Radiotherapy for Vestibular Schwannomas: A Critical Review

Int. J. Radiation Oncology Biol. Phys., Vol. 79, No. 4, pp. 985–997, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter

doi:10.1016/j.ijrobp.2010.10.010

CRITICAL REVIEW

RADIOTHERAPY FOR VESTIBULAR SCHWANNOMAS: A CRITICAL REVIEW ERIN S. MURPHY, M.D.,* AND JOHN H. SUH, M.D.* *Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH Vestibular schwannomas are slow-growing tumors of the myelin-forming cells that cover cranial nerve VIII. The treatment options for patients with vestibular schwannoma include active observation, surgical management, and radiotherapy. However, the optimal treatment choice remains controversial. We have reviewed the available data and summarized the radiotherapeutic options, including single-session stereotactic radiosurgery, fractionated conventional radiotherapy, fractionated stereotactic radiotherapy, and proton beam therapy. The comparisons of the various radiotherapy modalities have been based on single-institution experiences, which have shown excellent tumor control rates of 91–100%. Both stereotactic radiosurgery and fractionated stereotactic radiotherapy have successfully improved cranial nerve V and VII preservation to >95%. The mixed data regarding the ideal hearing preservation therapy, inherent biases in patient selection, and differences in outcome analysis have made the comparison across radiotherapeutic modalities difficult. Early experience using proton therapy for vestibular schwannoma treatment demonstrated local control rates of 84–100% but disappointing hearing preservation rates of 33–42%. Efforts to improve radiotherapy delivery will focus on refined dosimetry with the goal of reducing the dose to the critical structures. As future randomized trials are unlikely, we suggest regimented pre- and post-treatment assessments, including validated evaluations of cranial nerves V, VII, and VIII, and quality of life assessments with long-term prospective follow-up. The results from such trials will enhance the understanding of therapy outcomes and improve our ability to inform patients. Ó 2011 Elsevier Inc. Vestibular schwannoma, Radiosurgery, Fractionated stereotactic radiosurgery, Proton, Cranial neuropathy.

(RT). The role of observation, which might be the best option for some patients, has been described in detail. Surgical resection and RT can be subdivided into several treatment strategies and have evolved because of advances in the technology. For the present report, an extensive data review of the RT options, including single-session stereotactic radiosurgery (SRS), fractionated conventional RT, fractionated stereotactic RT (FSRT), and proton therapy, was undertaken. We have summarized the experience to date using RT in the management of VSs, with strategies for improving the current therapies discussed.

INTRODUCTION Vestibular schwannomas (VSs) are benign, slow-growing tumors of the sheath cells lining the eighth (vestibulocochlear) cranial nerve (CN). Patients often present with unilateral sensorineural hearing loss and associated vertigo and tinnitus. Other presenting symptoms have included CN V (trigeminal) and CN VII (facial) deficits. The incidence of VS has been increasing. The estimated incidence was 5 tumors per 1 million people annually in 1976 and had increased to just under 20 tumors per 1 million in 2001 (1). The apparent increasing incidence of VS has been related to the increase of incidental findings noted on magnetic resonance imaging (MRI) (1). The median age at diagnosis has remained stable at about 55 years of age (1). Greater than 90% of the tumors are unilateral at presentation (2, 3), with the remaining 10% bilateral related to the autosomal dominant neurofibromatosis type 2 syndrome.

Observation Vestibular schwannomas do not always grow, and when they do, the growth rate has generally been thought to be slow (1, 4–17). From two reviews of >20 reports of conservatively managed VSs, the mean growth rate of VS was 1.2–1.9 mm annually, with only 43–46% of tumors exhibiting any growth and only 18–20% requiring intervention after a mean follow-up >3 years (14, 17). Published studies have reported that 3–11% of these tumors

TREATMENT The management options for patients with VSs have included observation, surgical resection, and radiotherapy Reprint requests to: Erin S. Murphy, M.D., Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Ave., T28, Cleveland, OH 44195. Tel: (216) 445-4379; Fax: (216) 445-1068; E-mail: [email protected]

Conflict of interest: none. Received May 26, 2010, and in revised form Oct 1, 2010. Accepted for publication Oct 8, 2010. 985

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Table 1. Early studies of higher dose stereotactic radiosurgery for vestibular schwannoma

Source Leksell, 1971 (19) Flickinger, 1993 (24) Foote, 1995 (22) Mendenhall, 1996 (25) Kondziolka, 1998 (26) Suh, 2000 (23)

Mean tumor Median volume follow-up Patients (cm3)/mean diameter (cm) (mo) (n)

Marginal dose (Gy)

44.4

160

NA/<3.0

18–25

24

134

2.75/NA

16

36

3.14/NA

12–20 (median,17) 16–20y

>12

56

NA

10–22.5

>60

162

NA/2.2

16.6 (mean)

49

29

2.1/NA

8–24, (median,16)

Median prescription IDL (%) NA

Local control (%)

Useful CN V CN VII hearing preservation preservation preservation (%) (%) (%)

81

82

86

50

89.2 (4 y)

67.1

71.0

50

100

80z 50 80{

95 (5 y)

41.4 (2 y)

33.5 (2 y)

>78.6x

>78.6x

98 (5 y); 73 98 (10 y) 94 (5 y) 85 (5 y)

73 68 (5 y)

20* 35 41.7 (2 y) G-R I-II NA 51 26k

Abbreviations: IDL = isodose line; CN = cranial nerve; NA = not available; G-R = Gardner-Robertson grade. * Percentage of all patients. y Prescribed dose determined by size: #20 mm, 20 Gy; 21–30 mm, 18 Gy; >30 mm, 16 Gy. z For 71% of patients. x Of 56 patients, 12 developed new or progressive CN V and VII neuropathy. { For 61% of patients. k Determined by subjective hearing loss in 14 of 19 patients who presented with useful hearing.

will regress without any intervention (8, 13, 17). The slow growth of these tumors has made observation an appropriate course for minimally symptomatic tumors or elderly patients. Annual serial MRI is a common recommendation, along with hearing evaluations for conservatively managed patients (1, 5, 7, 9, 10, 16). Elderly patients presenting with small tumors represent the ideal group for conservative management with active observation. Several studies have investigated the role of observation in this population (6, 9–12). Three of these series with follow-up of $3 years revealed that 5.7–28% of patients required intervention for their VS (9, 11, 12). Hajioff et al. (7) reported outcomes at 10 years and found that the failures were more likely to occur in the first 5 years after diagnosis. In addition, they also demonstrated clinical outcomes for patients who experienced tumor progression equal to those who had been treated without a period of observation. Conservative management is an important option. Therefore, understanding the potential consequences of VS progression, which can include hearing loss and the possible loss of treatment options, is imperative. A retrospective study has shown that hearing deteriorates, even without tumor growth (7). In a prospective study of 636 patients undergoing annual MRI and audiologic evaluations, good hearing and speech discrimination was noted in 53% of patients at diagnosis and in 31% of patients at 10 years of observation (16). Therefore, patients who present with useful hearing and are candidates for treatment should consider treatment to halt the tumor growth and associated side effects. The second important consideration is whether tumor progression can lead to fewer future treatment options. Two

reports have claimed that with tumor growth, 11–33% of patients will lose eligibility for hearing preservation surgery (5, 13). Several groups have tried to pinpoint which patients undergoing observation are likely to have tumor progression. The findings have been disappointing due to the erratic growth pattern of some tumors (9, 13). Nonetheless, some evidence has shown that patients receiving conservative management who have larger tumors at diagnosis (14 mm vs. 8 mm) (18), have a cerebellopontine angle component instead of an intracanalicular only tumor (7), or who present with disequilibrium (18) are more likely to experience tumor progression and require treatment. With continued follow-up and prospective evaluations, the identification of ideal candidates for observation might be possible. Single-session SRS Leksell (19) first used SRS for the treatment of VSs at the Karolinska Hospital in 1969. The tumor control rate was 81% after a median follow-up of 3.7 years. Transient trigeminal neuropathy and facial neuropathy occurred in 18% and 14% of the patients, respectively. With these encouraging results, SRS was further evaluated (Table 1). SRS, delivered using both gamma knife (GK) and linear accelerators, was initially used for a limited number of indications, including patients of older age, recurrence after surgery, bilateral tumors, and patients with medically inoperable tumors (20–23). Initial GK results. In 1987, the University of Pittsburgh started their GK program and reported the 4-year outcomes after treating 134 patients with VSs (24). The 4-year actuarial tumor control rate was 89.2%, using a median tumor dose

Radiotherapy for vestibular schwannomas d E. S. MURPHY AND J. H. SUH

of 17 Gy. The rate of trigeminal and facial nerve preservation was 67% and 71%, respectively. Hearing measured by pure tone audiometry was preserved in 71%; however, the 4-year actuarial rate of useful hearing was only 35%. On multivariate analysis, decreasing tumor diameter and an increasing number of isocenters were significant for preservation of CN function, and neurofibromatosis type 2 status increased the risk of hearing loss. In an earlier analysis, the complications were reported and showed that the cranial neuropathies had a median onset of 5–6 months, with improvement over time (20). Four patients required ventriculoperitoneal shunts for communicating hydrocephalus, and eight had imaging evidence of edema or blood–brain barrier breakdown in the adjacent brain parenchyma. They concluded that GK radiosurgery would unlikely obviate the need for microsurgical removal but that it was a safe and effective tool for select patients. The Mayo Clinic treated their first patient with GK radiosurgery in 1989 using indications similar to those used by the Pittsburgh group (22). The prescription dose was determined by the largest tumor dimension, with tumors #20 mm, 21 to #30 mm, and 31 to #40 mm receiving 20, 18, and 16 Gy, respectively. After a median follow-up of 16 months, they reported a 100% local control rate but a 2year actuarial incidence of new or progressive facial neuropathy of 66.5% and trigeminal neuropathy of 58.9%. A greater tumor dose was significant on multivariate analysis for earlier onset of trigeminal neuropathy. In contrast to the findings from the Pittsburgh group, they found that the use of more than five isocenters was associated with an earlier onset of or worsening neuropathy. Regarding hearing preservation, they reported a 2-year actuarial preservation rate of 41.7%, which was classified as Gardner-Robertson (G-R) Class I or II. Initial linear accelerator–SRS results. Both the University of Florida and the Cleveland Clinic have used linear accelerator–SRS for VSs (21, 23, 25). The University of Florida published their 5-year outcomes of linear accelerator–SRS for VSs in 1996 (25). The prescription dose ranged from 10 to 22.5 Gy; however, 12.5–15 Gy was prescribed for 69.6% of patients, and was lower than the median dose of 17 Gy used by the Pittsburgh group, the 16–20-Gy dose used by the Mayo Clinic, and the 16Gy dose used by the Cleveland Clinic (22–24). The lower dose might have accounted for the improved rates of CN preservation, which was reported in 43 of 55 the University of Florida patients (78%). They found that the likelihood of complications depended on the dose and treatment volume (Table 2). Despite using lower doses, the tumor control rate remained excellent at 95% for 5 years. Cleveland Clinic reported a 94% local control rate at 5 years (23) and long-term estimated complications, including new or progressive trigeminal and facial nerve deficits of 15% and 32%, respectively. Subjective hearing decline occurred in 14 (74%) of the 19 patients who had had useful hearing before treatment. From this initial experience, we in-

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Table 2. Effect of linear accelerator stereotactic radiosurgery dose and volume on complication rate reported by Mendenhall et al. (25) * Radiation dose to tumor margin (Gy) 10–12.5y 15-17.5 (TV #5.5 cm3) 15-17.5 (TV >5.5 cm3) 20–22.5y

Complication rate (%) 13 9 71 100

Abbreviation: TV = tumor volume. * Complications included trigeminal and facial neuropathy and hydrocephalus requiring ventriculoperitoneal shunt. y Across all tumor volumes.

corporated the use of MRI-based planning and a reduction of prescription dose. Modern SRS results. When the University of Pittsburgh group published their long-term (5–10-year) results in 1998 with an excellent tumor control rate of 95%, radiosurgery was established as a standard alternative to microsurgical resection for many unilateral tumors #3 cm in extracanalicular diameter (26). Of the patients with intact trigeminal and facial nerves at presentation, function was preserved in 84% and 85%, respectively. The rate of recovery of facial neuropathy at 8 years was 63%. Similar to the University of Florida findings, both the tumor volume and the radiation dose to the tumor margin correlated with the risk of neuropathy on multivariate analysis. These early findings all demonstrated the need for dose reduction for enhanced CN preservation (22–26). Numerous reports (27–37) of the long-term outcomes after SRS using marginal tumor doses of 12–13 Gy (Fig. 1), with excellent progression-free survival (range, 92–100%), have been published (Table 3). Some institutions used MRI-based planning (27, 30, 31, 33, 34, 38), others used a combination of computed tomography and MRI (28, 29, 35, 37, 39), and only one used contrast-enhanced computed tomography alone (32). With these lower SRS doses and MRI-based treatment plans, permanent preservation of the trigeminal nerve and facial nerve has been possible in 92– 100% and 94–100% of the cases, respectively (27–37). In addition, the use of multiple isocenters has improved conformality, allowing for precise coverage of irregularly shaped VSs and decreasing the radiation dose to the CNs and normal brain tissue (29, 30). The consistency of these reported outcomes across institutions has been reassuring. These studies all included a mixed population of patients undergoing radiosurgery as primary management, for progression after surgical resection, or for residual disease after surgical resection. The percentage of patients who had undergone resection before radiosurgery ranged from 0–51%. It is important to note that patients who have undergone previous resection might have a greater risk of cranial neuropathies after SRS (40). Effect of SRS on CN V and VII. Multiple reviews of SRS for VS have revealed that the tumor size and prescription dose correlate with the risk of cranial neuropathy (30, 37,

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Fig. 1. Axial, coronal, and sagittal images of gamma knife radiosurgery treatment plan for vestibular schwannoma (VS), with 13 Gy prescribed to 51% isodose line covering VS contour; 24-Gy hotspot demonstrated within tumor volume. Brainstem and cochlea contoured, and maximal dose to these structures was 13.9 Gy and 8.9 Gy, respectively.

40, 41). Patients with CN V deficits might experience facial numbness, tingling, or paresthesia. In contrast, CN VII deficits cause facial weakness. Friedman et al. (37) found that for each cubic centimeter increase in tumor volume, the risk of facial weakness increased by 17%, and each 250-cGy dose increase resulted in 8.14 times the risk of facial weakness. The effect of conformity and the steepness of the dose gradient on both tumor control and CN V and VII dysfunction was also analyzed (42). They found that the dosimetric variables had no effect on any outcomes, but that the tumor volume and dose were predictive of CN function. However, the Pittsburgh group hypothesized that the length of the CN irradiated was the major factor in determining the risk of neuropathy (43). Their analysis showed that the pons–petrous distance and the mid-porous transverse tumor diameter correlated with the risk of neuropathy on both univariate and multivariate analysis. Thus, 3 cm has become the standard maximal diameter allowable for SRS treatments, although some SRS centers will treat larger lesions with the lower dose of 12 Gy. Effect of SRS on vestibular function of CN VIII. Limited data exist regarding the vestibular function of CN VIII, although dizziness and gait imbalance have been common presenting symptoms. Fukuoka et al. (29) reported that 17% of patients developed transient dizziness and 2% had persistent dizziness after SRS. They also reported on 56 patients not

included in their long-term evaluation who had consecutively undergone a thorough vestibular evaluation, including caloric testing, static stabilometry, and neurologic examinations both before and after SRS. The results revealed that 90% of the patients had vestibular dysfunction before SRS and that treatment had not significantly affected vestibular function. Combs et al. (44) reported that patients presenting with dizziness had no improvement after SRS. In our experience, 4% of patients developed new vestibular dysfunction, 61% who had presented with symptoms improved, and 22% had progression after long-term subjective evaluations after SRS (39). Effect of SRS on hearing preservation. With long-term follow-up, the range of hearing preservation after SRS from single-institution reports has been 32–71% (27–29, 31–35, 37, 38, 45, 46). All these institutions evaluated their patients before and after SRS using the G-R classification, with the exception of the results reported by Iwai et al. (31), who used only the pure tone average. G-R Grade I includes audiogram results of 0–30 dB pure tone average and 70–100% speech discrimination. Grade II includes 31–50 dB pure tone average and 50–69% speech discrimination. Hearing is considered preserved when the hearing level has been maintained at G-R Grade I or II after SRS. For accurate hearing data, it is important to follow these patients long term, because hearing can continue to decline for years after SRS. Prasad et al. (35) reported that a decline in hearing was not observed during the first 2 years

Table 3. Results from long-term studies of stereotactic radiosurgery with marginal tumor doses of 12–13 Gy for treatment of vestibular schwannoma

Patients (n)

Prasad, 2000 (35) Unger, 2002 (36) Chopra, 2007 (27) Hasegawa, 2005 (30)

4.27 6.3 5.7 >5

153 100 216 317

2.6–2.8*/NA 3.4/NA 1.3/NA 5.6/NA

13 (median) 13 (median) 13 (median) 13.2 (mean)

103 59 25zz 96x 152 103 26 295 19

NA 3.41/NA 0.27/NA 0.0001/NA 2.0/NA 1.95/1.77 NA/1.5 2.2*** 5.95/NA

12.2 (mean) 12 (median) 12 (all patients) 13 (median) 12 (median) 13 (median) 13 (median) 12.5 (median) 11–12

Myrseth, 2005 (34) Kim, 2007 (33) Iwai, 2008 (31) Niranjan, 2008 (45) Fukuoka, 2009 (29) Murphy, 2010 (39) Combs, 2006 (28) Friedman, 2006 (37) Kalogeridi, 2009 (32)

>3–4 6 7.4 3.5 $5 3.6 9 3.3 4.6

Marginal dose (Gy)

Mean IDL (%) 30–70 NA 50 51 NA 50 50 50 NA 50 80 70 or 80 54

PFS (%)

CN V preservation (%)

CN VII preservation (%)

Hearing preservation (%)

92y 96 98.3 (10 y) 93 (5 y){; 92 (10 y){ 93k 97 100 (5 y); 100 (10 y) 99 (2.3 y) 94 (5 y); 92.4 (8 y) 91.1 (5 y) 91 (5 y); 91 (10 y) 99 (5 y) 100zzz

98.3 100x 94.9 96 (>13 Gy); 98 (#13 Gy) NA 100 100 100 97.4 99 92 99.3yyy 100

98.4 98x 100 94 (>13 Gy); 99 (#13 Gy) 94.8 98.3** 100xx 100 100 95kk 95## 99.3yyy 100

58z 55z 44z 13 (>13 Gy); 68 (#13 Gy)z 32# z 33.3z yy 64{{ 64.5z 71 (assessment NA) NA 55z NA NA

Abbreviations: PFS = progression-free survival (determined by no additional intervention); other abbreviations as in Table 1. * For patients who underwent primary surgical resection followed by Gamma Knife, it was 2.6 cm3 and 2.8 cm3 for patients who underwent primary Gamma Knife. y Of 153 patients, 12 had progression on imaging. z Preservation of hearing as measured using Gardner-Robertson scale (Class I and II). x Five patients had mild transient trigeminal neuropathy and another four had transient facial neuropathy. { PFS, with 9% of patients requiring second intervention. k Included 5 patients who underwent microsurgical resection and 2 who required ventriculoperitoneal shunt for symptomatic hydrocephalus. # Of 31 patients, 10 maintained Gardner-Robertson Class I and II hearing. ** One patient developed aggravation of hemifacial spasms and underwent tumor resection. yy Of 12 patients, 4 had useful hearing preserved. zz Intracanalicular tumors only. xx One patient (4%) had transient facial neuropathy. {{ Measured by pure tone average <50 dB. kk Additional 5% of patients had transient facial neuropathy. ## Additional 15% of patients had transient facial neuropathy. *** Median treatment isodose volume. yyy Of those treated with 12.5 Gy. zzz PFS at follow-up of 55 months.

Radiotherapy for vestibular schwannomas d E. S. MURPHY AND J. H. SUH

Investigator

Follow-up (y)

Mean tumor volume (cm3)/mean diameter (cm)

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Fig. 2. (a) Axial, (b) coronal, and (c) sagittal images of Novalis radiosurgery plan for vestibular schwannoma. Tumor prescribed to dose of 45 Gy using 1.8 Gy/fraction. The large vestibular schwannoma compressed the brainstem.

of follow-up but that hearing had subsequently declined through 8 years of follow-up. Similarly, Chopra et al. (27) reported that after 3 years of follow-up, the preservation rate of G-R Grade I and II was 74% but had declined to 44% at 10 years. Radiographic findings and SRS failure. Patients should be followed up after SRS with clinical examination and contrast-enhanced MRI annually for the first 5 years and every 2 years thereafter. Reports have shown that #29% of VSs demonstrate a transient increase in volume after SRS (33). This radiographic change will be noted 6–30 months after treatment, with a mean interval to maximum tumor volume of 13.4 months (33). Given this observation, it is important not to hastily recommend additional treatment. The median interval to salvage surgery has ranged from 30 to 37 months for patients in whom GK therapy failed (30, 47). Larger reviews have reported that failure is rare >36– 60 months after SRS (30, 45).

Fractionated conventional RT Fractionated conventional RT was first described by Wallner et al. (48) as adjuvant therapy to subtotal resection and biopsy, reducing the tumor local recurrence rate from 46% to 6% when doses $45 Gy were delivered to the postoperative bed. The group reported an actuarial 15-year tumor control rate of 94%. The first report of long-term follow-up of RT as the primary treatment was of 24 patients who had undergone RT because of advanced age, to preserve their hearing in patients with neurofibromatosis type 2 after removal of contralateral tumors, or to treat recurrent disease (49). The investigators reported a local control rate of 88% at 5 years and 86% at 15 years, with a mean radiation dose of 51 Gy given in 1.8 Gy/fraction (50). After a median follow-up of 80 months, hearing had been preserved in 7 of 9 patients with bilateral VSs who had undergone previous resection of their contralateral tumor. Serviceable hearing was defined as sufficient auditory function of the treated side for communication. No

Table 4. Long-term outcomes for patients receiving fractionated stereotactic radiotherapy for vestibular schwannoma

Source

Tumor control (%)

CN V CN VII preservation (%) preservation (%)

54 42 33 45

19 51 80 101

NA/3.5 8.6/NA NA/2.5 NA/1.9

36/6y; 30/5z 57.6 (mean)/1.8–2 20/4k; 25/5# 40–50/2yy

85 NA NA 80

100 100 (2 y); 97.7 (5 y) 94 (5 y) 91.4 (5 y)

100 95.2 98 (5 y) 96

100 100 97 (5 y) 100

36 45.3 48 48.5 31.9 36.5

48 70 16 106 60 34

2.51/NA 2.4/NA NA/1.75 3.9/NA 4.9/NA 1.06/NA

54/1.8 54/1.8 50/2 57.6 (median)/1.8 50 (mean)/2 45/1.8

90 95 NA 90 95–100 90

100 100 (3 y); 98 (5 y) NA 94.3 (3 y); 93 (5 y) 96.2 (5 y) 100 (2 y); 95.7 (4 y)

97.8 96 NA 96.6 100 100

97.9 99 NA 97.7 100 94

Abbreviations: fx = fraction; PTV = planning target volume; other abbreviations as in Table 1. * Of those presenting with useful hearing, defined as Gardner-Robertson Class I and II, unless otherwise specified. y Dose regimen for first 6 patients. z Dose regimen for subsequent 13 patients. x Determined by audiometry. { Hearing allowing for sufficient communication without visual aids. k Dose regimen for first 19 patients. # Dose regimen for subsequent 68 patients. ** Subjectively assessed. yy Median total dose, 48 Gy. zz Subjectively defined as unaided ability to discriminate normal speech and use telephone with affected ear. xx According to patient self-assessment. {{ Determined by patient questionnaires for 65 patients and audiograms for 27. kk Defined as ability to use telephone with affected ear.

Hearing preservation* (%) 100x 85 (2 y); 85 (5 y){ 61** 71 93zz 84 (3 y)xx; 84 (5 y)xx 9 (4 y) 94 (5 y){{ 77.3kk 63 (2 y); 63 (3 y)

Radiotherapy for vestibular schwannomas d E. S. MURPHY AND J. H. SUH

Kalapurakal, 1999 (51) Fuss, 2000 (52) Meijer, 2003 (54) Sawamura, 2003 (55); Shirato, 2000 (53) Selch, 2004 (56) Chan, 2005 (47) Lin, 2005 (58) Combs, 2005 (57) Koh, 2007 (59) Thomas, 2007 (60)

Mean tumor Mean IDL Follow-up Patients volume (cm3)/mean Total dose (Gy)/dose covering (mo) (n) diameter (cm) per fx (Gy) PTV (%)

991

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Table 5. Comparison of stereotactic radiosurgery and fractionated stereotactic radiotherapy SRS 1-day Outpatient procedure Possible requirement of invasive head frame No margin for set-up uncertainty Limited to tumors #3 cm in diameter Vestibular schwannomas are slow-growing tumors with low a/ b ratio similar to late-responding tissues and do not have increased therapeutic ratio with fractionation Vestibular schwannomas are not typically hypoxic and therefore would not benefit from reoxygenation gained from fractionation

FSRT 5–6-wk Daily treatment Noninvasive relocatable head frame often used 1 to 2 mm margin for PTV Ability to treat tumors >3 cm and safely treat tumors adjacent to brainstem Fractionation allows for sublethal radiation-induced damage repair with advantage of reducing long-term damage and theoretically preserving hearing Vestibular schwannomas do not demonstrate accelerated repopulation; therefore overall treatment time has little influence on tumor control

Abbreviations: SRS = stereotactic radiosurgery; FSRT = fractionated stereotactic radiotherapy; PTV = planning target volume.

transient or permanent trigeminal or facial neuropathies were observed. RT was performed using either cobalt-60 g-rays or 9-MV photons with three-dimensional dosimetry for the 9MV plans using three to four RT beams. Fractionated stereotactic RT Stereotactic RT technology has allowed for more conformal dose distributions (Fig. 2). Since the late 1980s, FSRT has been used to treat patients with VS (51, 52). The data reporting long-term follow-up of FSRT for VS have revealed a local tumor control rate of 94–100% (47, 51–60) (Table 4). All studies that reported the details of their planning techniques used both computed tomography and MRI treatment plans (47, 51, 52, 54, 56, 57, 59, 60). Most institutions used a 1–2-mm margin on the contrast-enhancing tumor as seen on MRI (52, 54, 56, 57, 59, 60). Using various fractionation schemes, the rate of trigeminal and facial nerve preservation has been $95% and $94%, respectively (47, 51–60). Interest in FSRT grew after reports of the high rates of cranial neuropathy resulting from 16-Gy SRS (26). FSRT was first used for patients with tumors with a pons–petrous distance >1 cm and midporous transverse diameter >2 cm and because of the associated theoretical risk of SRSrelated neuropathy (43, 51). Kalapurakal et al. (51) used a hypofractionated regimen of 36 Gy in six fractions; however, the dose was reduced to 30 Gy in six fractions after 2 of the first 6 patients developed worsening ataxia. At a median follow-up of 4.5 years, excellent tumor control rates were observed, with tumor shrinkage in 10 of 19 patients and a stable tumor size in 9. None of the patients developed transient or permanent trigeminal or facial neuropathy. All 9 patients with evaluable hearing before treatment had hearing preservation, as measured by audiometric testing. A group from The Netherlands reported their prospective single-institution experience of treating 80 dentate patients with hypofractionated SRS (20 Gy in five fractions or 25 Gy in five fractions) and 49 edentate patients with a single treatment of radiosurgery (10 Gy or 12.5 Gy) (54). Their analysis demonstrated equivalent 5-year tumor control, facial nerve preservation, and hearing preservation. The trigeminal nerve preservation rate was significantly improved

for patients receiving the hypofractionated regimen at 98% vs. 92% (p = .048) for patients receiving the singlefraction regimen. The current radiation dose prescribed for FSRT ranges between 40–57.6 Gy in 1.8–2-Gy/fraction (47, 52, 53, 55–60). The ultimate goal of these fractionation schemes has been to improve the rate of hearing preservation. The reported hearing preservation rates have been 63–94% (47, 52, 53, 55–60). However, hearing preservation has not been consistently measured and recorded using the G-R hearing scale. Although hearing levels sufficient for using a telephone and other subjective measures are important for the patient, they do not allow for an objective assessment of the hearing function and preservation across the various treatment options. Comparison of outcomes after SRS and FSRT No prospective, randomized data comparing the outcomes for patients treated using the various radiotherapy methods have been completed. A wide variety of definitions of tumor control and CN preservation have been used, as reported by Bassim et al. (61), making comparisons difficult. The actual logistical and theoretical radiobiologic differences between SRS and FSRT are listed in Table 5. Despite the proposed radiobiologic benefits and technical differences of each approach, little evidence has supported that one technique is superior. The University of Heidelberg and Thomas Jefferson University have presented nonrandomized, single-institution reports of outcomes comparing the use of SRS and FSRT (44, 62) (Table 6). The Jefferson group originally sought to perform a randomized trial but was unable to enroll patients owing to either patient expectations or physician bias (62). Tumor size and physician bias influenced the treatment decision at both institutions. Both groups reported equivalent tumor control and preservation of CN V function. When a SRS dose of #13 Gy was considered, the Heidelberg group also reported equivalent preservation of CN VII and hearing. The Jefferson group reported significantly lower preservation of hearing with SRS (33% vs. 81%) compared with FSRT. The conflicting hearing results might have resulted from the different lengths of follow-up, a relatively small number of patients in the Heidelberg SRS group, and a very low

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Table 6. Single-institution study results comparing fractionated stereotactic radiotherapy and stereotactic radiosurgery Source

Treatment Patients type Follow-up (n)

Marginal dose (Gy)

Tumor CN V CN VII Hearing control (%) preservation (%) preservation (%) preservation (%)

Philadelphia: Andrews, 2001 (62) FSRT SRS

115 wk 119 wk

56 69

FSRT SRS SRS

75 mo 75 mo 75 mo

172 19 11

50 (2/fx) 12

97 98

93 95

98 98

81 33

96 (5 y)* 96 (5 y)* 96 (5 y)*

97 100 93

98 95z 88z

78 (5 y)y 78 (5 y)y NA

Heidelberg: Combs, 2010 (44) 57.6 (1.8/fx) #13 >13

Abbreviations: fx = fraction; other abbreviations as in Tables 1 and 5. * No statistically significant difference found between local control after FSRT vs. after SRS; specific data for each not provided. y Significant difference for hearing preservation outcomes according to SRS dose, with doses #13 Gy resulting in significantly better hearing preservation; comparing hearing preservation in SRS group treated with doses #13 Gy with that in FSRT group, no significant difference found. z Facial nerve dysfunction reported in 17% of SRS group overall, of which 5% was from 1 patient treated with 13 Gy.

hearing preservation rate in the Jefferson SRS group. The Jefferson group had shorter follow-up overall (<30 months) and, specifically, a short audiometry follow-up of 38–41 weeks. The investigators noted that trigeminal neuropathy occurred within 6 months in the SRS group but was delayed to 1 year in the FSRT group; therefore, longer follow-up would allow for a more appropriate comparison of the incidence of neuropathy. Thomas et al. (60) also reported that a delay in sensorineural hearing loss occurred with a latency of 1.5–5 years after fractionated RT. However, the Heidelberg group reported that most hearing detriment was noted at 6–10 months after treatment. The rate of hearing preservation after SRS in the Jefferson group was at the low end of the single-institution SRS data, which have been in the range of 32–71% when the standard dose was taken into account (27–29, 31, 33–36, 38, 45). The best results have been from FSRT, with a 63–94% hearing preservation rate at a total dose of 40–57.6 Gy (47, 52–55, 57, 59, 60), with the exception of a 9% hearing preservation rate (G-R Grade I-II hearing) in the study by Lin et al. (58). Because the follow-up has been shorter for FSRT than for SRS and the interval to hearing loss is unclear, one cannot conclude that fractionation is better until long-term follow-up data are available. As listed in Tables 3 and 4, the definition of hearing preservation has varied across modalities. The fractionated group has used the G-R hearing classification less often. However, this evaluation is easily reproduced and should be included in any prospective studies. Proton therapy The highly conformal properties of proton beam therapy and rapid dose falloff offer theoretical advantages for VSs. Proton therapy has been used in fractionated, hypofractioned, and radiosurgery approaches, with tumor control rates of 84–100% (63–66) (Table 7). At Loma Linda University Medical Center, 31 patients with VS, with a mean tumor volume of 4.3 cm3, were treated with fractionated RT (63).

According to the hearing status of patients, the prescribed dose was 54 cobalt Gray equivalent in 30 fractions and 60 cobalt Gray equivalent in 30–33 fractions for patients with functional and nonfunctional hearing, respectively. Both dose groups had excellent results, with a 100% tumor control rate and no CN V or VII neuropathy. Similar tumor control results were reported from the Massachusetts General Hospital experience with SRS and a median marginal dose of 12 cobalt Gray equivalent to the tumor (64, 66). Their trigeminal and facial nerve preservation rate was 89–95% and 91–95%, respectively. The benefit of the proton dose distribution did not seem to enhance hearing preservation in these early experiences. The hearing preservation rate was 31% in the fractionated series from Loma Linda Medical Center (63). The proton beam SRS and hypofractionated regimens yielded a hearing preservation rate of 33–42% (64–66). The moderate hearing preservation rates might have been because these proton beam studies had a small percentage of patients presenting with useful hearing. The Loma Linda group proposed a decrease in the prescribed dose with the hope of improving hearing preservation and maintaining tumor control (63). Baumert et al. (67) performed a dosimetric analysis that evaluated intensity-modulated photon SRT and intensity-modulated proton therapy and found that conformality was equivalent but that proton therapy provided a lower integral dose. Proton studies are needed to evaluate the techniques for hearing preservation and to determine the clinical effect of a reduced integral dose to normal tissues. FUTURE DIRECTIONS Refined dosimetry Detailed dosimetric analyses might provide insight into the effect of the radiation dose and fractionation on the preservation of CN VIII function. With regard to hearing preservation and SRS, Linskey (68) proposed five specific

42 90.5 Hypofractionated 5.9 51 Clinical 72; imaging 60 Vernimmen, 2009 (65)

Bush, 2002 (63)

Abbreviations: CGE = cobalt Gray equivalent; CN = cranial nerve; SRS = stereotactic radiosurgery; fx = fraction. * Of those presenting with useful hearing, defined as Gardner-Robertson Class I and II, unless otherwise specified. y Median dose (range 10–18 CGE). z Not including 9.4% (5 new, 1 exacerbated) intermittent facial paresthesia. x Not including 9.4% (5 new, 1 exacerbated) transient partial facial weakness and 9.4% synkinesis (5 new, 1 exacerbated). { Hearing assessment not specified; preservation defined as functional hearing. k For patients with useful hearing. # For patients without useful hearing. ** Actuarial rates of freedom from progression.

93 98 (5 y)**; 87 (10 y)**

100 100 100

54/30 fxk 60/30–33 fx# 26/3 fx Fractionated 4.3 31

33.3 33.3{ 91.1 95.3x 89.4 95.3z 95.3 (2 y); 93.6 (5 y) 94 (2 y); 84 (5 y) 12y 12 SRS SRS 1.4 2.49 88 68

38.7 Clinical 44; imaging 34 34

Source

Weber, 2003 (66) Harsh, 2002 (64)

Hearing preservation* (%) CN VII preservation (%) CN V preservation (%) Local control (%) Radiation dose (CGE) Radiation method Mean tumor volume (cm3) Patients (n) Follow-up (mo)

Table 7. Results of studies using proton beam radiotherapy for vestibular schwannoma

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dosimetric guidelines. These included strict attention to three-dimensional conformity to limit the dose to the ventral cochlear nucleus to <9 Gy, exclusion of the cochlear nerve (when visible on contrast-enhanced T2-weighted MRI) and the dura mater of the anterior border of the internal auditory canal, a tumor margin dose <12 Gy, optimization of the tumor treatment gradient index, and limiting the dose to the modiolus and the basal turn of the cochlea to as low as possible. Several reports have suggested dose limits to the cochlea of <3.7 to <4.75 Gy (69–72). Thomas et al. (60) found that the percentage of the cochlea volume receiving 90% of the prescription dose (45 Gy) predicted for hearing preservation. No other dosimetric variables, including the dose to the cochlear nucleus, correlated with hearing preservation. From the 13 studies reviewed for modern SRS results, only 2 groups (28, 32) report the delineation of organs at risk during treatment planning. Only 3 (52, 57, 60) of the 10 studies of long-term results of FSRT discussed contouring organs at risk as a part of their treatment planning. As we embark on improving treatment plans, we need to agree on a consensus of which critical structures should be included and how to contour the target and critical structures. MRI-based plans have enabled better delineation of the tumor volume and critical structures with the potential for diminished side effects (23). Because advanced technology is used in our treatment planning, it is imperative that we continue to scrutinize the outcomes. Pollock et al. (73) performed an analysis of contemporary low-dose SRS for VSs and found a tumor control rate of 97% at 7 years. Their multivariate analysis revealed that only increasing number of isocenters correlated with radiosurgery failure. The distortion of stereotactic MRI and the increased conformality and progressive dose reduction has led to portions of the tumor volume receiving less than the prescribed dose. In the future, we might have a better understanding of the effect of dose on the various intrinsic tumor characteristics. Detailed prospective follow-up Prospective studies should be designed to capture all possible symptoms attributed to VSs, treatment side effects and the impact on quality of life, and outcomes of various RT options. In particular, dizziness and tinnitus have rarely been described in published studies but can have a tremendous effect on patients’ quality of life. Objective evaluations such as patient questionnaires and the dizziness handicap index have been used after SRS for patients with VS and should be incorporated into the pre- and post-treatment workup (26, 28, 74, 75).With detailed follow-up, we can perhaps discover hearing loss earlier and develop investigational strategies to prevent further decline. In addition, with enhanced understanding of the outcomes of therapy, patient counseling will be improved and more informative. Follow-up should be conducted every 6 months and should include hearing evaluation with G-R classification, a complete neurologic examination with attention to the CNs, and dizziness and tinnitus questionnaires. Contrast-enhanced MRI should be

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performed on an annual basis for the first 5 years because this is the period during which most recurrences develop. More frequent imaging can be used for large or symptomatic tumors. CONCLUSIONS Equivalent local control has been demonstrated using SRS, fractionated conventional radiotherapy, FSRT, and proton therapy for VSs. Modern techniques of SRS and FSRT have allowed equivalent preservation of CN function, although differing hearing results have been reported. Radiobiologic principles have been used to

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support both approaches for treatment; however, the equally good outcomes from SRS and FSRT disregard the possible theoretical advantages. Treatment decisions could be based on patient preference between a minimally invasive 1-day procedure and 5–6 weeks of daily treatment, the availability of RT technology, and tumor size. The role of proton RT for VSs needs to be carefully evaluated until its benefits have been clearly demonstrated. Future prospective trials are needed to establish the best use of the various RT modalities and will ideally lead to an appropriate individualized management algorithm for patients with VS.

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