Abstract

Background: Treatment outcome data of stereotactic radiosurgery (SRS) for vestibular schwannomas (VS) in patients ≥75 years (late elderly) are lacking. Approximately 39% of patients ≥75 years with VS were reported to experience severe facial palsy after surgical removal. This study compared the treatment outcomes post-SRS for VS between patients ≥75 and 65–74 years (early elderly).

Methods: Of 453 patients who underwent gamma knife SRS for VS, 156 were ≥65 years old. The late and early elderly groups comprised 35 and 121 patients, respectively. The median tumor volume was 4.4 cc, and the median radiation dose was 12.0 Gy.

Results: The median follow-up periods were 37 and 56 months in the late and early elderly groups, respectively. Tumor volume control was observed in 27 (88%) and 95 (83%) patients (P = 0.78), while additional procedures were required in 2 (6%) and 6 (6%) patients (P = 1.00) in the late and early elderly groups, respectively. At the 60^th and 120^th months post-SRS, the cumulative tumor control rates were 87%, 75%, 85%, and 73% (P = 0.81), while the cumulative clinical control rates were 93% and 87%, 95%, and 89% (P = 0.80), in the late and early elderly groups, respectively. In the early elderly group, two patients experienced facial pain, and one experienced facial palsy post-SRS; there were no adverse effects in the late elderly group (both P = 1.00).

Conclusion: SRS is effective for VS and beneficial in patients ≥75 years old as it preserves the facial nerve.

Keywords: Gamma knife, Late elderly, Stereotactic radiosurgery, Tumor control, Vestibular schwannoma

INTRODUCTION

Stereotactic radiosurgery (SRS) is widely performed as a primary or postoperative procedure for patients with small-to-medium-sized vestibular schwannomas (VSs).[ 23 ] Although surgical removal remains the gold standard for VS, patients aged ≥75 years (late elderly) generally experience difficulties with surgery under general anesthesia due to systemic disorders, refusal to undergo surgery, and/or frailty.[ 6 ] Based on specific clinical factors, late elderly patients with VS are sometimes treated with SRS. The number of studies on geriatric medicine is increasing every year. Approximately 39% of patients aged ≥75 years with VS reported experiencing postoperative severe facial palsy; moreover, 75% of patients in the age category of those aged ≥80 years experienced severe facial paralysis after surgery.[ 9 ] Meanwhile, SRS is a minimally invasive procedure; however, there is a lack of evidence regarding functional prognoses, such as facial nerve outcomes, following SRS in older year ranges. Based on a cross-national comparative study of seven industrialized nations, the proportion of elderly individuals was anticipated to possibly reach 20% or even 28% of the entire population in most of these nations by 2030.[ 27 ] The Japanese population is aging rapidly, and our experience should serve as a worldwide model. At present, the World Health Organization defines an age from 65 to 74 years as early elderly and ≥75 years as late elderly. Therefore, category data are increasingly important, with these age categories being used in previous studies.[ 26 ]

In this study, we retrospectively reviewed the long-term treatment outcomes after gamma knife (GK) SRS for SRS between late and early elderly patients.

MATERIALS AND METHODS

Study design and patient selection

Our institutional review board approved this retrospective cohort study (IRB No. R03-01, May 14^th, 2021, University of Tsukuba Hospital), for which we employed our prospectively accumulated database. The database included 453 patients who underwent GK SRS for VS between 1990 and 2019. Among the 453 patients [ Figure 1 ], 165 patients aged ≥65 years were included in the study. Among the 165 patients, 9 were excluded, 8 were lost to follow-up, and 1 was excluded as the treatment objective was not tumor control but trigeminal pain. Ultimately, 156 patients were included in the final analysis and divided into two age groups: those aged ≥75 years (late elderly group, n = 35 patients; median age, 77 years [range, 75–91 years]) and those aged 65–74 years (early elderly group, n = 121; median age, 70 years [range, 65–74 years]).

Figure 1:

Flowchart of inclusion and exclusion criteria for included patients. VS: Vestibular schwannoma, F/U: Follow-up, SRS: Stereotactic radiosurgery.

The clinical characteristics of the 156 patients studied are summarized in Table 1a . Before the study, 7 (20%), 1 (3%), and 2 (6%) patients in the late elderly group and 29 (24%), 5 (4%), and 3 (2%) patients in the early elderly group underwent tumor removal, ventricular–peritoneal shunt placement, and SRS, respectively (P = 0.82, P = 1.00, and P = 0.31). The median tumor volume was 4.4 (range: 0.1–30.1) cc in the late elderly group and 1.9 (range: 0.1–13.5) cc in the early elderly group (P = 0.0027). Cystic-type tumors, which were cysts comprising >60% of the entire tumor volume, were found in 10 (29%) and 20 (17%) patients in the late and early elderly groups, respectively (P = 0.14). The Koos classification was used to classify tumor extension,[ 14 ] while facial and cochlear nerve functions were graded using the House-Brackmann (HB) system[ 10 ] and pure tone audiometry (PTA), respectively. Regarding the pre-SRS facial nerve function in the late and early elderly groups, the HB grade was I in 24 (69%) and 77 (64%), II in 8 (23%) and 34 (28%), and III–V in 3 (9%) and 10 (8%) patients, respectively (P = 1.00).

Table 1a:

Prestereotactic radiosurgical (SRS) clinical characteristics (n=156).

Radiosurgical technique

Radiosurgery was performed according to the method outlined in a previous study.[ 25 ] SRS preparations involved a comprehensive explanation of the treatment strategy to each patient and a minimum of one adult relative by one (MY) of coauthor. As the patients were initially referred by their primary neurosurgeons, the decision to proceed with SRS was already established upon their arrival at our facility. Concurrently, the advantages and disadvantages of SRS were detailed by the second author to each patient, and written informed consent was acquired from all study participants. Radiosurgery was conducted using a Gamma Unit Model B (Elekta Instrument AB, Stockholm, Sweden). The SRS procedures employed a Leksell GK Model B unit (1988–2003, Elekta), Model C unit (2003–2013, Elekta), and Model Perfection unit (2013–Elekta). A Leksell Model G stereotactic coordinate frame (Elekta Instrument AB) was affixed to the patient’s head using local anesthesia. To establish target coordinates and plan the dosage, we routinely obtained stereotactic T1-weighted axial magnetic resonance (MR) images with gadolinium enhancement. The slice thickness varied between 1 and 2 mm, depending on the size of the tumor. We consistently employed three-dimensional constructive interference in steady-state axial MR images and computed tomographic axial images without contrast enhancement for this purpose.

Dose planning was executed through a Leksell GammaPlan system (Elekta Instrument AB). Table 1b provides a summary of the radiosurgical parameters applied, encompassing radiosurgical doses, coverage, and Paddick’s conformity[ 1 , 19 ] and gradient[ 1 , 20 ] indices. The target volume was calculated and essentially covered with a 60% isodose gradient to administer 12.0 Gy at the tumor periphery.[ 25 ] To mitigate excessive irradiation of the facial and cochlear nerves, a 10.0-Gy isodose gradient covered the anterior portion of the tumor in patients with serviceable facial and/or cochlear functions before SRS.

Table 1b:

Radiosurgical parameters.

Post-SRS follow-up

In a prior publication,[ 25 ] we outlined our post-SRS follow-up plan. The recommended assessments during follow-up encompassed the following aspects: (1) neurological findings, with a specific focus on the functions of the trigeminal, facial, cochlear, and lower cranial nerves; (2) MR image results, encompassing evaluations of tumor size, enhancement changes, and ventricular size; and (3) PTA, at 3-month intervals up to the 18^th post-SRS month, followed by 6-month intervals up to the 36^th post-SRS month and subsequently at 12-month intervals. Among the 156 patients, MR images were obtained during follow-up at our facility for 88 (56%) individuals. In this subset of 88 patients, the Leksell GammaPlan system was used to calculate tumor volume at each examination.

Clinical outcomes

In assessing tumor growth control, we anticipated measurement errors of 25% for volume and 10% for diameter estimation. A volume ≥125% and/or a diameter ≥110% compared with baseline values indicated “growth,” while a volume ≤75% and/or a diameter ≤90% indicated “shrinkage.” Any other observations were considered as “no change.” Clinical tumor control was characterized by the absence of further procedures (FP), such as salvage tumor removal or restereotactic radiosurgery (re-SRS). FP-free survival time was defined as the duration between SRS and the day of salvage surgery/re-SRS or the latest follow-up. The determination of FP considered not only an increased tumor volume but also a patient’s inability to tolerate symptom progression. In assessing the endpoint, FP was considered the event, while other outcomes were censored.

For calculating PTA results, the formula PTA = (a + 2b + c)/4 was utilized, where “a,” “b,” and “c” represent threshold levels at 500 Hz, 1,000 Hz, and 2,000 Hz, respectively. Hearing levels were categorized using the Gardner and Robertson system [ 5 ], with a PTA ≤50 dB defined as serviceable hearing.

Statistical analysis

Summary statistics for baseline variables included the use of frequencies and proportions for categorical data, while medians, means, and standard deviations were employed for continuous variables. The cumulative incidences of FP for time-to-event outcomes were determined using the Kaplan-Meier method.[ 12 ] Multivariate analyses involved the application of the Cox proportional hazards model. Statistical analyses were conducted using JMP 10.0 (SAS Institute, Cary, NC). A P < 0.050 was deemed statistically significant.

RESULTS

Tumor control and FP-free interval

The median follow-up periods were 37 (range: 4–145) and 56 (range: 6–192) months in the late and early elderly groups, respectively. Table 1c shows the post-SRS clinical and neuroimaging results. Excluding 3 patients lacking tumor volume information, we documented tumor shrinkage/no change/growth in 18 (55%)/9 (27%)/4 (12%), and 60 (52%)/35 (30%)/19 (17%) patients in the late and early elderly groups; the crude growth control rates were 88% and 83%, respectively (P = 0.78). At the 60^th and 120^th post-SRS months, the tumor control rates were 87%, 75%, 85%, and 73% in the late and early elderly groups, respectively (P = 0.81) [ Figure 2a ]. In the late elderly group, salvage surgery was required in two (6%) patients, and none underwent re-SRS. Meanwhile, salvage surgery and re-SRS were necessary for four (3%) and three (2%) patients, respectively, in the early elderly group (P = 1.00). Among the patients who underwent salvage treatment, the timing of salvage surgery in the late elderly group was 8 or 85 post-SRS months, and the timing of salvage surgery in the early elderly group was a median of 45 post-SRS (range, 23–74) months. According to the follow-up, Figure 2b shows the FP-free survival interval. At the 60^th and 120^th post-SRS months, the FP-free rates were 93%, 87%, 95%, and 89% in the late and early elderly groups, respectively (P = 0.80).

Table 1c:

Postradiosurgical clinical and neuroimaging results.

Figure 2:

Cumulative rate of (a) growth control and (b) clinical control after stereotactic radiosurgery(SRS).

We previously described the case of a 92-year-old man with a large VS.[ 24 ] Adding the recently estimated tumor volume, post-SRS long-term tumor shrinkage was documented, as shown in Figure 3 . This is a rare case wherein SRS was performed because the patient was very old and had a large tumor, and there were no other treatment options. In this case, SRS was successful.

Figure 3:

Chronological tumor volume changes of an illustrative case. Age at the time of stereotactic radiosurgery was 91 years old, late elderly. The tumor (30.6 cc) was irradiated with a peripheral dose of 12.0 Gy (maximum dose, 20.0 Gy) and shrunk significantly over the 6–12-month period. GK: Gamma knife, SRS: stereotactic radiosurgery.

Post-SRS functional outcomes

During a median follow-up period of 37 (range: 4–145) and 56 (range: 6–192) months in the late and early elderly groups, trigeminal neuropathy developed in zero and two (2%) patients, respectively. (P = 1.00). Among these two patients in the late elderly, symptoms were well controlled by administering carbamazepine in one patient, whereas symptoms persisted in the other, necessitating nerve block injection and carbamazepine administration. No patient suffered from facial nerve palsy in the late elderly group, whereas one (1%) patient developed facial nerve palsy in the early elderly group (P = 1.00). Among the 46 patients with serviceable hearing pre-SRS, this level of hearing acuity was preserved in two (50%) and eight (27%) patients in the late and early elderly groups, respectively (P = 0.56). Among the 149 patients without pre-SRS shunting, a ventricular– peritoneal shunt had to be placed for the management of symptomatic hydrocephalus in three (9%) patients in each group (P = 0.12).

Factors associated with tumor and clinical control

Tables 2a and b presents the pre-SRS clinical factors that may be related to tumor and/or clinical control. Multivariate analysis followed by univariate analysis revealed that a lower conformity index (<0.75) (hazard ratio [HR], 2.80, 95% confidence interval [CI], 0.74–12.62, P = 0.13), lower mean irradiation dose (<15 Gy) (HR, 2.26, 95% CI, 0.11–1.32, P = 0.17), and Koos classification grade IV (HR, 2.53, 95% CI, 0.72–8.49, P = 0.14) tended to be related to the failure of tumor control in our cohort. Furthermore, a Koos classification of grade IV tended to be related to the need for FP in this cohort (HR, 6.50, 95% CI, 1.00–56.38, P = 0.050). Paddick’s gradient index was not correlated with post-SRS facial and cochlear nerve functions.

Table 2a:

Factors associated with the failure of tumor control after SRS.

Table 2b:

Factors associated with the failure of clinical control after SRS.

DISCUSSION

To the best of our knowledge, this is the first study that analyzed the treatment results of SRS for VS in patients aged ≥75 years compared with those in patients aged 65–74 years. There were no marked differences in the SRS results, including the crude/cumulative tumor control rates, FP-free intervals, hearing preservation rates, and incidences of complications between the two age groups. In the VS in patients ≥75 years cohort, considerably rare cases of facial neuropathy developed than in the existing reports[ 9 ] of postoperative cases.

Tumor and clinical control in late elderly (aged ≥75 years) patients with VS

Among the various pre-SRS clinical factors and radiosurgical parameters, advanced age was not considered in previous studies, i.e., previous studies included younger patients; the mean or median age of the study cohort was 45–61 years [ Table 3 ]. According to these studies, tumor control rates of 82–97% or clinical control rates of 82–97% were reportedly based on median follow-up periods of 68– 150 months.[ 2 , 7 , 16 , 17 , 25 , 28 ] However, no prior reports have focused on elderly patients with VS in this aging society. In our study, with median follow-up periods of 37 in the late elderly groups, the crude tumor control rates were 88%, while the clinical control rates were 94%. Actuarial tumor control rates were 87% and 75% at the 60^th and 120^th post-SRS month in the late elderly group. The cumulative FP-free rates of the late elderly groups were 93%/95% at the 60^th and 120^th post-SRS month. In terms of tumor and clinical control, our results of late elderly were highly consistent with those of previously reported studies focused on younger patients.[ 2 , 7 , 16 , 17 , 25 , 28 ] It may be concluded that tumor and clinical control itself could be obtained by SRS as well as in younger cohorts, even over the age ≥75 years.

Table 3:

Summary of published reports on postradiosurgical long-term follow-up for all-age vestibular schwannomas.

Facial nerve preservation of SRS in late elderly (aged ≥75 years) patients with VS

Post-SRS preservation rates of facial nerve functions are 95–100% at the 5^th post-SRS year.[ 3 , 4 , 7 , 8 , 15 , 18 , 21 , 22 ] In this study, none of the patients in the late elderly group experienced facial nerve palsy, whereas one in the early elderly group, in whom the palsy was caused by surgical removal of tumor regrowth, developed this complication. Yang et al. performed a multiple-center study on facial nerve preservation after SRS for VS in an all-year age range cohort; the facial nerve preservation rate was 96.2% after SRS for VS.[ 29 ] Meanwhile, Helal et al.[ 9 ] performed a retrospective study on 24 patients aged ≥75 years undergoing surgical removal of tumors with an average size of 2.7 cm and reported postoperative facial nerve function, i.e., HB grade I or II, in 75% of patients aged 75–79 years and 29% of patients aged ≥80 years. They concluded that microsurgical resection of VS may be associated with an increased risk of facial nerve function deterioration. In our study comprised of patients with relatively small VS and within the same age range who underwent SRS, no facial palsy occurred. Therefore, SRS for VS in the late elderly may be more beneficial than surgical removal for facial nerve preservation.

Weaknesses of our study

The major weakness of our study might be its retrospective design. In addition, clinical factors are heterogeneous; there was some disproportion between the two age groups in terms of both tumor volume and PTA. However, these imbalances were minimal and acceptable. Another weakness is that the late elderly group had a shorter follow-up period than the early elderly group, which may be because the late elderly tended to die earlier or were lost to follow-up due to various causes. Another possible weakness of this study is the lack of meticulous neuro-otological examination results before and after SRS. Ideally, hearing functions should be evaluated using both PTA and the speech discrimination score (SDS). Jacob et al. reported that SDS is significantly correlated with the time to nonserviceable hearing.[ 11 ] A Japanese study already demonstrated a correlation between PTA and SDS in patients with VS[ 13 ] and that all patients with VS with a PTA of ≤50 dB maintained ≥50% of their hearing acuity according to the SDS. Finally, the lack of patient-reported outcomes, such as balance outcomes, might be a weakness of this study.

CONCLUSION

When compared with patients with VS aged 65–74 years, SRS is an effective treatment option for VS in patients aged ≥75 years in terms of both long-term tumor control and post-SRS complication rates. SRS in late elderly patients may be more beneficial than surgical removal with respect to facial nerve preservation. Further studies are needed to draw more robust conclusions.

Ethical approval

The research/study was approved by the Institutional Review Board at the University of Tsukuba Hospital, number R03-01, dated 14 May 2021.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Use of artificial intelligence (AI)-assisted technology for manuscript preparation

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript, and no images were manipulated using AI.

Disclaimer

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Journal or its management. The information contained in this article should not be considered to be medical advice; patients should consult their own physicians for advice as to their specific medical needs.

References

1. Aiyama H, Yamamoto M, Kawabe T, Watanabe S, Koiso T, Sato Y. Clinical significance of conformity index and gradient index in patients undergoing stereotactic radiosurgery for a single metastatic tumor. J Neurosurg. 2018. 129: 103-10

2. Carlson ML, Jacob JT, Pollock BE, Neff BA, Tombers NM, Driscoll CL. Long-term hearing outcomes following stereotactic radiosurgery for vestibular schwannoma: Patterns of hearing loss and variables influencing audiometric decline. J Neurosurg. 2013. 118: 579-87

3. Chopra R, Kondziolka D, Niranjan A, Lunsford LD, Flickinger JC. Long-term follow-up of acoustic schwannoma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys. 2007. 68: 845-51

4. Friedman WA, Bradshaw P, Myers A, Bova FJ. Linear accelerator radiosurgery for vestibular schwannomas. J Neurolsurg. 2006. 105: 655-61

5. Gardner G, Robertson JH. Hearing preservation in unilateral acoustic neuroma surgery. Ann Otol Rhinol Laryngol. 1988. 97: 55-66

6. Gill TM, Gahbauer EA, Allore HG, Han L. Transitions between frailty states among community-living older persons. Arch Intern Med. 2006. 166: 418-23

7. Hasegawa T, Kida Y, Kato T, Iizuka H, Kuramitsu S, Yamamoto T. Long-term safety and efficacy of stereotactic radiosurgery for vestibular schwannomas: Evaluation of 440 patients more than 10 years after treatment with gamma knife surgery. J Neurosurg. 2013. 118: 557-65

8. Hayhurst C, Monsalves E, Bernstein M, Gentili F, Heydarian M, Tsao M. Predicting nonauditory adverse radiation effects following radiosurgery for vestibular schwannoma: A volume and dosimetric analysis. Int J Radiat Oncol Biol Phys. 2012. 82: 2041-6

9. Helal A, Graffeo CS, Perry A, Van Abel KM, Carlson ML, Neff BA. Differential impact of advanced age on clinical outcomes after vestibular schwannoma resection in the very elderly: Cohort study. Oper Neurosurg (Hagerstown). 2021. 21: 104-10

10. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck Surg. 1985. 93: 146-7

11. Jacob JT, Carlson ML, Schiefer TK, Pollock BE, Driscoll CL, Link MJ. Significance of cochlear dose in the radiosurgical treatment of vestibular schwannoma: Controversies and unanswered questions. Neurosurgery. 2014. 74: 466-74

12. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958. 53: 457-81

13. Kimitsuki T, Matsumoto N, Shibata S, Tamae A, Ohashi M, Noguchi A. Correlation between the maximum on speech discrimination score and pure-tone threshold. Audiology. 2011. 57: 158-63

14. Koos WT. Criteria for preservation of vestibulocochlear nerve function during microsurgical removal of acoustic neurinomas. Acta Neurochir (Wien). 1988. 92: 55-66

15. Litvack ZN, Norén G, Chougule PB, Zheng Z. Preservation of functional hearing after gamma knife surgery for vestibular schwannoma. Neurosurg Focus. 2003. 14: e3

16. 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: 149-53

17. Milligan BD, Pollock BE, Foote RL, Link MJ. Long-term tumor control and cranial nerve outcomes following γ knife surgery for larger-volume vestibular schwannomas. J Neurosurg. 2012. 116: 598-604

18. Murphy ES, Barnett GH, Vogelbaum MA, Neyman G, Stevens GH, Cohen BH. Long-term outcomes of gamma knife radiosurgery in patients with vestibular schwannomas. J Neurosurg. 2011. 114: 432-40

19. Paddick I. A simple scoring ratio to index the conformity of radiosurgical treatment plans. Technical note. J Neurosurg. 2000. 93: 219-22

20. Paddick I, Lippitz B. A simple dose gradient measurement tool to complement the conformity index. J Neurosurg. 2006. 105: 194-201

21. Pollock BE, Link MJ, Foote RL. Failure rate of contemporary low-dose radiosurgical technique for vestibular schwannoma. J Neurosurg. 2009. 111: 840-4

22. Timmer FC, Hanssens PE, Van Haren AE, Van Overbeeke JJ, Mulder JJ, Cremers CW. Follow-up after gamma knife radiosurgery for vestibular schwannomas: Volumetric and axial control rates. Laryngoscope. 2011. 121: 1359-66

23. Tsao MN, Sahgal A, Xu W, De Salles A, Hayashi M, Levivier M. Stereotactic radiosurgery for vestibular schwannoma: International stereotactic radiosurgery society (ISRS) practice guideline. J Radiosurg SBRT. 2017. 5: 5-24

24. Watanabe S, Yamamoto M, Kawabe T, Koiso T, Aiyama H, Kasuya H. Long-term follow-up results of stereotactic radiosurgery for vestibular schwannomas larger than 8 cc. Acta Neurochir (Wien). 2019. 161: 1457-65

25. Watanabe S, Yamamoto M, Kawabe T, Koiso T, Yamamoto T, Matsumura A. Stereotactic radiosurgery for vestibular schwannomas: Average 10-year follow-up results focusing on long-term hearing preservation. J Neurosurg. 2016. 125: 64-72

26. Yamamoto M, Serizawa T, Sato Y, Higuchi Y, Kasuya H, Barfod BE. Stereotactic radiosurgery for brain metastases: A retrospective cohort study comparing treatment results between two lung cancer patient age groups, 75 years or older vs 65-74 years. Lung Cancer. 2020. 149: 103-12

27. Yancik R, Ries LA. Cancer in older persons: An international issue in an aging world. Semin Oncol. 2004. 31: 128-36

28. Yang HC, Kano H, Awan NR, Lunsford LD, Niranjan A, Flickinger JC. Gamma knife radiosurgery for larger-volume vestibular schwannomas. Clinical article. J Neurosurg. 2011. 114: 801-7

29. Yang I, Sughrue ME, Han SJ, Fang S, Aranda D, Cheung SW. Facial nerve preservation after vestibular schwannoma gamma knife radiosurgery. J Neurooncol. 2009. 93: 41-8