82 Radiosurgery and Radiotherapy for Neurofibromatosis Type 2 Focusing on Vestibular Schwannoma

10.1055/b-0039-169236

82 Radiosurgery and Radiotherapy for Neurofibromatosis Type 2 Focusing on Vestibular Schwannoma

Amparo Wolf and Douglas Kondziolka

82.1 Introduction

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease with an incidence of approximately 1 in 25,000 to 1 in 60,000.s. Literatur A hallmark feature of NF2 is the presence of bilateral vestibular schwannomas (VSs). Additional nervous system tumors in NF2 include schwannomas of other cranial and spinal nerves, meningiomas, ependymomas, and gliomas. Approximately 90 to 95% of patients with NF2 will develop bilateral VSs.s. Literatur NF2-associated tumors develop from the inactivation of both alleles of the NF2 tumor-suppressor gene, located on chromosome 22q12. NF2-associated VSs tend to infiltrate and involve the cochlear nerve,s. Literatur resulting in gradual sensorineural hearing loss (SNHL) and high-pitched tinnitus as the presenting symptoms in 60% of adults and up to 30% of children.s. Literatur ^, s. Literatur Furthermore, NF2-related VSs tend to behave more aggressively than sporadic tumors in terms of recurrence and result in a greater incidence of cranial nerve deficits.s. Literatur ^, s. Literatur

Treatment options for NF2-associated VS include observation, medical therapies, microsurgery, and stereotactic radiosurgery (SRS). As in sporadic tumors, surgery is indicated in patients with large VS resulting in significant brainstem compression or hydrocephalus. In some NF2 patients, there is an important role for SRS. The purpose of this chapter is to review the current evidence on single-session SRS and multisession stereotactic hypofractionated or conventionally fractionated radiotherapy in NF2-associated VS, as it relates to tumor control rates, hearing, and facial nerve outcomes.

82.2 The Natural History of NF2-Associated Vestibular Schwannomas

The natural history of VS in NF2 is characterized by highly variable growth rates that decrease inversely with age.s. Literatur ^, s. Literatur From a recent natural history study of a select group of 46 NF2 patients with 74 tumors followed up for a mean of 6 years, in which patients with more severe forms of the disease were excluded, the median growth rate was 1.4 mm per year (0–8 mm/year).s. Literatur However, growth rates as high as 10 mm/year have been reported.s. Literatur ^, s. Literatur Rare studies have shown that VS may spontaneously decrease in size over time, particularly after the resection of contralateral tumors in NF2 patients.s. Literatur The heterogeneity in growth rates may be partly attributable to the type of NF2 gene mutation (e.g., nonsense or frame shift mutations producing a truncated protein vs. missense mutations) and phenotype (Wishart vs. Gardner).s. Literatur

The natural history of SNHL in untreated VS is also unpredictable. In a study investigating hearing outcomes in relation to tumor growth following conservative management of bilateral VS in NF2 patients, a serviceable hearing preservation rate of 74% was reported at a mean follow-up of 6 years, but with only 66% of patients conserving binaural serviceable hearing.s. Literatur Initial tumor size and growth rate are not predictive of hearing status in NF2 patients.s. Literatur ^, s. Literatur Chapter 80 further reviews the natural history of VS in patients with NF2.

82.2.1 Stereotactic Radiosurgery in NF2-Associated Vestibular Schwannomas: Control Rates

Table 82‑1 summarizes the published studies to date that evaluated tumor control rates in patients with NF2-associated VS after SRS. SRS provides tumor control in reportedly 70 to 100% of cases with reported long-term local control rates of 80% at 15 years in NF2 patients.s. Literatur Overall, the results for VS in NF2 patients after SRS support good local control, although comparatively less favorable than sporadic VS patients in the long term, where up to 98% control is seen at 10 years.s. Literatur Fig. 82‑1 demonstrates a 50-year-old NF2 patient with bilateral hearing loss and a growing right-sided VS. The left-sided VS has been stable over serial MRIs. The patient underwent SRS at a margin dose of 12 Gy. At 4-year follow-up, the right-sided VS has reduced in size.

**Fig. 82.1** MR images of a 50-year-old NF2 patient who underwent SRS for a right-sided vestibular schwannoma. (a) SRS treatment plan at a margin dose of 12 Gy at the 50% isodose volume. (b) Axial T1-gadolinium and T2-weighted MRI 4 years after SRS showing reduction in size of the right vestibular schwannoma and stable left vestibular schwannoma.

Table 82.1 Summary of studies of stereotactic radiosurgery in NF2-associated vestibular schwannomas
Study	#patients / # tumors	Dose (Gy)	Tumor volume (cm³)	Local tumor control	Median follow-up time (mo)	Hearing preservation (%)	CN VII weakness	CN V dysfunction	MT
Subach et al (1999)s. Literatur	40/45	15	4.8 (mean)	98%	36 (median)	43% (pre 1992); 67% (post 1992)	19%	6%	NR
Kida et al (2000)s. Literatur	20/20	13	2.4 (mean)	100%	33.6 (mean)	33.3%	0	0	NR
Rowe et al (2003)s. Literatur	96/122	15.2	4.6 (mean)	52% at 8 y	51 (median)	38% at 3 y	5%	2%	NR
Roche et al (2004)s. Literatur	37/50	12.3	3.5 (mean)	85% at 10 y	62 (median)	36% at 5 y	2%	NA	NA
Mathieu et al (2007)s. Literatur	62/74	14	5.7 (mean)	81% at 15 y	53 (median)	48% at 5 y	8%	4%	0
Phi et al (2009)s. Literatur	30/36	12.1	3.2 (median)	66% at 5 y	36.5	33% at 5 y	3.3%	3.3%	0
Sharma et al (2010)s. Literatur	30/54	12	3.7 (mean)	67.3% at 5 y	26.6	66.7%	3.1%	0	0
Massager et al (2013)s. Literatur	18/25	12	2.04 (median)	80.2% at 5 y	52.8	78%	0	0	0
Mallory et al (2014)s. Literatur	26/32	14	2.7 (median)	85% at 5 y	91.2 (median)	25%	50%	NR	NR
Sun et al (2014)s. Literatur	46/73	12.9	5.1 (mean)	87% at 5 y 41% at 10 y	109 (median)	31.9%	5%	8%	NR
Abbreviations: MT, malignant transformation; NA, not available; NR, not reported.

Predictors of local control include age, tumor volume, margin dose, and NF2 phenotype.s. Literatur ^, s. Literatur Higher margin doses in NF2 tumors may result in improved tumor control; however, no study has directly investigated this prospectively and in a randomized fashion. One retrospective report from the Mayo Clinic examined the effect of dose on tumor response, taking into account that their institution continued to use a margin dose of 14 Gy until 1996. They reported that the median margin dose for tumors that decreased in size after SRS was 15.5 Gy compared with 13 Gy for tumors with continued growth after treatment.s. Literatur In the study of Mathieu et al,s. Literatur higher radiation dose did not have an impact on tumor control, but it did impact hearing preservation and complication rates. Progression-free survival rates after SRS for patients with the more aggressive phenotype NF2 are reportedly reduced compared to patients with less severe phenotype NF2.s. Literatur

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