n = 29) of the patients presented with cranial neuropathies, usually diplopia or facial pain. One patient had a suspected radiation-induced meningioma as a consequence of receiving craniospinal irradiation for medulloblastoma 44 years prior. No patient had a diagnosis of type 2 neurofibromatosis. Diagnosis was based on imaging alone for 32 patients and on histology for 18 patients. In the cases without histologic diagnoses, the morbidity of a biopsy was felt to be unwarranted given the typical features of meningioma seen on magnetic resonance imaging (MRI) and computed tomography (CT). For the patients with histologic diagnoses, pathology reports of 33% (6 of 18) of patients noted tumors had atypical features without meeting criteria for atypical meningioma. These features included hypercellularity, small cells with a high nucleus-to-cytoplasm ratio, sheet-like growth pattern, prominent nucleoli, and areas of necrosis. Four of the 6 patients with atypical features were also noted to have proliferation marker MIB-1 labeling indices greater than 5%, although this assay was not routinely performed. For patients undergoing proton SRS as primary treatment, the indication for treatment was either development or progression of symptoms (n = 27 patients) or radiographic progression (n = 5

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Table 3. Treatment characteristics for 51 meningiomas Treatment characteristic Tumor volume Prescription volume* Conformity index* Prescribed dose Maximum dose to tumor* Minimum dose to tumor* Homogeneity index* Gradient scorey

Median

Range

0.3–9.7 2.1 cm3 1.1–17.7 4.3 cm3 2.2 1.1–4.7 13.0 Gy(RBE) 10.0–15.5 14.4 Gy(RBE) 11.3–17.1 12.2 Gy(RBE) 4.5–15.7 1.1 1.0–1.3 81.7 67.1–113.5

IQR 1.1–3.4 2.7–7.0 1.8–2.7 12.0–15.0 13.6–16.7 11.8–13.5 1.1–1.1 76.3–89.8

Abbreviation: IQR = interquartile range. * Data available for 50 treatments. y Data available for 48 treatments. patients). For patients who underwent previous resection, the indication for treatment was either residual tumor following STR (n = 8 patients) or radiographic progression following STR or gross total resection (n = 10 patients). Two patients received prior RT for meningioma, including fractionated photons to 54 Gy to the same tumor and fractionated protons to 54 Gy radiobiologic equivalent (Gy[RBE]) to a different tumor in another location.

Treatment Proton SRS was administered at the Harvard Cyclotron Laboratory, Cambridge, MA, and the Francis H. Burr Proton Therapy Center, Boston, MA, using energy-degraded 160-MeV and 230-MeV beams, respectively. Three 1/16-inch surgical steel fiducial markers were placed in the outer table of the skull to ensure accurate localization on the day of treatment (24). Patients were immobilized either by means of a customized stereotactic fixation system or relocatable dental fixation with a modified Gill-Thomas-Cosman frame. A CT scan was obtained from the patient in the treatment position and used to define the tumor volume. MRI was obtained for most patients to assist with tumor delineation. SRS treatment was delivered in a single fraction with two to four convergent beams, each shaped by an individually designed brass aperture and a range compensator. Treatment characteristics are displayed in Table 3. The median dose was 13 Gy(RBE) (range, 10-15.5 Gy[RBE]) prescribed to the 90% isodose line. The median dose for treatments between 1996 and 2001 was 15 Gy(RBE) and 12 Gy(RBE) for treatments between 2002 and 2007. Although the intent was to have the 90% isodose line encompass the entire tumor volume, plans were designed to limit the brainstem dose to #12 Gy(RBE), the chiasm dose to #8 Gy(RBE), and the optic nerve dose to #8 Gy(RBE). The median tumor volume, contoured by the treating physician, was 2.5 cm3 (range, 0.3-16.3 cm3), and the median prescription volume, defined as the volume encompassed by the 90% isodose line, was 4.4 cm3 (range, 1.1-33.0 cm3). The median conformity index (CI), calculated as the prescription volume divided by the tumor volume, was 2.1 (range, 1.0-4.7) (25). The median homogeneity index, calculated as the maximum dose to the tumor divided by the prescribed dose, was 1.1 (range, 1.0-1.3). The gradient score of the Conformity/Gradient Index (CGIg) was calculated as CGIg = 100 – {100  [(REff,50%Rx – REff,Rx) – 0.3]}, where REff,50%Rx is the effective radius of the isodose line equal to one-half of the prescription volume, and REff,Rx is the effective radius of the prescription volume (26). The effective radius is calculated as REff = 3O[(3  volume)/(4  p)]. The median CGIg was 81.7 (range, 67.1113.5). For target volumes of $4.0 cm3 (n = 11 targets), the median CGIg was 74.1 (range, 69.9-99.4).

Fig. 1. Actuarial tumor control rate after proton SRS (with 95% confidence intervals).

Follow-up and statistical analysis Patients underwent MRI during regular follow-up visits, at the discretion of the treating physician. For some patients who resided outside Massachusetts, follow-up was completed by the referring physician, with images reviewed at Massachusetts General Hospital. The primary outcome of the study was tumor control, measured from the date of treatment to the date of local recurrence or last MRI follow-up. Local recurrence was defined as increased tumor size on imaging or the need for a subsequent intervention. Actuarial tumor control rate was calculated by the Kaplan-Meier method. Competing risks regression with end-of-follow-up competing with recurrence was used to identify clinical and treatment factors associated with local recurrence. A two-sided p value of 0.05 was used as the threshold for significance in all tests. All statistical analyses were performed using Stata version 11.0 (College Station, TX).

RESULTS Tumor control During a median follow-up period of 32 months (range, 6133 months), 46 of 51 (90%) benign meningiomas treated with proton SRS were controlled locally. MRI at last follow-up or at time of progression revealed 33 meningiomas with stable size (65%), 13 meningiomas with decreased size (25%), and 5 meningiomas with increased size (10%). The 3-year actuarial tumor control rate for treatment of benign meningiomas was 94% (95% confidence interval, 77%-98%). Figure 1 shows the Kaplan-Meier curve. Characteristics of recurrent tumors are shown in Table 4. The median time to progression was 48 months (range, 23-109 months). Four of the 5 patients who progressed had undergone prior resection and 1 patient had received prior fractionated photon RT to the same tumor. Two patients had atypical features noted on pathology. Three patients had recurrence in areas that received the prescribed dose during proton SRS. One patient had recurrence at the inferior margin of the treatment field, which received less than the prescribed dose. One patient did not have imaging available

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Table 4. Recurrence characteristics Months to recurrence

Histology

Size (cm3)

Location

Prior surgery

Prior Dose RT [Gy (RBE)]

Site of failure

Salvage treatment Surgical resection Fractionated SRT SRS

23

Benign with atypical features

4.8

Clivus

STR  3

54 Gy

13

Unknown

24

Benign

4.1

Cavernous sinus

GTR

None

15

In field

48

Diagnosed by imaging

1.4

Cavernous sinus

none

None

15

64 109

Benign with atypical features Benign

0.9 2.5

CPA Intra-ventricular

STR GTR

None None

15 13

Marginal miss In field In field

SRS SRS

Abbreviations: RT = radiation therapy; CPA = cerebellopontine angle; STR = subtotal resection; GTR = gross total resection; SRT = stereotactic radiation therapy; SRS = stereotactic radiosurgery.

to assess the site of failure but was considered to have recurrence because the operative report for a salvage resection at an outside hospital stated the meningioma had recurred. The other patients were salvaged with RT, including 3 patients who received additional proton SRS and 1 patient who received fractionated photon stereotactic radiation therapy (SRT). The 3-year actuarial tumor control rate was 80% (95% confidence interval, 20%-97%) when atypical features were seen on histology (n = 7) and 96% (95% confidence interval, 76%-99%) without atypical features (n = 44). The 3-year actuarial tumor control rate was 75% (95% confidence interval, 31%-93%) for tumors that recurred after prior surgery or RT (n = 12) and 100% (95% confidence interval, 100%-100%) for tumors irradiated as primary treatment or immediately following STR (n = 39). On univariate analysis, patients with atypical features on histology had a significantly decreased tumor control rate (p = 0.03). Patients with tumor recurrence following surgery or RT also had a significantly decreased tumor control rate (p = 0.006). Age, gender, treatment center, tumor location (cranial base vs. other), previous surgery, prescribed dose, minimum dose, tumor volume, and CI were not significantly associated with tumor control. Clinical outcome Of 47 patients who were symptomatic prior to treatment with SRS, 34 patients had clinical follow-up adequate to assess the effect of proton SRS on presenting symptoms. A total of 47% (n = 16) of patients had improved symptoms, 44% (n = 15) of patients had unchanged symptoms, and 9% (n = 3) of patients had worsened symptoms. Improved symptoms included diplopia (n = 6 patients), facial numbness/pain (n = 7 patients), dizziness (n = 3 patients), blurry vision (n = 1 patient), tinnitus (n = 1 patient), and headaches (n = 1 patient). Two of the 3 patients with worsened symptoms had tumor progression. The third patient had increase in the frequency and severity of seizures despite having a stable tumor on imaging. Morbidity Three patients (5.9%) developed transient adverse effects attributed to proton SRS, including 2 patients with worsening facial pain within 2 weeks of treatment with 12 to 13

Gy(RBE). Both patients were treated with a short course of steroids, with complete resolution of the neuropathies that were the original indication for SRS. The third patient developed seizures associated with cerebral edema on MRI at 6 months following treatment to 15 Gy(RBE). The patient’s seizures resolved after short-term use of antiepileptic medication. Three patients (5.9%) developed permanent adverse effects attributed to proton SRS if there was no other probable cause. Two patients required long-term antiepileptic medication after developing seizures 5 to 6 months following treatment. One of these patients had evidence of cerebral edema on MRI at the onset of seizures. The third patient was diagnosed with panhypopituitarism 4 years following SRS treatment, after presenting with lethargy and bradykinesia. The patient was treated with a long-term course of levothyroxine and prednisone. All 3 patients with permanent adverse effects received treatment to 15 Gy(RBE). No patients developed new cranial deficits following treatment with proton SRS. DISCUSSION In this initial report of proton SRS for the treatment of benign meningiomas, the 3-year actuarial tumor control rate was 94%. Although the median follow-up time was short, this rate is consistent with previous series of benign meningiomas treated with SRS using photon or gamma delivery systems reporting 5-year tumor control rates of 87% to 98% (4–20). The rate of symptom improvement or stability (91%) is also consistent with previously reported rates of 81% to 96% (4, 8, 9, 11–13, 15, 18–20). In the context of the well-established results of SRS for benign meningiomas, our initial data suggest that proton SRS is an effective therapy for benign meningiomas of <4 cm in diameter. Previously published studies of the use of proton RT for benign meningiomas have concentrated on fractionated proton RT alone or in combination with photon RT (27–29), more recently as a means to escalate dose to atypical and malignant meningiomas (30, 31). Two small series with short follow-up have reported the results of hypofractionated proton SRT for skull-based meningiomas (32, 33).

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The median tumor volume in our series was 2.4 cm3 (interquartile range, 1.1-3.4 cm3), which is smaller than those in other benign meningioma series with median or mean tumor volumes of 4.1-12.7 cm3 (4-20). At our institution, patients with larger tumors are often treated with fractionated SRT. Since larger tumor volumes are associated with lower tumor control rates (5, 11), the small median tumor volume may suggest that our series should have a tumor control rate at the high end of the range reported. It is unclear why the tumor control rate in our series was perhaps lower than expected. One possible explanation is that 6 patients (12%) in the current study had atypical features but did not meet criteria for atypical meningioma. On univariate analysis, the presence of atypical features was significantly associated with decreased tumor control. Four of these patients were diagnosed before the 2000 World Health Organization (WHO) classification system established more standardized criteria. The 1993 WHO classification system defined an atypical meningioma as one in which ‘‘several’’ atypical features were present. In contrast, the 2000 WHO classification defined an atypical meningioma as one with increased mitotic activity, defined as $4 mitoses per 10 high-power fields, or with at least three of the following features: hypercellularity, small cells with a high nucleus-to-cytoplasm ratio, prominent nucleoli, uninterrupted patternless or sheet-like growth, and foci of ‘‘spontaneous’’ or ‘‘geographic’’ necrosis. This change upgraded many meningiomas from grade I to II (34). We were unable to obtain slides for review of all cases with atypical features, so we included these cases because they were considered benign meningiomas. However, such cases may represent more aggressive histology results with an increased likelihood of recurrence compared to typical benign meningiomas. The results of this study must be interpreted in the context of its design, which is a retrospective series that spans a long treatment period. The main limitation is that longer, more complete follow-up is needed to assess the durability of tumor control. In our study, 3 of the 5 patients had recurrence after the median follow-up of 32 months. Given the lack of complete follow-up, there may have also been an ascertainment bias such that patients who had recurrence had a greater propensity for follow-up evaluation and consideration for further treatment. The advantage of proton SRS is that it allows a significantly lower normal tissue integral dose than photon SRS. Figure 2 shows an example of a proton SRS and a photon SRS plan for a patient with a cavernous sinus meningioma. For small intracranial targets, Bolsi et al. (23) showed that using passive scattering proton RT rather than stereotactic arc therapy reduced the integral dose from 9.3 to 3.2 Gy cm3/103 and V20 for brain from 5.7% to 3.5% (23). A lower integral dose may be especially important in patients with benign tumors who generally have long life expectancy and thus may be more likely to experience radiationrelated late effects, including hypopituitarism and secondary cancers. However, although proton SRS achieves far less ex-

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posure of normal structures to radiation than currently available photon techniques, and thus would be expected to result in the lowest incidence of long-term sequelae, the difference between techniques may be small and would require large numbers of patients followed for long periods to demonstrate any clinically significant advantage. Proton techniques have also been shown to provide superior conformality and better sparing of organs at risk (23,35), which is especially important for unresectable meningiomas that are adjacent to the optic apparatus or brainstem. Contrary to the notion of superior conformality, the median CI of 2.4 in our series was higher than the median CI reported in Gamma Knife series. Dibiase et al. (5) reported a median CI of 1.34 (range, 0.65-3.16) for a median tumor size of 4.5 cm3, and Han et al. (8) reported a mean CI of 1.09 (range, 0.88-1.56) for a mean tumor size of 6.3 cm3. The lower median tumor size in our series may partially explain this discrepancy, as decreasing tumor volume has been associated with increasing CI (36). In our series, the CI for tumors #1.5 cm3 was significantly higher than tumors >1.5 cm3 (median, 2.6 vs. 2.1, respectively; p = 0.02). However, the CI may also be a poor measurement of the conformality of proton techniques. Bolsi et al. (23) showed that although the mean doses to the brainstem and ipsilateral optic nerve were significantly lower for adjacent intracranial targets treated with proton techniques than photon techniques, the calculated CI values were not significantly different between the two types of techniques (23). The median CGIg of 81.7 (range, 67.1-113.5) was consistent with or perhaps superior in certain cases to previously published results. When they introduced the index for LINAC-based SRS, Wagner et al. (26) indicated that CGIg scores of $90 are typical for small targets with simple geometries, whereas scores of 60 to 80 are attainable for larger or more complex targets. In a recently published series of patients treated with volumetric IMRT intracranial SRT by Mayo et al. (37), the mean CGIg score was 64.9 (range, 39.9-105.6) for 14 targets with a mean target volume of 2.8 cm3 (range, 0.3-12.6). The median CGIg in our series was higher, but given the small number of patients, it is difficult to judge without direct comparison. In our study, among the 11 patients with target volumes of $4.0 cm3, CGIg ranged from 69.9 to 99.4, suggesting it may be interesting to compare gradient indices of proton and photon plans for large, complex targets. Still, the higher CI in our series underscores previous findings that the superior conformality of proton techniques are most pronounced for large, irregular targets. In a planning comparison study, Serago et al. (38) showed that the risk for complications was lower with proton techniques than with dynamically shaped or circular photon techniques for intracranial targets that were irregularly shaped or large but not for a spherical target of 1.1 cm3. In a study comparing proton, LINAC, and Gamma Knife plans, Verhey et al. (39) showed that protons had the advantage of providing simultaneous conformality and dose uniformity for large, irregularly shaped targets. Gamma Knife provided good

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Fig. 2. Comparison of dose distributions for proton (left panel) and photon (right panel) SRS treatment plans for a cavernous sinus meningioma. SRS = stereotactic radiosurgery; RT = radiation therapy; RT. OPTIC N. = right optic nerve; LT. OPTIC N. = left optic nerve.

conformality with significant dose inhomogeneity for irregularly shaped targets that were small or moderately sized. Multiarc LINAC plans provided good conformality for targets regardless of size if they had a regular shape. However, since these studies were published, each of these techniques has advanced, and the results may be different with current technology. Photon SRS is improved with multiple isocenter and IMRT techniques. Likewise, the development of more sophisticated proton planning methods such as intensitymodulated proton therapy may improve the conformality and gradient of proton SRS.

Another property of proton SRS dosimetry, which is reflected in the current series, is dose homogeneity within the target (23, 39). The homogeneity index was between 1.0 and 1.3 for all cases, which is well below the threshold of 2.0 that the Radiation Therapy Oncology Group has used for quality assurance in radiosurgery trials (25). Whether greater homogeneity influences tumor control rates in SRS cases is unknown, and some argue that high central doses may improve local control in radiosurgical cases (40). Regardless, greater homogeneity may lead to lower complication rates (41). In our series, although there were 2

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patients with transient exacerbations of cranial nerve deficits, no new cranial deficits were seen. Three permanent adverse events, including 2 patients with seizures and 1 patient with hypopituitarism, were seen following proton SRS. This rate of 5.9% is consistent with previously reported rates of permanent complications of 1% to 10% (4–20). In addition, all permanent adverse effects occurred in patients who were treated to 15 Gy(RBE), so perhaps with further follow-up, we could see a decreased complication rate among patients treated to 12 Gy(RBE).

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CONCLUSIONS These initial results demonstrate that proton SRS is effective for patients with small benign meningiomas with a 3year tumor control rate of 94%. To our knowledge, this is the first series to examine the outcomes of proton SRS for treatment of meningiomas. Longer term follow-up is needed to determine the durability of control and whether radiationinduced side effects are minimized with proton SRS compared to photon SRS.

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19. 20. 21. 22.

23.

24. 25. 26. 27.

28.

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