Outcomes of Stereotactic Radiosurgery and

CHAPTER 21 SYNTHES SKULL BASE SURGERY AWARD

Outcomes of Stereotactic Radiosurgery and Stereotactic Radiotherapy for the Treatment of Vestibular Schwannoma Winward Choy, BA, Marko Spasic, BA, Patrick Pezeshkian, MD, Brendan M. Fong, MD, Daniel T. Nagasawa, MD, Andy Trang, BS, Ishani Mathur, BS, Antonio De Salles, MD, PhD, Alessandra Gorgulho, MD, Michael Selch, MD, Quinton S. Gopen, MD, and Isaac Yang, MD

A

lthough microsurgery remains the gold standard for the treatment of vestibular schwannoma (VS),1,2 radiotherapy is a safe, noninvasive treatment option that has demonstrated excellent rates of tumor control.3-7 Stereotactic radiosurgery (SRS) delivers high-dose radiation over a few fractions8 to maximize radiation to the tumor and to minimize collateral damage to healthy parenchyma. Although risks for SRS include damage to adjacent cranial nerves,9-13 improved imaging modalities and lower marginal doses may reduce this associated morbidity.14-16 Stereotactic radiotherapy (SRT) minimizes the risk for toxicity associated with high doses of radiation through the delivery of lower doses over more fractions than SRS. SRT has also demonstrated excellent rates of tumor control9,17 and has been found to reduce the detrimental effects of ionizing radiation delivered to healthy brain compared with conventional radiotherapy. Although the goals of radiotherapy are to control tumor progression, to preserve functionality, and to minimize treatment complications, its optimal application in VS is still unclear. In this analysis of our institutional experience, we assess the outcomes of patients with VS receiving either SRS or SRT to evaluate potential prognostic factors influencing rates of local tumor control, hearing preservation, and treatment complications.

METHODS AND MATERIALS Patient Selection A retrospective review of patients receiving evaluation and care for acoustic neuromas at the University of California Los Angeles Medical Center from May 1996 to August 2011 was completed. Patients who had been treated with either SRS or SRT therapy for VS were included. Those lacking adequate pretreatment assessment and imaging to evaluate tumor size or with inadequate clinical and radiological follow-up were excluded. Patients with bilateral tumors or other intracranial neoplasms were also excluded.

Copyright © 2013 by The Congress of Neurological Surgeons 0148-396X

Radiation Therapy Treatment planning for radiation therapy was performed with 1.5-T magnetic resonance imaging and computed tomography scans. Computed tomography-magnetic resonance imaging fusion was used during 3-dimensional calculation of the target. Isodose treatment plans were created with the BrainLAB iPlan software (Westchester, Illinois). Treatment plans were finalized in a collaborative effort by the neurosurgeon, radiation oncologist, and physicist. The 6-MV Novalis linear accelerator (LINAC) (Novalis, Heimstetten, Germany) was used to deliver the radiation. Those receiving SRS or SRT were treated with a fitted thermoplastic facemask (U-PLAST, BrainLAB, Munich, Germany).

Data Collection Physical examination and magnetic resonance imaging to assess tumor size was performed every 6 months or more frequently, depending on clinical indication. Hearing was categorized as useful hearing, poor hearing, or no hearing on physical examination. Useful hearing was defined as the capacity to use the phone unaided and to discriminate normal speech in the affected ear. Hearing preservation was defined by either stable or improved hearing at the last clinical follow-up compared with pretreatment baseline hearing. Tumor size was measured by the largest diameter in any of 3 dimensions, and status at last follow-up was categorized as tumor progression, stable, or tumor response. Tumor progression was defined as an increase of $ 2 mm and tumor response by a decrease of $ 2 mm in any dimension on imaging compared with pretreatment size. Local tumor control was defined as either stable tumor or tumor response.

Statistical Analysis Kaplan-Meier analysis was used to evaluate rates of tumor progression, and the Fisher exact test was used to evaluate outcome differences in subgroup analysis. Tests for significance were 2 tailed, with values of P , .05 considered statistically significant.

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Clinical Neurosurgery Volume 60, 2013

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Radiotherapy for Vestibular Schwannoma

RESULTS Patient Population A total of 138 patients, 81 men and 57 women, met study criteria. The mean age for all patients was 56.1 years (Table 1). The mean follow-up for all patients was 42 months (range, 4.5-148 months). Average tumor size before treatment was 17.8 mm (range, 3-50 mm). There were no deaths resulting from recurrent tumor or other morbidities during the follow-up periods. Five of 138 patients (3.6%) were asymptomatic during the initial evaluation for treatment. The most common presenting symptom was some degree of hearing loss, present in 92.5% of all patients. Eighty-three patients presented with symptoms other than hearing impairment. Of these, the most common presenting symptoms were tinnitus (n = 50), ataxia (n = 22), vertigo (n = 19), trigeminal neuralgia (n = 16), and facial nerve palsy (n = 12). Twenty-four patients received prior resection. The mean interval between surgery and radiotherapy in these patients was 29.3 6 43.5 months.

Radiation Therapy Thirty-five patients received SRS, with a mean dose of 1237 cGy (range, 1200-1400 cGy) delivered in a single fraction. A total of 103 patients received SRT. A mean total of 5288 cGy (range, 4860-5400 cGy) was delivered through 27 to 30 fractions of 180 cGy prescribed to the 90% isodose line. Within these SRS and SRT groups, useful hearing was present at presentation in 31% and 66%, respectively. Although the total dose delivered for SRS was variable, all patients with useful hearing uniformly received 1200 cGy delivered to the 90% isodose line. None of the 5 patients who

TABLE 1. Tumor Characteristics, Patient Characteristics, and Tumor Control Based on Stereotactic Radiosurgery or Stereotactic Radiotherapya Patients, n Sex, n Male Female Hearing, n (%) Useful hearing Poor hearing No hearing Follow-up, mo Age, y Tumor size, mm Previous surgery, n Mean dose, cGy Tumor outcomes, n (%) Tumor response Stable Tumor recurrence

Overall

SRT

SRS

138

103

35

81 57

64 39

17 18

79 (57.25) 33 (23.91) 26 (18.84) 41.5 56.1 17.8 24

68 (66.0) 27 (26.2) 8 (7.8) 43.5 55.5 17.9 12 5288

11 (31.4) 6 (17.1) 18 (51.4) 35.5 57.7 17.3 12 1237

35 (25.4) 94 (68.1) 9 (6.5)

22 (21.4) 74 (71.8) 7 (6.8)

13 (37.1) 20 (57.1) 2 (5.7)

a

SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy.

received the higher dose of 1400 cGy had any hearing at initial presentation. For those receiving SRT, all patients with useful hearing at presentation received either 5040 cGy delivered in 28 fractions of 180 cGy (n = 15) or 5400 cGy delivered in 30 fractions of 180 cGy (n = 53). In all patients, SRS and SRT were well tolerated.

Tumor Control Tumor progression at the last radiological follow-up was found in 9 of 138 patients (6.5%) receiving SRS or SRT. Overall rates of 3-, 5-, and 10-year progression-free survival (PFS) for all patients were 93.8%, 89.6%, and 89.6%, respectively (Figure 1). Differences in rates of tumor progression were not statistically significant between SRS and SRT (P = .98; Figure 2). For SRT, 7 patients (6.8%) had tumor recurrence, with 3-, 5-, and 10-year rates of Progression-Free Survival (PFS) of 94.1%, 89%, and 89%, respectively. For those receiving SRS, tumor recurrence was present in 2 patients, and 3-, 5-, and 10-year rates for PFS were all 93.1%. Average time to progression in all patients was 21.65 months (range, 7.2-50 months), with 77% of recurrences occurring within 2 years after radiation therapy. Tumor size, radiation dose, and hearing status at presentation did not predict rates of tumor progression. Table 1 summarizes the rates of tumor control after SRS and SRT. Difference in rates of tumor control were not statistically different between SRS and SRT. Tumor control was achieved in 129 patients (93.5%). A large number of these patients demonstrated a transient increase in tumor size on imaging before an eventual decrease in size. This transient increase in size on imaging was observed in 73.7% and 20% of patients with stable tumors and tumor response, respectively. Most of the transient increases (76%) occurred within 12 months of radiation therapy.

Hearing Preservation Of the 77 patients with useful hearing before treatment, 66 and 11 underwent SRT and SRS, respectively. Subjective improvements in hearing were noted in 6% receiving SRT and 9% receiving SRS. Stable hearing was achieved in 80% receiving SRT and 46% receiving SRS. SRT was associated with a significant increase in rates of hearing preservation. Hearing was preserved in 86% of patients receiving SRT and

FIGURE 1. Kaplan-Meier plot of hearing preservation for all patients. Rates of 3-, 5-, and 10-year progression-free survival (PFS) are 93.8%, 89.6%, and 89.6%, respectively.

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FIGURE 2. Kaplan-Meier analyses of hearing preservation of patients receiving stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT). Rates of 3-, 5-, and 10-year progression-free survival (PFS) were 94.1%, 89%, and 89% for SRT, respectively. Rates of 3-, 5- and 10-year PFS were all 93.1% for SRS. These differences were not statistically significant (P = .9).

55% of patients receiving SRS (P = .02). Mean time to decline was 43.19 6 42.4 months.

Predictors of Hearing Preservation Subgroup analysis was performed to identify factors predictive of hearing preservation in patients with useful hearing before treatment (Table 2). For all patients, tumors . 16 mm were associated with poorer rates of hearing preservation. Fortyfive patients had tumors # 16 mm, and 33 patients had tumors . 16 mm. The mean tumor size for the small tumor group and the large tumor group was 10.8 6 3.5 and 23.0 6 5 mm, respectively. The rate of hearing preservation was 91.1% in patients with tumors # 16 mm and 68.8% in patients with tumors . 16 mm (P = .02). When the analysis was done separately for SRS and SRT, tumor size was no longer a significant prognostic factor for hearing preservation. For patients receiving SRS, rates of

hearing preservation were 75% for tumors # 16 mm and 42.85% for larger tumors (P = .5). For those receiving SRT, rates of hearing preservation were 92.7% and 76% for small and large tumors, respectively (P = .07). Age , 50 years was associated with worse rates of hearing preservation for all patients. Of the patients with useful hearing at presentation, 30 patients were , 50 years of age at the start of treatment, and 47 patients were . 50 years. Mean age was 42.4 6 6.3 and 63.8 6 8.7 years for the 2 groups, respectively. Hearing preservation was achieved in 21 patients (70%) , 50 years of age and 42 patients (89.4%) . 50 years of age (P = .04). However, patients . 50 years of age were more likely to present with larger tumors than younger patients; mean tumor sizes of the younger and older age groups were 13.8 and 19.3 mm, respectively (P = .001). Age was not a significant prognostic factor when separate analyses were done for patients receiving SRS and SRT. For patients receiving SRS, rates of hearing preservation were 40% and 66.6% for younger and older patients, respectively (P = .5) For SRT, rates of hearing preservation were 76% and 92.7% for younger and older patients, respectively (P = .07). Sex, symptoms at presentation, and radiation dose were not significant prognostic factors for predicting rates of hearing preservation. All patients with useful hearing treated with SRT received a marginal dose of either 5040 or 5400 cGy. Hearing was preserved in 100% of patients receiving 5040 cGy and 81.1% of patients receiving the larger total dose of 5400 cGy (P = .10).

Complications A number of patients developed new symptoms that were not present before SRS or SRT. Rates of newly developed tinnitus, ataxia, vertigo, and trigeminal nerve dysfunction were not statistically significant between SRS and SRT. However, SRS demonstrated a significantly increased risk for developing facial nerve dysfunction (20%) compared with SRT (2%; P = .006).

TABLE 2. Univariate Analysis of Potential Prognostic Factors for Hearing Preservationa Factors Treatment SRS SRT Sex Male Female Age, y , 50 . 50 Size, mm # 16 . 16 SRT dose, cGy 5040 5400 a

Hearing Preservation, %

P

54.50 86.40

.02

81.6 78.6

.7

70.0 89.4

.04

91.1 68.8

.02

100.0 81.1

.1

SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy.

DISCUSSION Management of VS includes observation, microsurgical resection, and radiation with either SRS or SRT. However, resection may be associated with significant risks for surgical complications,5,18-20 and symptoms do not always resolve after excision. Although microsurgery is considered a primary treatment option for VS, radiotherapy provides an attractive, noninvasive alternative because of the high rates of local tumor control and a reduced risk of treatment-related complications.21,22

Tumor Control In the present study, both SRS and SRT demonstrated excellent rates of tumor control comparable to those reported in the literature. Selch et al9 reviewed 50 patients treated with LINAC radiotherapy receiving 5400 cGy prescribed at the 90% isodose line. Five-year PFS was 100%, with a median follow-up of 36 months. In a series of 70 patients followed for a median of 45.3 months, Chan et al23 reported 5-year PFS of 98% after SRT with a median dose of 5400 cGy. A large


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number of studies investigating the role of SRS for VS reported similar rates of 10-year PFS ranging from 92% to 98%3-7 and overall rates of tumor control ranging from 93% to 99%.24-28 Friedman et al29 reviewed 296 patients with VS receiving LINAC radiosurgery with a mean prescribed dose of 1250 cGy and reported 5-year PFS of 90%. In a review of 74 patients undergoing Gamma Knife surgery with a mean dose of 1227 cGy, Liu et al5 reported similarly high rates of 5- and 10-year PFS of 95.9%. In the present study, differences in the rates of tumor control between SRS and SRT were not statistically significant, an observation that is consistent with previous reports. Meijer et al30 treated 80 patients with SRT and 40 patients with LINAC-based SRS and achieved identical 100% tumor control rates at 5 years for both treatment groups. Combs et al21 similarly reported no statistically significant differences in tumor control between patients treated by SRT with a median total dose of 5760 cGy and those treated with SRS with a median dose of 1300 cGy. In addition, higher radiation doses do not appear to confer added benefits to rates of tumor control. Despite delivering a lower radiation dose for both SRS and SRT in our study compared with that of Combs et al,21 our patients achieved similarly high rates of tumors control. A study of 96 patients receiving SRT found no difference between patients receiving a higher dose of 5040 cGy (26 fractions of 180 cGy) and a lower dose of 4680 cGy (26 fractions of 180 cGy).31 The rate of tumor control was 100% in both treatment arms. Hence, our lower dose of radiation still demonstrates excellent rates of tumor control and may be recommended to minimize adverse treatment effects. Further studies are be needed to identify the optimal dose reduction that balances patient safety and tumor control.

Hearing Preservation Although tumor control after radiation therapy is reported within a consistent and narrow range, hearing preservation is much more variable. Reported rates of hearing preservation range from 68% to 100% after SRT of 5000 to 5800 cGy.32-34 Although the dose delivered in this study is within the lower end of that range, our patients receiving SRT achieved comparable rates of hearing preservation. A review of LINAC-based SRT delivering 5400 cGy prescribed to the 90% isodose line, as in our study, reported a 93% preservation rate of useful hearing.9 In accordance with our results, studies using SRS with median doses of 1200 to 1300 cGy report rates of hearing preservation from 32% to 71%.4,16,35-42 However, direct comparison of different study results may be confounded by a number of factors, including treatment scheme, variable use of fractionation schemes and total doses, different standards of hearing assessment, and variable lengths of follow-up.32-34,42 For instance, total radiation dose, particularly to the cochlea, has been identified as a strong prognostic factor for hearing preservation.43 Additionally, although hearing preservation has often been defined by maintenance of grade I or II on the Gardner-Robertson scale, our study applied a more stringent criterion of auditory preservation, defined as the absence of any hearing decline, to provide a better resolution


of this potential complication. Thus, the definition used in this study likely results in underestimation of hearing preservation compared with other reports. There is currently no consensus on whether SRS or SRT affords improved rates of hearing preservation. Both Andrews et al44 and Combs et al21 published nonrandomized singleinstitution studies examining the outcomes of patients receiving either SRS or SRT. In the report by Andrews et al, 56 patients received LINAC-based SRT with a marginal dose of 5000 cGy, and 69 patients received Gamma Knife–based SRS with a marginal dose of 1200 cGy. Follow-up was 115 and 119 weeks, respectively. Although the difference in tumor control was not statistically significant, SRT was associated with improved rates of hearing preservation (81%) compared with SRS (33%), a trend supported by our study. In contrast, Combs et al treated patients with either SRT receiving a marginal dose of 5760 cGy or SRS receiving a median dose of 1300 cGy and found no statistically significant difference in hearing preservation between the 2 treatment groups at a mean follow-up interval of 75 months. The precise course of hearing loss after radiation therapy also requires further elucidation. Combs et al21 found that the majority of hearing loss occurred within 10 months of treatment, whereas our study found that auditory decline is observed mainly within 2 years of treatment. Moreover, Thomas et al43 found that hearing loss may occur at much longer intervals, from 1.5 to 5 years after radiotherapy. Chopra et al4 reported that although the rate of hearing preservation was 74% at the 3-year follow-up, it fell to 44% at 10 years. Because auditory function may decline several years after radiation therapy, long-term follow-up may be a necessary criterion to accurately evaluate overall rates of hearing preservation and represents a potentially confounding factor. A number of studies have shown that higher doses of radiation are associated with poorer rates of hearing preservation. Andrews et al31 investigated the impact of SRT radiation dose for the treatment of VS in 89 patients followed with serial audiometric analysis. Patients in the low-dose cohort (4680 cGy) compared with the high-dose cohort (5040 cGy) had significantly improved rates of hearing preservation. However, our data do not demonstrate a correlation between radiation dose and hearing preservation in patients receiving SRT. A number of factors may account for this inconsistency, including delivered dose, lengths of followup, and the small sample size receiving 5040 cGy.

Treatment Risks Although preservation of hearing is one of the main goals of radiotherapy, the risk of cranial nerve dysfunction must also be carefully evaluated. The range of trigeminal nerve toxicity reported in the literature ranges from 0% to 13% for patients receiving SRT22,30,32 and from 4.4% to 27% in SRS.11,12,14,30,45-47 Similarly, rates of facial nerve toxicity range from 0% to 3% in studies using SRT22,30,32 and from 0% to 23% in studies using SRS.11,12,14,30,45-47 Our findings suggest that SRS may be associated with an increased risk for new facial nerve dysfunction compared with SRT.


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Limitations The present study is a retrospective analysis of the experiences at a single institution. The small sample size with useful hearing before receiving SRS may have limited our analysis of prognostic factors for hearing preservation. Length of follow-up may also influence hearing preservation because decline in hearing may present several years after the completion of radiotherapy. Additionally, cochlear dose, which may present a potentially confounding factor, was not assessed in this study.

CONCLUSION The goal of radiation therapy is to maximize both tumor control and functional preservation. Both SRS and SRT offer excellent rates of long-term tumor control for VS. SRT was associated with improved hearing preservation, suggesting that limiting the dose per fraction may improve patient outcomes. Because SRT dose had no association with tumor control or hearing preservation, lower doses are recommended to lessen potential for treatment-related toxicity. SRS may be reserved for patients without functional hearing who may benefit from shorter treatment lengths. Although patient age and tumor size did not predict hearing preservation for patients receiving SRS or SRT, larger prospective studies are needed to delineate prognostic factors and optimal radiation therapy strategies that are tailored according to tumor features, patient characteristics, and patient preferences.

Disclosure W. Choy was partially supported by a American Association of Neurological Surgeons research fellowship and a American Academy of Neurology research scholarship. M. Spasic was partially supported by an Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship. Dr Yang was partially supported by a Visionary Fund Grant, an Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research UCLA Scholars in Translational Medicine Program Award, the Jason Dessel Memorial Seed Grant, the UCLA Honberger Endowment Brain Tumor Research Seed Grant, and the STOP CANCER Research Career Development Award. The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Fong BM, Pezeshkian P, Nagasawa DT, et al. Hearing preservation after LINAC radiosurgery and LINAC radiotherapy for vestibular schwannoma. J Clin Neurosci. 2012;19(8):1065-1070. 2. Spiegelmann R, Lidar Z, Gofman J, et al. Linear accelerator radiosurgery for vestibular schwannoma. J Neurosurg. 2001;94(1):7-13. 3. Hasegawa T, Ishii D, Kida Y, et al. Gamma Knife surgery for skull base chordomas and chondrosarcomas. J Neurosurg. 2007;107(4):752-757. 4. Chopra R, Kondziolka D, Niranjan A, Lunsford LD, Flickinger JC. Longterm follow-up of acoustic schwannoma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys. 2007;68(3):845-851. 5. Liu D, Xu D, Zhang Z, Zhang Y, Zheng L. Long-term outcomes after Gamma Knife surgery for vestibular schwannomas: a 10-year experience. J Neurosurg. 2006;105(suppl):149-153. 6. Lunsford LD, Niranjan A, Flickinger JC, Maitz A, Kondziolka D. Radiosurgery of vestibular schwannomas: summary of experience in 829 cases. J Neurosurg. 2005;102(suppl):195-199.

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