Abstract
Purpose
To compare clinical outcomes following stereotactic radiosurgery (SRS) and fractionated stereotactic radiosurgery (fSRS) for vestibular schwannomas (VS).
Materials/methods
We identified 64 VS patients from the RSSearch Patient Registry (12 treated with SRS and 52 patients treated with fSRS). Potential factors predictive of local control (LC) and toxicity were estimated using the Kaplan-Meier method, Cox proportional hazards model, and binary logistic regressions with propensity score weighting.
Results
SRS (100%) and fSRS (94.2%) resulted in similar LC (p = 0.33). fSRS was associated with a higher likelihood of experiencing toxicities (42.3% vs. 8.3%; p = 0.054 on time-to-event analysis) that was maintained following a propensity-score weighted binary logistic regression (p = 0.037) and propensity-score weighted Cox regression (p = 0.039; hazard ratio (HR) = 8.85 (95% CI: 1.1 – 70.1)).
Conclusion
In a multi-institutional analysis, we note equivalent LC but higher toxicity with fSRS compared to SRS for VS.
Keywords: Toxicity, vestibular schwannoma, stereotactic radiosurgery, acoustic neuroma, hypofractionation, registry
Introduction
Vestibular schwannomas (VS) are benign Schwann-cell derived tumors of the eighth cranial nerve that account for roughly 8% of CNS tumors in adults, with an incidence of approximately 1/100,000 person-years.1-2 Approximately 95% of patients have symptomatic cochlear nerve impairment at presentation with complaints of either hearing loss or tinnitus.3 Other common symptoms at presentation include vertigo (vestibular nerve involvement), facial paresthesias or pain (trigeminal nerve involvement). Management approaches for VS include microsurgery, radiation therapy, or observation with clinical decision-making based on gross tumor volume (GTV), patient age, the severity of symptoms, and tumor progression.4 While stereotactic radiosurgery (SRS; the use of one dose of radiation to lesions of interest) and fractionated stereotactic radiosurgery (fSRS; the use of 3-5 fractions of radiation to lesions) have gained acceptance as effective treatment options/alternatives to microsurgery for VS, the optimal fractionation schedule remains controversial. Theoretical benefits of fSRS over SRS are based on the lower dose-per-fraction that may allow for normal tissue repair between fractions thereby reducing treatment related toxicity.5,6 However, there have been few studies comparing the efficacy of SRS and fSRS, with many of the investigations being based on single institution experiences limited by selection bias7-11.
The RSSearch Patient Registry (RSSPR) is a growing, multi-institutional, prospectively-collected international database comprised of clinical information of patients treated with SRS and stereotactic body radiotherapy (SBRT). As one of the largest and fastest-growing databases specific to SRS/SBRT, it has currently accrued clinical information for over 20,000 patients. Recent analyses of the RSSPR have demonstrated it to be an effective tool, collecting accurate and literature-comparable data regarding SRS and SBRT outcomes for pancreatic cancer, glioblastoma multiforme, liver metastases, and trigeminal neuralgia12-15. Given the multi-institutional nature of the RSSPR, we sought to examine clinical outcomes and toxicities of patients with VS treated with SRS or fSRS across multiple clinical settings to better guide clinical application for VS.
Materials and Methods
The RSSPR was initially designed in 2006 and is currently managed by the Radiosurgery Society®, a multi-disciplinary non-profit organization aimed at advancing the study and practice of SRS and SBRT with the objective of allowing the prospective collection of information regarding patient outcomes following SRS or SBRT for a variety of cancer sites.16 The registry was initially founded as the ReCKord registry and at first enrollment was limited to patients treated with CyberKnife® but has since been expanded to allow for the inclusion of patients treated with SRS or SBRT via any platform. The RSSPR encourages all centers utilizing SRS or fSRS as a treatment modality to participate in the registry. Prior to participation in the registry, respective Institutional Review Board and Ethics Committee approval is required of each institution. Patients are asked for informed consent before having their information logged in the registry. Information that is collected includes but is not limited to patient demographics (such as age, ethnicity, and performance status), lesion characteristics (such as size, location, and tumor staging), radiotherapy planning and delivery (including prescription and maximum dose as well as fractionation schedule), and clinical outcomes such as local control, overall survival, and toxicity. No compensation is provided to participating physicians or patients. All patients included in this study were treated with the CyberKnife® Robotic Radiosurgery System utilizing inverse planning on the MultiPlanSystem® (Accuray Incorporated, Sunnyvale, CA). Planning of SRS and fSRS as well as treatment delivery differed per respective institutional preferences.
The RSSPR was queried for patients with vestibular schwannomas treated with SRS or fSRS for primary management of their disease between January 2008 to November 2016 that had information regarding prognostic factors of interest (i.e. GTV, treatment planning (prescription doses and fractionation), and follow-up imaging to assess treatment response. Patients that had received previous surgery or radiation therapy were excluded to minimize the bias of increased toxicity associated with combined modality therapy and re-irradiation. Of 506 VS patients in the registry, a total of 66 patients were identified at various centers participating in the RSSPR as meeting inclusion criteria, with two additional patients excluded given recorded doses more than double the typical range for benign lesions (54 Gy/3 fractions and 60 Gy/3 fractions) to avoid ascertainment bias.
Statistical summaries of relevant patient, treatment, and lesion characteristics were performed with descriptive analyses. Potential factors impacting local control (LC) were examined via the Kaplan-Meier method with log-rank t-tests to compare outcomes between groups. The last follow-up was defined as a clinical investigation, radiographic assessment of LC, or both a clinical investigation and radiographic assessment simultaneously performed at one follow-up visit. Prognostic factors that were evaluated included treatment planning (i.e. prescription dose, biological equivalent doses (BED10 and BED3), and fractionation), GTV, initial Karnofsky Performance Score (KPS), and patient age. BED was examined with respect to examination of clinical outcomes and dose escalation to allow for comparison among different fractionation schedules. The relationship between side-effect incidence (with toxicities graded based on Common Terminology Criteria for Adverse Events (CTCAE) guidelines) and treatment planning was evaluated via univariate binary logistic regressions, two-tailed Fisher’s exact test, time-to-event analysis with the Kaplan-Meier method, the Cox proportional hazards model with propensity score weighting, and binary logistic regressions with propensity score weighting. The propensity score for fractionation was formed based on the conditional probability of treatment selection conservatively calculated with all observable co-variates (gender, age, KPS, GTV, and dose) and then incorporated as a continuous covariate into a multivariate logistic regression as well as Cox proportional hazards model for toxicity incidence. All calculations were conducted using Stata 14.0 (StataCorp LP, College Station, TX) with a p < 0.05 considered statistically significant for all analyses.
Results
Patient, lesion, and treatment characteristics
A summary of the cohort examined as well as characteristics of treated lesions and radiotherapy planning can be found in Table 1. The median age of patients in the cohort was 60.5 years (range: 31-88), with 38 female patients and 26 male patients. The median initial KPS prior to treatment was 90% (range: 60% – 100%). The median time elapsed between SRS or fSRS and last follow-up was 30.4 months (range: 7.5 – 107.0 months). For the SRS cohort, the median follow-up was 49.45 months (range: 12.2 months – 107.0 months) as compared to 29.6 months for the fSRS cohort (range: 7.53 months – 77.7 months) that was significantly longer for the SRS cohort on t-test (p = 0.0014). The median pre-treatment GTV was 1.09cc (range: 0.008 34.8). Twelve patients were treated with SRS (median prescription dose = 12.25 Gy (range: 6 Gy – 14 Gy)), 41 patients with 3 fractions (median prescription dose of 18 Gy (range: 18-22.5 Gy)), and 11 patients with 5 fractions (median prescription dose of 25 Gy (range: 18-25 Gy)). When examining if there was a correlation between choice of either SRS or fSRS and GTV (i.e. if fSRS was associated with higher GTVs), no correlation was identified after two-sample t-test between GTV and choice of either SRS or fSRS (p = 0.48) with median GTVs of 0.6 cc and 1.1 cc, respectively. Also, given that total dose has previously been shown to be related to toxicity outcomes, we aimed to analyze if there were any differences in BED between SRS and fSRS.17,18 Both BED10 (p = 0.31) and BED3 (p = 0.23) were not found to be statistically significantly different for SRS and fSRS regimens following two-sample t-test.
Table 1.
Summary of patient and lesion characteristics and radiotherapy planning
| Variable | |
| Gender | Female – 38 patients |
| Male – 26 patients | |
| Median Age (years) (range) | 60.5 (31 - 88) |
| Race | Caucasian – 50 patients |
| African-American – 5 patients | |
| Hispanic – 1 patient | |
| Asian – 1 patient | |
| Unknown – 7 patients | |
| Median Initial KPS (range) | 90% (60% - 100%) |
| Median time to last follow-up after SRS or fSRS (months) (range) | 30.4 (range: 7.5 – 107.0) |
| Median Initial GTV (cc) (range) | 1.09 (range: 0.008 - 34.8) |
| Median number of fractions (range) | 3 (1 - 5) |
| Median Prescription Dose (Gy) (range) | 1 fraction (n = 12): 12.25 (6 - 14) |
| 3 fractions (n = 41): 18 (18 - 22.5) | |
| 5 fractions (n = 11): 25 (18 – 25) | |
| Median BED3 (Gy3) (range) | Entire cohort: 54 (18 – 79.3) |
| 1 fraction (n = 12): 62.3 (18 – 79.3) | |
| 3 fractions (n = 41): 54 (54 – 78.75) | |
| 5 fractions (n = 11): 66.6 (39.6 – 66.6) | |
| Median BED10 (Gy10) (range) | Entire cohort: 28.8 (9.6 – 39.4) |
| 1 fraction (n = 12): 27.27 (9.6 – 33.6) | |
| 3 fractions (n = 41): 28.8 (28.8 – 39.4) | |
| 5 fractions (n = 11): 37.5 (24.5 –37.5) | |
| Median Isodose (%) (range) | 1 fraction (n = 12): 80% (53.1% – 100%) |
| 3 fractions (n = 41): 81.5% (55.9% - 100%) | |
| 5 fractions (n = 11): 73% (70% – 85%) | |
Local Control Following SRS and fSRS
Treatment responses following SRS and fSRS are displayed in Table 2. Sixty-one of 64 patients (95.3% of the cohort) had radiographic local control at last follow-up, with 42 patients with stable disease, 15 patients with a partial response, and 4 patients with a complete response. Median GTV at last radiographic follow-up was found to be 0.95 cc (range: 0.0001 – 24.5 cc). For the 3 patients with local progression of their disease, the median time to failure of local control was 31.9 months (range: 18.2 months – 34.2 months).
Table 2.
Summary of treatment response at last follow-up
| Variable | |
| Median GTV at last follow-up (cc) (range) | 0.95 (0.0001 – 24.5) |
| Treatment response at last radiographic follow-up | Complete Response: 6.3% (4 patients) |
| Partial Response: 23.4% (15 patients) | |
| Stable Disease: 65.6% (42 patients) | |
| Locally Progressive Disease: 4.7% (3 patients) | |
| Median time to local progression following SRS (n = 3) (months) (range) | 31.9 (18.2 – 34.2) |
The assessment of potential prognostic factors on LC based on Kaplan-Meier univariate analysis is depicted in Table 3. There were no local failures among patients treated with SRS as compared to fSRS (3/52 patients; 5.8%), though fSRS was not found to be statistically inferior (p = 0.33; Figure 1). With regards to GTV, 3/46 patients (6.5%) with GTVs ≥ 0.95 cc had locally progressive disease at last follow-up as compared to 0/18 patients with smaller-sized schwannomas that was not significantly different (p = 0.33). When examining BED10 and BED3 cutoffs of 30 Gy10 and 54 Gy3, respectively, we did not find an LC benefit to dose escalation with respect to BED10(p = 0.66) or BED3(p = 0.85). Other prognostic factors evaluated, including patient age, prescription dose, and initial KPS, were also not found to be related to LC.
Table 3.
Kaplan-Meier Analysis of Potential Prognostic Factors on LC following SRS and fSRS
| Variable | Number of Patients | Number of Local Failures (Crude) | p-value |
| Fractionation | 0.33 | ||
| 1 fraction | 12 | 0 (0%) | |
| 3 or 5 fractions | 52 | 3 (5.8%) | |
| BED10 | 0.66 | ||
| < 30 Gy10 | 52 | 2 (3.8%) | |
| ≥ 30 Gy10 | 12 | 1 (8.3%) | |
| BED3 | 0.85 | ||
| ≤ 54 Gy3 | 43 | 2 (6.7%) | |
| > 54 Gy3 | 21 | 1 (4.8%) | |
| Age | 0.48 | ||
| < 75 years | 54 | 3 (5.6%) | |
| ≥ 75 years | 10 | 0 (0%) | |
| GTV | 0.33 | ||
| < 0.95 cc | 18 | 0 (0%) | |
| ≥ 0.95 cc | 46 | 3 (6.5%) | |
| Initial KPS | 0.68 | ||
| < 80% | 5 | 0 (0%) | |
| ≥ 80% | 59 | 3 (5.1%) |
Figure 1.
Kaplan-Meier curves examining LC following SRS and fSRS
Toxicities
Incidences of both acute and late CNS toxicities following SRS and fSRS were relatively mild in nature with no > Grade 2 toxicities reported. Twenty-three of 64 patients (35.9%) reported either CTCAE Grade 1 or 2 toxicities with a summary of these toxicities provided in Table 4. The most common toxicities following SRS and fSRS were dizziness (12.5%), tinnitus (12.5%), and hearing impairment (10.9%). With regards to CN V, VII, and CN VIII, 7 patients (10.9%), 3 patients (4.7%), and 3 patients (4.7%) reported hearing impairment, trigeminal neuropathy, or facial nerve neuropathy following treatment, respectively. All cases of trigeminal neuropathy were reported to be Grade 1. With respect to hearing impairment, five cases were deemed to be of Grade 1 and two cases of Grade 2.
Table 4.
Summary of Patient-Reported Toxicities following SRS and fSRS
| CTCAE Grade 1 Toxicities | CTCAE Grade 2 Toxicities |
| Tinnitus – 8 patients | Dizziness – 3 patients |
| Dizziness – 8 patients | Hearing Impairment – 2 patients |
| Hearing Impairment – 5 patients | Ataxia – 1 patient |
| Trigeminal Nerve Neuropathy - 3 patients | Facial Nerve Neuropathy – 1 patient |
| Facial Nerve Neuropathy – 2 patients | |
| Ataxia - patient | |
| Involuntary Movement – 1 patient | |
| Fatigue – 1 patient |
Given similar disease control for patients treated with SRS or fSRS, we also aimed to examine whether there was any difference in toxicity incidence between different fractionation regimens. Notably, 1/12 patients (8.3%) reported toxicities following SRS as compared to 22/52 patients (42.3%) treated with fSRS. Following univariate logistic regression, fSRS trended towards higher toxicity incidence but was not statistically significant (p = 0.054). However, fSRS was significantly associated with toxicity incidence on time-to-event Kaplan-Meier analysis (p = 0.039; Figure 2). To further strengthen the results and account for potential indication bias from non-randomized data, a sensitivity analysis was performed with propensity score weighting formulated based upon a conditional probability of treatment selection for SRS versus fSRS and then incorporated as a continuous covariate into a binary logistic model confirming the impact of fractionation on risks of toxicity when controlling for age, KPS, gender, BED10, and GTV (p = 0.037). Similarly, a propensity-score weighted Cox proportional hazards regression also found fSRS to be associated with higher rates of toxicity (p = 0.039; hazard ratio (HR) = 8.85 (95% CI: 1.1 – 70.1)). When examining whether this association also held true with respect to hearing impairment, 0/12 patients treated with SRS reported hearing issues as compared to 7/52 patients (13.5%) treated with fSRS with no significant difference noted following Fisher’s exact test (p = 0.33) or time-to-event analysis (p = 0.14).
Figure 2.
Time-to-event analysis examining toxicity incidence for SRS and fSRS
With regards to dose escalation, 4/12 patients (33%) and 5/21 patients (23.8%) in the cohort reported toxicities when treated to a BED10≥ 30 Gy or a BED3> 54 Gy, respectively. Dose escalation was defined by either BED10(p = 0.84; p = 0.73) or BED3(p = 0.16; p = 0.17) and was not found to be significantly associated with toxicity incidence following univariate logistic regression nor time-to-event analysis. Similarly, with respect to hearing impairment, we found that dose escalation by either BED10(p = 0.64; p = 0.63) or BED3(p = 0.25; p = 0.21) definitions was not related to higher rates of hearing impairment following univariate logistic regression and time-to-event analysis.
Discussion
Previous studies have shown that SRS and fSRS provide similar LC for VS patients. However, the optimal treatment modality to minimize long-term treatment-related toxicities remains controversial. Multiple previous single-institutional investigations have provided outcomes data for each respective treatment modality.6-11 In this study, we demonstrate one of the first multi-institutional toxicity comparisons of SRS and fSRS for VS through utilization of the RSSPR, showing equivalent LC (SRS 100% and fSRS 94.2%; p = 0.33) but increased toxicity with fSRS compared to SRS (SRS 8.3% vs. fSRS 42.3%; p = 0.039). Notably, toxicity findings were found to be in favor of SRS despite significantly longer median follow-up in the SRS group as compared to the fSRS group that would bias results in favor of fSRS as less potential toxicities could be reported in a shorter follow-up time. Findings were further strengthened by a propensity score adjusted binary logistic regression and a Cox proportional hazards model. Of note, the differences in toxicity were not found to be related to total dose as both BED10 and BED3 were not found to be significantly different between SRS and fSRS. However, when looking specifically at the development of hearing loss, we did not find a statistically significant difference between SRS (0%) and fSRS (13.5%; p = 0.14).
Others have previously reported single institution experiences comparing LC and toxicity outcomes following SRS and fSRS. Meijer, et al. were among the first to compare SRS (49 patients treated with 10-12 Gy at an 80% isodose line) and fSRS (80 patients treated with 16 Gy/4 fractions or 20 Gy/5 fractions at an 80% isodose line), demonstrating 5-year LC rates of 100% vs. 94%, respectively, with a higher 5-year hearing preservation rate in the SRS cohort (75% vs. 61%) and similar facial nerve preservation rate (93% vs. 97%) that were not significantly different.7 Only the 5-year trigeminal nerve preservation rate was found to be significantly different in favor of fSRS (92% vs. 98%; p = 0.048). Puataweepong, et al. have also documented their experience with SRS (39 lesions measuring < 3 cm and patients with non-serviceable hearing) with a median dose of 12 Gy at an 80% isodose and fSRS (79 lesions) with a median dose of 25 Gy/5 fractions at an 80% isodose. Five-year LC rates were 95% and 100% following SRS and fSRS, respectively, resulting in hearing preservation rates of 75% and 87% with no significant differences between SRS and fSRS found, and limited incidences of trigeminal or facial neuropathy.9 Similarly, Anderson, et al. found no difference in outcomes with fSRS (with a regimen of 20 Gy/5 fractions) as compared to SRS (prescription dose of 12.5 Gy). The five-year serviceable hearing rate was 63.2% for 37 patients treated with fSRS as compared to 60% for 48 patients treated with SRS with similar toxicity rates of both the trigeminal and facial nerves. Five-year local-control was also similar and not significantly different among the two regimens (90.5% for fSRS and 97% after SRS).11
With respect to other published experiences with fSRS and SRS, a systematic review and meta-analysis by Nguyen, et al. found that fSRS of 3-5 fractions with doses of 18-25 Gy resulted in LC rates ranging from 85-100% with an LC estimate of 95%. This is quite similar to prior reports of SRS that have reported LC rates ranging from 91.8%-100%. With respect to hearing preservation, slightly superior hearing preservation rates (50-93%) have been reported with fSRS as compared to SRS (32-81%).19 However, as discussed earlier, many prior studies comparing fSRS and SRS have found no significant difference with respect to incidences of hearing loss. As such, the hearing preservation rate following fSRS by Nguyen, et al. was estimated to be roughly 37%, albeit with a wide range given varying prior experiences (95% CI: 19-59%).17 Another systematic review by Persson, et al. of 19 SRS and 2 fractionated stereotactic radiotherapy (FSRT) case series also found similar average long-term (defined as 5 years following treatment or greater) local failure rates after SRS (5%) as compared to fractionated SRT (4.8%). Also, 49% of patients treated with SRS reported hearing impairment as compared to 45% following SRT. However, estimates were said to be more uncertain for FSRT given the limited number of case series with long-term follow-up.20
Unlike the registry data used herein, a lack of diversity of treatment administration is an inherent limitation of single-institution studies which can make their findings difficult to apply across widespread clinical settings. However, there are also notable limitations to this study which merit attention. First, the small sample size limits the power to detect small differences due to a low number of events, especially as it related to the LC endpoint, as well as for the estimate for toxicity incidence for the 12-patient SRS cohort. However, patients in the SRS cohort had significantly longer median follow-up than the fSRS cohort that would bias toxicity findings in favor of the fSRS cohort, though SRS patients were found to have a significantly lower likelihood of toxicity incidence. Second, the presented findings are dependent on the input of data from numerous nurses, physicians, and staff which increases the chance for recording bias. Third, due to missing data we were unable to account for pre-treatment baseline toxicity, which can be important in VS as multiple previous studies have documented pre-treatment baseline hearing function as a strong determinate of subsequent risks for toxicity and thus potentially biases the presented results.21-23 Also, follow-up is limited with a median follow-up of roughly 30 months that may have an impact on analyses with respect to both LC as well as toxicity analysis for a benign disease with a long natural history. Of note, we also lacked information regarding institutional preferences with regards to whether practitioners added PTV expansions for fSRS that would be of interest with regards to both LC and toxicity. The RSSPR also did not have data regarding the amount of radiation received by the cochlea for each patient and as such could not be analyzed with respect to its relevance to hearing impairment. Finally, with regards to hearing impairment, there was no standard with regards to follow-up or assessment of hearing with audiometric evaluation between institutions.
This investigation serves as a pilot study for future analyses of the vestibular schwannoma cohort in the RSSPR and a framework for future studies involving other multi-institutional patient databases. Additional analyses should be performed both incorporating large, multi-institutional data cohorts as well using the RSSPR as it accumulates additional outcome data with longer follow-up for additional VS patients. Notably, we have identified a potential toxicity advantage with SRS over fSRS that merits further study in larger cohorts with additional follow-up to further examine long-term LC and toxicity outcomes. Also, this is one of a few studies that have specifically examined outcomes for VS exclusively with the CyberKnife system with similar isodose lines given use of the same platform from a multitude of primarily community-based institutions. With adequate future data input, such multi-institutional databases have the potential to produce a highly accurate, widespread visualization of clinical outcomes and guide optimal treatment design.
Acknowledgements
We would like to thank all participating physicians, patients, and administrators of the RSSPR whose efforts made this study possible.
Authors’ disclosure of potential conflicts of interest
Dr. John Austin Vargo reports unrelated speaking honoraria from BrainLAB. Other authors have nothing to disclose.
Author contributions
Conception and design: Raj Singh, Hayden Ansinelli, Sanjeev Sharma, John Austin Vargo
Data collection: Jan Jenkins, Joanne Davis
Data analysis and interpretation: Raj Singh, Hayden Ansinelli, Sanjeev Sharma, John Austin Vargo
Manuscript writing: Raj Singh, Hayden Ansinelli, Sanjeev Sharma, John Austin Vargo
Final approval of manuscript: Raj Singh, Hayden Ansinelli, Sanjeev Sharma, John Austin Vargo
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