Journal of Clinical Neuroscience 21 (2014) 1083–1088
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Fractionated radiation therapy for vestibular schwannoma Brian J. Jian a, Gurvinder Kaur b, Eli T. Sayegh b, Orin Bloch b, Andrew T. Parsa b,⇑, Igor J. Barani c a
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA Department of Neurological Surgery, Northwestern University, 676 N. St. Clair Street, Suite 2210, Chicago, IL 60611-2911, USA c Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA b
a r t i c l e
i n f o
Article history: Received 26 August 2013 Accepted 13 November 2013
Keywords: Facial preservation Fractionated radiotherapy Hearing preservation Risks Vestibular schwannoma
a b s t r a c t Vestibular schwannomas are the most common tumors of the cerebellopontine angle. Multiple management paradigms exist for patients with these benign tumors, including observation, microsurgery, stereotactic radiosurgery, and fractionated radiation therapy, or some combination of these. While the proper course of management is controversial, the goals of therapy are to achieve excellent local tumor control and optimize functional outcomes with as little treatment-related morbidity as possible. Decision-making is tailored to patient-specific factors such as tumor size, clinical presentation, patient age, and goals of hearing preservation. We review the literature in order to summarize the application of fractionated radiation therapy to this tumor entity, where it is used as a primary treatment or, more commonly, as an adjunct therapy. We also provide an overview of the use of fractionated radiation therapy for the preservation of hearing and facial function, and dosing and other technical considerations, in light of the indolent natural history of vestibular schwannomas. We also discuss potential risks associated with this treatment modality, including its effects on temporal bone structures and cranial nerves among other possible complications. Lastly, we outline future directions in this rapidly evolving segment of vestibular schwannoma therapy, which has benefited from the advent of intensity-modulated radiation therapy coupled with stereotactic localization. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Vestibular schwannomas (VS), or acoustic neuromas, account for 6–8% of all intracranial tumors and are the most common tumors of the cerebellopontine angle [1]. Considerable debate arises over the proper management of these tumors based on variables such as tumor size, patient presentation, goals of hearing preservation, and patient age. There are currently four management options available, being observation (‘‘watchful waiting’’), microsurgery, stereotactic radiosurgery, and fractionated radiation therapy, or some combination of these. Most of these therapeutic interventions result in excellent local control outcomes, but since most of these tumors are benign, the management focus is on minimizing treatment-related morbidity and maximally preserving functional outcome. Two radiation therapy (RT) modalities in particular offer patients an excellent balance of tumor control, safety, and functional outcome: stereotactic fractionated radiation therapy (SFRT), including its variants, and stereotactic radiosurgery (SRS). Benign intracranial tumors, while generally non-invasive and slow growing, sometimes preclude the use of high-dose (or
⇑ Corresponding author. Tel.: +1 312 695 1801; fax: +1 312 695 0225. E-mail address: [email protected] (A.T. Parsa). http://dx.doi.org/10.1016/j.jocn.2013.11.005 0967-5868/Ó 2013 Elsevier Ltd. All rights reserved.
single-fraction) radiosurgery because of their proximity to critical neural structures. Instead, SFRT is used in the treatment of benign intracranial tumors, either as a primary treatment or, more frequently, as an adjunct therapy. Conventional fractionation is the application of daily doses of 1.8–2.0 Gy in five fractions per week. The weekly dose is 9–10 Gy for a total treatment dose of 50.4–54 Gy. The conventional fractionation schedule has been developed empirically to provide an optimal balance between tumor control and toxicity. With the advent of intensity-modulated radiation therapy (IMRT), coupled with stereotactic localization, higher doses of fractionated therapy can be delivered with minimal irradiation of nearby neural structures. IMRT uses multi-leaf collimators that permit modulation of the beam intensity and delivery of a more conformal dose to irregularly shaped tumors. With the improved precision of IMRT and the use of stereotactic localization (SFRT), a debate has arisen regarding the appropriate patient selection and utilization of each treatment modality.
2. Natural history/growth rate Given the indolent growth of VS, an initial strategy of observation and frequent MR imaging for serial follow-up has commonly been employed. Conservative management of these patients has been
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abundantly studied but has yielded widely disparate tumor growth rates (between 0 and 30 mm/year), with a median growth rate ranging from 0.35 to 2.2 mm/year (mean = 1.42 mm/year) [2–6]. A subset of these tumors demonstrates no growth on follow-up (18–86%, mean = 43%), and there are also some instances of spontaneous tumor regression (2.5 mm/year is observed, the authors recommended that treatment be offered [10].
have reported on its virtues as a primary treatment [12–18]. In one such series, all tumors were treated with 6 MV photons to 54 Gy in 30 fractions, prescribed to 90% isodose line; the authors reported a small, progressive increase in size (2 mm in any tumor dimension and reported a local tumor control rate of 100% in the 48 patients during the follow-up period. Other papers have claimed tumor control rates between 85% and 97% [20–22]. The variance in results seems largely related to the length of follow-up and varied definitions of tumor control. Instances of tumor progression can usually be detected within 3 years of treatment, although even later progression has been reported [15] and recent evidence suggests that changes in tumor response can occur as late as 5 years after RT [23]. Table 1 summarizes outcomes of selected, modern fractionated RT series. Dosimetric studies have compared delivery of radiation to critical structures by IMRT versus SRS [24–26]. In lesions requiring single dose planning, SRS appears to be the preferable therapy as the radiation dose to critical structures is significantly less. The accuracy of fixed head registration and conformality of SRS provide an overall advantage over IMRT. SRS therapy, however, can be problematic in the patient with preexisting mass effect from VS. Single-session RT has been shown to cause local swelling and associated mass effect, possibly necessitating surgical intervention. An advantage of IMRT plans over SRS is their fractionated format of radiation dosing. Consequently, in patients with large VS who cannot undergo surgery, administration of 1.5–2.0 Gy/day via fractionated RT avoids complications of tumor swelling [24].
3. Fractionated radiation therapy
4. Hearing preservation
Fractionated RT has traditionally been used as an adjunct to surgery in incompletely excised tumors, but recently several papers
Modern techniques have allowed for comparable rates of tumor control and facial nerve preservation with primary surgery versus
Table 1 Summary of outcomes of selected modern fractionated radiation therapy series Author
Year
n
Technique Dose/Fx (cGy) Tumor size (reported)
Lederman et al. [48]
1997
38 FSRT
Poen et al. [49]
1999
46 FSRT
Shirato et al. [50]
1999
37 FSRT
Fuss et al. [21]
2000
51 FSRT
3600/20 4000/22 5760/32
Andrews et al. [20]
2001
56 FSRT
5000/25
Meijer et al. [14]
2003
80 FSRT
1600/4 2500/5 (weekly) 2100/3
Williams et al. [51]
2003
80 FSRT
Selch et al. [19]
2004
48 FSRT
2000/5 2500/5 4000/20 5000/25 2500/5 3000/10 5400/30
Chung et al. [53]
2004
27 FSRT
4500/25
Combs et al. [52]
2005 106 FSRT
5760/32
Chan et al. [54]
2005
70 FSRT
5400/30
Chang et al. [47]
2005
61 FSRT
2100/3
Horan et al. [13]
2007
42 FSRT
5000/30
Sawamura et al. [15] 2003 101 FSRT
Local control Hearing preserv.
CN V CN VII Follow-up neuropathy neuropathy
6–50 mm (27 mm, mean)
100%
93.50% (pure tone audiometry)
0%
2.6%
0.5–2.7 yrs (2 yrs, median)
7–42 mm (20 mm, median) 7–30 mm (17 mm, median) 0.4–32.4 cm3 (5.5 cm3, median) 2.78 cm, mean
97%
77% at 2 yrs (G–R 1–2) 53% at 5 yrs (G–R 1–2) 85.2% at 5 yrs (word discrim.) 81% at 5 yrs (G–R 1–2) 61% at 5 yrs (subjective)
16%
3%
0%
0%
3.9%
0%
7%
2%
2%
3%
4%
0.9%
0%
0%
2.2%
2.1%
7% (transient) 3.40%
4% (transient) 2.3%
4%
1%
0%
0%
0%
3.2%
0.5–4 yrs (2 yrs, median) 0.3–5.8 yrs (2 yrs, median) 3.5 yrs (mean) 9.6 yrs (mean) 1–8.9 yrs (3 yrs, median) 0.5–10.6 yrs (3.8 yrs, median) 0.3–3.8 yrs (1.6 yrs, median) 0.5–6.1 yrs (3 yrs, median) 2.1 yrs (median) 0.3–14.3 yrs (4 yrs, median) 3.8 yrs (median) 3–5 yrs (4 yrs, median) 0.3–6.5 yrs (1.6 yrs, median)
8–38 mm (25 mm, mean) 3–40 mm (15.5 mm, median) 0.04–2.1 mm 1.9–40 mm 6–40 mm (22 mm, median) 7–37 mm (16 mm, median) 2.7–30.7 cm3 (3.9 cm3, median) 0.05–21.1 cm3 (2.4 cm3, median) 5–32 mm (18.5 mm, median) 10–40 mm (20 mm, median)
86.2% 97.7% 97% 94% 91.4% 97% 100% 100% 95.3% 98% 98% 96.9%
71.7% at 5 yrs (G–R 1–2) 67.6% at 1.6 yrs (word discrim.) 91.4% at 5 yrs (word discrim.) 57% at 2 yrs (G–R 1–2) 98% at 5 yrs 64% in NF2 patients 84% (subjective) 74% (G–R 1–2) 73% at 2.5 yrs (word discrim.)
CN = cranial nerve, discrim. = discrimination, FSRT = fractionated stereotactic radiotherapy, Fx = fraction, G–R = Gardner–Robertson, NF2 = neurofibromatosis 2, preserv. = preservation, yrs = years.
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radiation. Hence, differences in hearing preservation separate the two therapies in their overall effectiveness and intrinsic value. Prior to MRI, patients with VS typically presented after developing hearing loss. Earlier access to MRI has facilitated the diagnosis of small tumors, and consequently more patients with intact hearing are being identified. The judgment of which technique is superior for hearing preservation has been complicated by controversy over the definition of good or acceptable hearing [27]. There are currently two different classification schemes widely used in practice: the Gardner–Robertson modified hearing classification system and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Foundation hearing classification system. Currently, the most popular metric is the Gardner–Robertson scale [28], which sorts hearing into five classes (I–V) based upon speech discrimination and pure-tone audiogram (Table 2) [28]. The AAO-HNS Foundation hearing classification system consists of four classes (A–D) based upon slightly different sub-classification of pure-tone average and speech discrimination scores (Table 3) [29]. In both classification systems, serviceable hearing is defined by a puretone average less than or equal to 50 dB and a speech discrimination score greater than or equal to 50%. Where the classification systems diverge is in their characterization of non-serviceable hearing: the Gardner–Robertson system divides this range into three subgroups whereas the AAO-HNS system describes two subgroups. Frequently, patients diagnosed with small VS who retain useful hearing have been managed conservatively on the assumption that hearing will be preserved if the tumor remains static. However, some studies contend that there is no direct correlation between the rate of tumor growth and risk of hearing loss and that, for instance, hearing can be preserved even in large tumors. Yamamoto et al. prospectively followed 13 patients with VS, and found no appreciable change in audiometric scores among the seven patients whose tumors grew by at least 20% [30]. Conversely, the meta-analysis by Sughrue et al. mentioned earlier analyzed 982 patients and significantly correlated tumor growth rate >2.5 mm/ year (but not any other analyzed factor) with loss of hearing [10]. In a separate prospective study by the same authors, 59 VS patients with serviceable hearing on presentation were conservatively managed over a 22 year period [35]. Consistent with their previous findings, a tumor growth rate >2.5 mm/year at any point during follow-up was linked to a much faster rate of hearing loss. Median time to hearing loss was 7.0 years for faster-growing tumors and 14.8 years for tumors growing slower than 2.5 mm/year (p < 0.0001). Still, hearing loss has been documented in the absence of obvious radiographic signs of tumor growth [31–34]. Eventual hearing loss with non-growing tumors is poorly understood and cannot be attributed to a compressive effect. It has been speculated that hearing loss in this subset of patients stems from encroachment on neural structures within the internal acoustic canal, although a later study found no significant difference in median time to hearing loss with intracanicular extension [35]. Alternatively, it may be that chronic compression steadily abates cochlear
Table 2 Gardner–Robertson modified hearing classification Grade
Pure-tone average (dB)
Speech discrimination score (%)
I: Good–Excellent II: Serviceable III: Non-serviceable IV: Poor V: None
0–30 31–50 51–90 91–maximum Not testable
70–100 50–69 5–49 1–4 0
Note that when pure-tone average and speech discrimination score do not correspond, the lower class is used.
Table 3 American Academy of Otolaryngology-Head and Neck Surgery hearing classification Class
Pure-tone average (dB)
Speech discrimination score (%)
A: Useful B: Useful C: Aid-able D: Non-functional
630 >30 and 650 >50 Any level
P70 P50 P50 4.2 Gy. An analogous dose threshold has yet to be identified in the analysis of fractionated RT outcomes [68], but conservatively limiting the mean total fractionated dose to the cochlea to 35 Gy, when possible, should minimize the risk of sensorineural hearing loss [66]. 7. Risk to other cranial nerves Neuropathies of non-VII/VIII cranial nerves are typically rare in both the natural history of VS and as sequelae of therapeutic intervention (RT or surgery). The most common of these neuropathies involves the trigeminal nerve and, less frequently, the glossopharyngeal/vagal nerve complex. About 10% of patients experience symptoms related to disruption of the trigeminal complex as part of the natural history of VS, largely as a function of tumor size [69]. Lower cranial nerve involvement is described in only 3% of patients [69]. Of the cranial nerves not entering the internal auditory meatus, the trigeminal nerve is at greatest risk of injury from radiosurgery and fractionated RT. Recent SRS data suggest an injury rate of 2–3% [70], while a similar risk of 2–7% is observed with fractionated RT [14,19–21]. Lower cranial nerve dysfunction is very unusual with modern treatment techniques [70,71].
profile, which, for larger tumors, is arguably superior to that of either surgery and/or single-fraction radiosurgery. On the other hand, fractionated RT requires a significant time commitment (5–6 weeks) and may not be a viable option for some patients. Moreover, realization of the optimal outcomes reported for SFRT requires that the treating physician and therapist team be highly skilled and experienced in the delivery of this treatment. 9. Future directions Fractionated radiation therapy with modern technological advances, such as IMRT with stereotactic localization, allows delivery of high radiation doses to pathologic tissue with minimal impact on nearby critical structures. Consequently, FSRT may be wellsuited for select head, neck and central nervous system tumors that cannot be treated using radiosurgical techniques. Treatment risks to cranial nerves other than cranial nerve VIII are low (13 Gy to the isodose line [58], it is unclear if the larger dose indirectly increases the dose to the cochlea. It would be valuable to assess cochlear dose and hearing outcomes in patients receiving a radiation dose of >13 Gy. Insights derived from such a study could optimize dosing strategy in parallel with diminished cochlear radiation toxicity. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements
8. Additional risks Other non-cranial nerve complications that accompany surgery, radiosurgery, or fractionated RT are largely unique to each technique, and therefore not easily comparable. The principal complications of fractionated RT include tinnitus, balance disturbance, and hydrocephalus (rare). Compared to SRS, fractionated RT minimizes brain edema, and is the treatment modality of choice in inoperable patients with large tumors and significant, pre-existing tumor-related edema or brainstem compression. Hydrocephalus was entirely absent in one reported series with SFRT [19], whereas it was reported in 11% of patients in another [15]. Transient or exacerbated tinnitus is not uncommon, but permanent tinnitus was only seen in
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Fractionated radiation therapy for vestibular schwannoma Brian J. Jian a, Gurvinder Kaur b, Eli T. Sayegh b, Orin Bloch b, Andrew T. Parsa b,⇑, Igor J. Barani c a
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA Department of Neurological Surgery, Northwestern University, 676 N. St. Clair Street, Suite 2210, Chicago, IL 60611-2911, USA c Department of Radiation Oncology, University of California, San Francisco, San Francisco, CA, USA b
a r t i c l e
i n f o
Article history: Received 26 August 2013 Accepted 13 November 2013
Keywords: Facial preservation Fractionated radiotherapy Hearing preservation Risks Vestibular schwannoma
a b s t r a c t Vestibular schwannomas are the most common tumors of the cerebellopontine angle. Multiple management paradigms exist for patients with these benign tumors, including observation, microsurgery, stereotactic radiosurgery, and fractionated radiation therapy, or some combination of these. While the proper course of management is controversial, the goals of therapy are to achieve excellent local tumor control and optimize functional outcomes with as little treatment-related morbidity as possible. Decision-making is tailored to patient-specific factors such as tumor size, clinical presentation, patient age, and goals of hearing preservation. We review the literature in order to summarize the application of fractionated radiation therapy to this tumor entity, where it is used as a primary treatment or, more commonly, as an adjunct therapy. We also provide an overview of the use of fractionated radiation therapy for the preservation of hearing and facial function, and dosing and other technical considerations, in light of the indolent natural history of vestibular schwannomas. We also discuss potential risks associated with this treatment modality, including its effects on temporal bone structures and cranial nerves among other possible complications. Lastly, we outline future directions in this rapidly evolving segment of vestibular schwannoma therapy, which has benefited from the advent of intensity-modulated radiation therapy coupled with stereotactic localization. Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction Vestibular schwannomas (VS), or acoustic neuromas, account for 6–8% of all intracranial tumors and are the most common tumors of the cerebellopontine angle [1]. Considerable debate arises over the proper management of these tumors based on variables such as tumor size, patient presentation, goals of hearing preservation, and patient age. There are currently four management options available, being observation (‘‘watchful waiting’’), microsurgery, stereotactic radiosurgery, and fractionated radiation therapy, or some combination of these. Most of these therapeutic interventions result in excellent local control outcomes, but since most of these tumors are benign, the management focus is on minimizing treatment-related morbidity and maximally preserving functional outcome. Two radiation therapy (RT) modalities in particular offer patients an excellent balance of tumor control, safety, and functional outcome: stereotactic fractionated radiation therapy (SFRT), including its variants, and stereotactic radiosurgery (SRS). Benign intracranial tumors, while generally non-invasive and slow growing, sometimes preclude the use of high-dose (or
⇑ Corresponding author. Tel.: +1 312 695 1801; fax: +1 312 695 0225. E-mail address: [email protected] (A.T. Parsa). http://dx.doi.org/10.1016/j.jocn.2013.11.005 0967-5868/Ó 2013 Elsevier Ltd. All rights reserved.
single-fraction) radiosurgery because of their proximity to critical neural structures. Instead, SFRT is used in the treatment of benign intracranial tumors, either as a primary treatment or, more frequently, as an adjunct therapy. Conventional fractionation is the application of daily doses of 1.8–2.0 Gy in five fractions per week. The weekly dose is 9–10 Gy for a total treatment dose of 50.4–54 Gy. The conventional fractionation schedule has been developed empirically to provide an optimal balance between tumor control and toxicity. With the advent of intensity-modulated radiation therapy (IMRT), coupled with stereotactic localization, higher doses of fractionated therapy can be delivered with minimal irradiation of nearby neural structures. IMRT uses multi-leaf collimators that permit modulation of the beam intensity and delivery of a more conformal dose to irregularly shaped tumors. With the improved precision of IMRT and the use of stereotactic localization (SFRT), a debate has arisen regarding the appropriate patient selection and utilization of each treatment modality.
2. Natural history/growth rate Given the indolent growth of VS, an initial strategy of observation and frequent MR imaging for serial follow-up has commonly been employed. Conservative management of these patients has been
1084
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abundantly studied but has yielded widely disparate tumor growth rates (between 0 and 30 mm/year), with a median growth rate ranging from 0.35 to 2.2 mm/year (mean = 1.42 mm/year) [2–6]. A subset of these tumors demonstrates no growth on follow-up (18–86%, mean = 43%), and there are also some instances of spontaneous tumor regression (2.5 mm/year is observed, the authors recommended that treatment be offered [10].
have reported on its virtues as a primary treatment [12–18]. In one such series, all tumors were treated with 6 MV photons to 54 Gy in 30 fractions, prescribed to 90% isodose line; the authors reported a small, progressive increase in size (2 mm in any tumor dimension and reported a local tumor control rate of 100% in the 48 patients during the follow-up period. Other papers have claimed tumor control rates between 85% and 97% [20–22]. The variance in results seems largely related to the length of follow-up and varied definitions of tumor control. Instances of tumor progression can usually be detected within 3 years of treatment, although even later progression has been reported [15] and recent evidence suggests that changes in tumor response can occur as late as 5 years after RT [23]. Table 1 summarizes outcomes of selected, modern fractionated RT series. Dosimetric studies have compared delivery of radiation to critical structures by IMRT versus SRS [24–26]. In lesions requiring single dose planning, SRS appears to be the preferable therapy as the radiation dose to critical structures is significantly less. The accuracy of fixed head registration and conformality of SRS provide an overall advantage over IMRT. SRS therapy, however, can be problematic in the patient with preexisting mass effect from VS. Single-session RT has been shown to cause local swelling and associated mass effect, possibly necessitating surgical intervention. An advantage of IMRT plans over SRS is their fractionated format of radiation dosing. Consequently, in patients with large VS who cannot undergo surgery, administration of 1.5–2.0 Gy/day via fractionated RT avoids complications of tumor swelling [24].
3. Fractionated radiation therapy
4. Hearing preservation
Fractionated RT has traditionally been used as an adjunct to surgery in incompletely excised tumors, but recently several papers
Modern techniques have allowed for comparable rates of tumor control and facial nerve preservation with primary surgery versus
Table 1 Summary of outcomes of selected modern fractionated radiation therapy series Author
Year
n
Technique Dose/Fx (cGy) Tumor size (reported)
Lederman et al. [48]
1997
38 FSRT
Poen et al. [49]
1999
46 FSRT
Shirato et al. [50]
1999
37 FSRT
Fuss et al. [21]
2000
51 FSRT
3600/20 4000/22 5760/32
Andrews et al. [20]
2001
56 FSRT
5000/25
Meijer et al. [14]
2003
80 FSRT
1600/4 2500/5 (weekly) 2100/3
Williams et al. [51]
2003
80 FSRT
Selch et al. [19]
2004
48 FSRT
2000/5 2500/5 4000/20 5000/25 2500/5 3000/10 5400/30
Chung et al. [53]
2004
27 FSRT
4500/25
Combs et al. [52]
2005 106 FSRT
5760/32
Chan et al. [54]
2005
70 FSRT
5400/30
Chang et al. [47]
2005
61 FSRT
2100/3
Horan et al. [13]
2007
42 FSRT
5000/30
Sawamura et al. [15] 2003 101 FSRT
Local control Hearing preserv.
CN V CN VII Follow-up neuropathy neuropathy
6–50 mm (27 mm, mean)
100%
93.50% (pure tone audiometry)
0%
2.6%
0.5–2.7 yrs (2 yrs, median)
7–42 mm (20 mm, median) 7–30 mm (17 mm, median) 0.4–32.4 cm3 (5.5 cm3, median) 2.78 cm, mean
97%
77% at 2 yrs (G–R 1–2) 53% at 5 yrs (G–R 1–2) 85.2% at 5 yrs (word discrim.) 81% at 5 yrs (G–R 1–2) 61% at 5 yrs (subjective)
16%
3%
0%
0%
3.9%
0%
7%
2%
2%
3%
4%
0.9%
0%
0%
2.2%
2.1%
7% (transient) 3.40%
4% (transient) 2.3%
4%
1%
0%
0%
0%
3.2%
0.5–4 yrs (2 yrs, median) 0.3–5.8 yrs (2 yrs, median) 3.5 yrs (mean) 9.6 yrs (mean) 1–8.9 yrs (3 yrs, median) 0.5–10.6 yrs (3.8 yrs, median) 0.3–3.8 yrs (1.6 yrs, median) 0.5–6.1 yrs (3 yrs, median) 2.1 yrs (median) 0.3–14.3 yrs (4 yrs, median) 3.8 yrs (median) 3–5 yrs (4 yrs, median) 0.3–6.5 yrs (1.6 yrs, median)
8–38 mm (25 mm, mean) 3–40 mm (15.5 mm, median) 0.04–2.1 mm 1.9–40 mm 6–40 mm (22 mm, median) 7–37 mm (16 mm, median) 2.7–30.7 cm3 (3.9 cm3, median) 0.05–21.1 cm3 (2.4 cm3, median) 5–32 mm (18.5 mm, median) 10–40 mm (20 mm, median)
86.2% 97.7% 97% 94% 91.4% 97% 100% 100% 95.3% 98% 98% 96.9%
71.7% at 5 yrs (G–R 1–2) 67.6% at 1.6 yrs (word discrim.) 91.4% at 5 yrs (word discrim.) 57% at 2 yrs (G–R 1–2) 98% at 5 yrs 64% in NF2 patients 84% (subjective) 74% (G–R 1–2) 73% at 2.5 yrs (word discrim.)
CN = cranial nerve, discrim. = discrimination, FSRT = fractionated stereotactic radiotherapy, Fx = fraction, G–R = Gardner–Robertson, NF2 = neurofibromatosis 2, preserv. = preservation, yrs = years.
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radiation. Hence, differences in hearing preservation separate the two therapies in their overall effectiveness and intrinsic value. Prior to MRI, patients with VS typically presented after developing hearing loss. Earlier access to MRI has facilitated the diagnosis of small tumors, and consequently more patients with intact hearing are being identified. The judgment of which technique is superior for hearing preservation has been complicated by controversy over the definition of good or acceptable hearing [27]. There are currently two different classification schemes widely used in practice: the Gardner–Robertson modified hearing classification system and American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) Foundation hearing classification system. Currently, the most popular metric is the Gardner–Robertson scale [28], which sorts hearing into five classes (I–V) based upon speech discrimination and pure-tone audiogram (Table 2) [28]. The AAO-HNS Foundation hearing classification system consists of four classes (A–D) based upon slightly different sub-classification of pure-tone average and speech discrimination scores (Table 3) [29]. In both classification systems, serviceable hearing is defined by a puretone average less than or equal to 50 dB and a speech discrimination score greater than or equal to 50%. Where the classification systems diverge is in their characterization of non-serviceable hearing: the Gardner–Robertson system divides this range into three subgroups whereas the AAO-HNS system describes two subgroups. Frequently, patients diagnosed with small VS who retain useful hearing have been managed conservatively on the assumption that hearing will be preserved if the tumor remains static. However, some studies contend that there is no direct correlation between the rate of tumor growth and risk of hearing loss and that, for instance, hearing can be preserved even in large tumors. Yamamoto et al. prospectively followed 13 patients with VS, and found no appreciable change in audiometric scores among the seven patients whose tumors grew by at least 20% [30]. Conversely, the meta-analysis by Sughrue et al. mentioned earlier analyzed 982 patients and significantly correlated tumor growth rate >2.5 mm/ year (but not any other analyzed factor) with loss of hearing [10]. In a separate prospective study by the same authors, 59 VS patients with serviceable hearing on presentation were conservatively managed over a 22 year period [35]. Consistent with their previous findings, a tumor growth rate >2.5 mm/year at any point during follow-up was linked to a much faster rate of hearing loss. Median time to hearing loss was 7.0 years for faster-growing tumors and 14.8 years for tumors growing slower than 2.5 mm/year (p < 0.0001). Still, hearing loss has been documented in the absence of obvious radiographic signs of tumor growth [31–34]. Eventual hearing loss with non-growing tumors is poorly understood and cannot be attributed to a compressive effect. It has been speculated that hearing loss in this subset of patients stems from encroachment on neural structures within the internal acoustic canal, although a later study found no significant difference in median time to hearing loss with intracanicular extension [35]. Alternatively, it may be that chronic compression steadily abates cochlear
Table 2 Gardner–Robertson modified hearing classification Grade
Pure-tone average (dB)
Speech discrimination score (%)
I: Good–Excellent II: Serviceable III: Non-serviceable IV: Poor V: None
0–30 31–50 51–90 91–maximum Not testable
70–100 50–69 5–49 1–4 0
Note that when pure-tone average and speech discrimination score do not correspond, the lower class is used.
Table 3 American Academy of Otolaryngology-Head and Neck Surgery hearing classification Class
Pure-tone average (dB)
Speech discrimination score (%)
A: Useful B: Useful C: Aid-able D: Non-functional
630 >30 and 650 >50 Any level
P70 P50 P50 4.2 Gy. An analogous dose threshold has yet to be identified in the analysis of fractionated RT outcomes [68], but conservatively limiting the mean total fractionated dose to the cochlea to 35 Gy, when possible, should minimize the risk of sensorineural hearing loss [66]. 7. Risk to other cranial nerves Neuropathies of non-VII/VIII cranial nerves are typically rare in both the natural history of VS and as sequelae of therapeutic intervention (RT or surgery). The most common of these neuropathies involves the trigeminal nerve and, less frequently, the glossopharyngeal/vagal nerve complex. About 10% of patients experience symptoms related to disruption of the trigeminal complex as part of the natural history of VS, largely as a function of tumor size [69]. Lower cranial nerve involvement is described in only 3% of patients [69]. Of the cranial nerves not entering the internal auditory meatus, the trigeminal nerve is at greatest risk of injury from radiosurgery and fractionated RT. Recent SRS data suggest an injury rate of 2–3% [70], while a similar risk of 2–7% is observed with fractionated RT [14,19–21]. Lower cranial nerve dysfunction is very unusual with modern treatment techniques [70,71].
profile, which, for larger tumors, is arguably superior to that of either surgery and/or single-fraction radiosurgery. On the other hand, fractionated RT requires a significant time commitment (5–6 weeks) and may not be a viable option for some patients. Moreover, realization of the optimal outcomes reported for SFRT requires that the treating physician and therapist team be highly skilled and experienced in the delivery of this treatment. 9. Future directions Fractionated radiation therapy with modern technological advances, such as IMRT with stereotactic localization, allows delivery of high radiation doses to pathologic tissue with minimal impact on nearby critical structures. Consequently, FSRT may be wellsuited for select head, neck and central nervous system tumors that cannot be treated using radiosurgical techniques. Treatment risks to cranial nerves other than cranial nerve VIII are low (13 Gy to the isodose line [58], it is unclear if the larger dose indirectly increases the dose to the cochlea. It would be valuable to assess cochlear dose and hearing outcomes in patients receiving a radiation dose of >13 Gy. Insights derived from such a study could optimize dosing strategy in parallel with diminished cochlear radiation toxicity. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements
8. Additional risks Other non-cranial nerve complications that accompany surgery, radiosurgery, or fractionated RT are largely unique to each technique, and therefore not easily comparable. The principal complications of fractionated RT include tinnitus, balance disturbance, and hydrocephalus (rare). Compared to SRS, fractionated RT minimizes brain edema, and is the treatment modality of choice in inoperable patients with large tumors and significant, pre-existing tumor-related edema or brainstem compression. Hydrocephalus was entirely absent in one reported series with SFRT [19], whereas it was reported in 11% of patients in another [15]. Transient or exacerbated tinnitus is not uncommon, but permanent tinnitus was only seen in
