Fate of Residual Tumor After Subtotal-resected, Previously-irradiated Vestibular Schwannoma: Long-term Follow-up of a Single Institutional Series

doi:10.21203/rs.3.rs-859915/v2

Background: The fate of residual tumor after salvage surgery for recurrent vestibular schwannoma (VS) after radiosurgery has not been elucidated. We reviewed our surgical series of salvage surgery for recurrent VS and the natural history of the residual tumor after salvage surgery.

Methods: This study enrolled 14 patients who were received salvage surgical resection in our institute and were followed-up for >12 months.

Results: There were 3 male and 11 female patients with a median age of 55 years (range: 16-70). The pre-SRS tumor volume was a median 6591 mm³. All patients were treated by GKS. The median duration from GKS to surgery was 52 months (range: 10-116). Solid tumor growth was observed in 6 (42.9%) patients and cyst formation was observed in 8 patients (57.1%). Subtotal resection was performed in 13 (92.9%) patients and gross total resection was only achieved in one (7.1%) patient. Postoperative facial paresis occurred in 5 (35.7%) patients. Postoperative surgical complications occurred in 2 (14.3%) patients. After salvage resection for irradiated VS, no patient showed tumor progression or recurrence during the follow-up period (13 subtotal resection and 1 total resection). In addition, 2 patients in the subtotal resection group showed residual tumor shrinkage after salvage surgery during the follow-up period

Conclusion: The behavior of residual tumors after salvage surgery for irradiated VS was stable. Adjuvant treatment for these residual tumors may not be necessary.

Oncology

Neurology

salvage surgery

vestibular schwannoma

radiosurgery

recurrence

Stereotactic radiosurgery (SRS) is the popular treatment for small to medium-sized vestibular schwannoma (VS). ^1,2 In recent studies, the control rate of VS after SRS is 90% and its complication rate was 1~4%.¹ Temporary tumor expansion after SRS occurred in 11 to 74% of cases; however, most of these cases could be managed conservatively.³ Although SRS showed excellent clinical outcomes, recurrence could happen in some cases. In some recurrent cases, salvage microsurgical resection is necessary to relieve the local mass effect and the intracranial hypertension. Microsurgery of irradiated-VS is difficult due to the radiation effect, including tumor texture changes and neurovascular adhesions. This difficult surgery leads to a high possibility of residual tumor and postoperative complications. ^4,5 For residual tumors after salvage surgery, adjuvant treatment may be considered to prevent regrowth of the tumor. However, there has been a great deal of controversy about the need for adjuvant treatment of subtotal-resected, previously irradiated VS. Herein, we present our experience of salvage surgery for recurrent vestibular schwannoma after radiosurgery/.

2-1. Patient population

The study protocol and review of medical records were approved by the institutional review board of Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Between January 2005 and December 2019, 788 patients with a presumed diagnosis of vestibular schwannoma (VS), based on radiologic analysis, were treated by gamma-knife radiosurgery (GKS) in our institution. Among these patients, 14 (1.7%) underwent salvage surgery during the follow-up period. This study enrolled 14 patients who received salvage surgical resection in our institution and were followed up for >12 months. Follow-up included brain magnetic resonance imaging (MRI), initially at 6 months or 1 year after SRS and then every 1 or 2 years until tumor growth requiring therapeutic intervention was observed.

GKS was performed using a Leksell gamma knife model B (April 1990 to March 2004), Leksell GK Model C (March 2004 to November 2011) or a Leksell GK perfexion (December 2011 until the present). Dose planning for the GKRS treatments used MRI analysis in the Leksell gamma plan. The Elekta and marginal prescription dose was from 12 to 13 Gy.

2-2. Measurements of tumor volume and growth rate

At each follow-up examination, all tumors were volumetrically measured during enhanced MRI using 1.5 to 3 mm thick slices; the slices were processed using software developed in-house (AsanJ, based on a plug-in package for ImageJ (http://rsbweb.nih.gov/ij)). To minimize measurement error, the volume of each tumor was measured three times by three different board-certified neurosurgeons at each follow-up visit, and the mean value at each visit was recorded. Growing tumors were defined as those showing a 33% increase in volume from baseline, corresponding approximately to a 10% increase in diameter. ⁶ .

The follow-up period was defined as the interval between the dates of the initial and last brain MRI.

All statistical analyses were performed using PASW Statistics for Windows, version 24.0 (IBM Corp., Armonk, New York, USA) and R-3.0.2 statistical software (http://www.r-project.org), with a p value <0.05 considered statistically significant.

There were 3 male and 11 female patients with a median age of 55 years (range: 16-70). The median pre-SRS tumor volume was 6591 mm³. All patients were treated by GKS. The median duration from GKS to surgery was 52 months (range: 10-116). Solid tumor growth was observed in 6 (42.9%) patients and cyst formation was observed in 8 patients (57.1%). Subtotal resection was performed in 13 (92.9%) patients, and gross total resection was achieved in only one (7.1%) patient. Postoperative facial paresis occurred in 5 (35.7%) patients. Postoperative surgical complications occurred in 2 (14.3%) patients. The median follow-up period was 48 months (12-112). Representative patient MR findings are presented in Figure 1. Details of the patients’ characteristics are presented in Table 1.

According to the surgical records, the irradiated tumors had a relatively hard and firm texture compared to non-irradiated tumors. Identification of facial nerves was not too difficult; however, it was difficult to dissect them from the tumor capsule. Most of the tumor was adherent to the cerebellum and brainstem and the dissection plane between the tumor and neural structure was not well preserved. Also, arachnoid membrane thickening could be seen around the tumor. A representative intraoperative image is shown in Figure 2.

We analyzed the tumor growth after SRS and the size of the residual tumor after salvage surgery. The pattern of tumor growth after SRS was varied (Figure 3-A). Six of 14 (42.8%) tumors showed solid tumor growth, while 8 of 14 (57.1%) showed peritumoral cyst formation or internal cyst formation.

Thirteen of 14 (92.9%) patients underwent subtotal resection. The median residual tumor volume was 2346 mm³ (range: 334-9059 mm³) and the mean degree of resection was 85.7% (43.0~98.4%). Postoperative facial weakness occurred in 5 (35.7%) patients. Postoperative cerebellar swelling or infarction occurred in 2 (14.2%) patients.

After salvage resection for irradiated VS, no patient showed tumor progression or recurrence during the follow-up period (13 subtotal resection and 1 total resection). In addition, 2 patients in the subtotal resection group showed residual tumor shrinkage after salvage surgery during the follow-up period (Case #3 and Case #6 in Table 2). Details of the enrolled patients’ clinical characteristics are presented in Table 2 and tumor growth after the salvage surgery is presented in Figure 2.

The treatment options for VS are microsurgery, SRS and ‘wait and watch’. The natural history of untreated VS has been reported. Paldor et al. reported that the average growth rate of VS was 0.99-1.11 mm/year.⁷ Considering the slow growth of VS, small asymptomatic tumors could be managed by a wait and watch strategy.^8,9 However, Regis et al. reported that over 70% patients who were managed by wait and watch eventually needed treatment.⁹ Also, Prasad et al. reported that 26% of patients treated conservatively eventually underwent surgery and over 40% of patients lost hearing function during the wait and watch period.⁸ Thus, in clinical practice, treatment is usually recommended for VS to arrest the tumor growth.

SRS has shown favorable treatment outcomes for small to medium sized tumors.¹⁰ A favorable control rate of SRS for VS has been reported. Hasegawa et al. reported long term outcomes of VS treated by gamma knife surgery and the ten-year actuarial progression-free survival of GKS-treated VS was 87%. Although SRS showed good tumor control of VS, treatment failure of SRS was almost inevitable. The risk factors of failure of radiosurgery are a large tumor volume, a young age and neurofibromatosis type 2 association. ¹¹ In the previous report of Hasegawa et al., a tumor volume over 10 cm³ was the only predictor of treatment failure.¹² The SRS-treatment failure cases need salvage treatment. The salvage treatment options for recurrent VS after SRS are salvage radiosurgery and microsurgery.^4,13 Fu et al. reported favorable outcomes of re-irradiation for recurrent VS; however, the volume of the recurrent tumors were small and the post-SRS complications were high. ¹³

In cases of a rapidly growing tumor, a tumor with a mass effect, or a cyst enlarging tumor, salvage microsurgery is a more suitable treatment than radiosurgery or radiotherapy. Microsurgical resection of irradiated VS is difficult. Difficult dissection is encountered in over 90% of cases and there is a high rate of worsening of facial nerve function, and for these reasons, complete excision of the tumor is difficult.^4,11

In our experience, irradiated VS tumor is densely adherent to neural and vascular structures, thus defining the dissection plane between the tumor and normal tissue is difficult (Figure 3). For this reason, to minimize postoperative complications, subtotal tumor resection may be necessary. In our series, total resection could be achieved in only one patient and facial nerve paresis occurred in 35.7% of the patients.

For residual tumor after salvage surgery, there is controversy about the necessity of the treatment of the residual tumor. Adjuvant radiosurgery after subtotal resection for VS shows excellent tumor control ¹⁴. Redo-SRS may be only option for residual tumor after salvage microsurgery after SRS; however, irradiation-induced complications include necrosis, and malignant transformation may be a worrisome problem.⁵

The fate of the residual tumor after microsurgery for VS has been reported. Park et al. reported the natural history of residual tumor after subtotal resection for VS. ¹⁵ In their report, a large proportion of residual tumors were stable; however, 17% of tumors showed regrowth. They suggested the reasons for the stability of the residual tumor was tumor devascularization during surgery. Chen et al. reported that there was no growth after near total resection for VS; however, all cases of subtotal-resected tumor showed tumor growth.¹⁰ Thus, there is debate about the necessity of adjuvant treatment for residual tumor after salvage surgery for irradiated VS.

In our series, there was no regrowth of residual tumor during the median 4 years follow-up period. Moreover, 2 tumors in our series showed tumor shrinkage after salvage resection. Shuto et al. reported that in 12 consecutive cases of salvage surgery for VS, 11 of 12 patients’ residual tumors were stable, and 8 of 12 patients’ residual tumors showed tumor shrinkage without adjuvant treatment.⁴ An effect of the prior radiation may still exist after salvage resection. These results could be interpreted to mean that the residual tumor after salvage surgery was more stable than a not-irradiated tumor

Redo-radiosurgery may be safer than salvage surgery when it comes to acute complications. However, SRS has a high risk of radiation injury. Considering the benign nature of VS, the stability of the residual tumor, and the high risk of radiation injury, residual tumor after salvage surgery for irradiated-VS could be managed with a ‘first leave them alone’ strategy.

Limitations

Due to the rarity of cases, our study contains only 14 patients. This study was also retrospectively designed, which thus precludes a fully meaningful analysis, as it could possibly be subject to selection bias. Additionally, this is a single institutional series spanning a 15-year study period, and the variable length of the follow-up data means that it is difficult to reveal the definitive fate of residual tumor after salvage surgery and draw definite conclusions about the best treatment strategies. However, this study is valuable since it reviewed the natural history of residual tumors after salvage surgery for irradiated VS in a single institute, so our results may become a reference study for future meta-analysis or prospective studies.

Residual tumors after salvage surgery for irradiated VS were stable. It is difficult to perform total resection of irradiated VS and the risk of postoperative facial paresis is high due to the effects of previous radiation. Adjuvant treatment of these residual tumors may not be necessary, but additional large studies or meta-analyses are necessary to confirm this conclusion.

The authors declare no competing interests regarding this study.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Availability of data and material

The data supporting the findings of this study are included in the article and its supplementary material file.

Authors’ contributions

Author contributions JB and YHK conceived and designed the study. SWS and CKH conducted the literature search. JB, YHK, SWS and CKH were involved in the analysis and interpretation of data. JB drafted the manuscript. The study was supervised by CKH and JHK. All authors read and approved the final manuscript.

Ethics approval

This retrospective study has been approved by the appropriate ethics committee and was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. (Approval by IRB of Asan Medical Center, No. 2021-1137). For this type of study, formal patient consent is not required. The IRB of Asan Medical Center gave the right of exemption of 'informed consent' for this study. The reason described below.

The risk expected from this 'retrospective observational study' is not greater than the Level I risk. In addition, all of included patients’ dataset were anonymized. There is no reason to presume the refusal of the research subject's consent, and the risk to the enrolled patients is extremely low even if consent is waived. Consent exemption does not infringe on the rights or welfare of the subject. It is not the research for drug/medical device approval, and it is not a research regulated by a foreign regulatory agency.

Acknowledgments

The authors thank the neuroradiologists, member of Gamma-Knife Center of our institution. We also thank Se Hee Kim, a statistician in our institute, who performed the statistical analysis and assisted in the writing of the Methods section of this report.

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Régis, J. et al. Wait-and-see strategy compared with proactive Gamma Knife surgery in patients with intracanalicular vestibular schwannomas. Journal of Neurosurgery 113, 105-111 (2010).
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Table 1. Basal characteristics of the patients undergoing surgery after radiosurgery for vestibular schwannoma

N (%)

Sex

Male

Female

3 (21.4%)

11 (78.6%)

Age (years)

55 (16-70)

Initial tumor volume (mm³)

Koo’s grade

2

3

4

6591 (1689-14689)

3 (21.4%)

5 (57.1%)

6 (42.9%)

NF association

0

Modality of SRS

GKS

14 (100%)

Duration from SRS to surgery (months)

Median 52 (10-116)

Recurrence pattern

Solid growth

Cyst formation

6 (42.9%)

8 (57.1%)

Extent of resection

Gross total resection

Subtotal resection

1 (7.1%)

13 (92.9%)

Postoperative facial palsy (6 months)

House-Brackmann grade

Grade 1

Grade 2

Grade 4

9 (64.3%)

2 (14.3%)

3 (21.4%)

Postoperative complication

Cerebellar hemorrhage/infarction

2 (14.3%)

2

Recurrence after surgery

0

FU duration after surgery (months)

Mean 48 (12-112)

NF: neurofibromatosis, SRS: stereotactic radiosurgery, GKS: gamma-knife surgery, FU: follow-up

Table 2. Detailed characteristics of the enrolled patients.

Age/Sex

Tumor volume (mm3)

Tumor type

Koo’s grade

Hearing status

SRS modality/ dose (isodose line (50%))

Recurrence pattern

Time from SRS to surgery

(months)

Preop. Tumor volume (mm³)

EOR

Residual tumor volume (mm³) (EOR degree, %)

Preop/Postop. (6 months) H-B grade

Recurrence of residual tumor

Case 1

70/F

4,600

Solid

3

non-serviceable

GK/12Gy

Solid growth

72

17,991

STR

525 (97)

1/4

No-recur

Case 2

44/F

2,300

Solid

2

non-serviceable

GK/12Gy

Solid growth

116

6,077

STR

966 (84)

1/4

No-recur

Case 3

67/F

4,500

Solid

2

non-serviceable

GK/12Gy

Cyst formation

10

41,797

STR

7351 (82)

1/1

No-recur (mass decreased)

Case 4

66/F

14,300

Solid+Cystic

4

non-serviceable

GK/9Gy

Cyst formation

31

23,833

STR

1292 (94)

1/2

No-recur

Case 5

46/F

2,523

Solid

3

non-serviceable

GK/12Gy

Cyst formation

38

10,400

STR

827 (92)

1/1

No-recur

Case 6

62/M

5,500

Solid+cystic

3

non-serviceable

GK/12Gy

Solid growth

36

12,313

STR

730 (94)

1/1

No-recur

(mass decreased)

Case 7

49/M

10,100

Solid

4

non-serviceable

GK/12Gy

Cyst formation

93

19,517

STR

4120 (78)

1/1

No-recur

Case 8

16/F

5,113

Solid

4

non-serviceable

GK/12Gy

Solid growth

50

11,786

STR

1110 (90)

1/1

No-recur

Case 9

56/F

7,400

Solid

4

Serviceable

GK/12Gy

Cyst formation

63

15,900

STR

9059 (43)

1/1

No-recur

Case 10

64/F

1,689

Solid

2

non-serviceable

GK/12Gy

Cyst formation

20

9,451

STR

2556 (72)

1/1

No-recur

Case 11

43/F

4,900

Solid

3

non-serviceable

GK/13Gy

Solid growth

54

10,951

GTR

0

1/2

No-recur

Case 12

59/M

6,600

Solid

4

non-serviceable

GK/13Gy

Cyst formation

41

12,556

STR

1237 (90)

1/1

No recur

Case 13

52/F

14,689

Solid

4

non-serviceable

GK/10Gy

Solid growth

49

22,342

STR

746 (96)

1/4

No-recur

Case 14

54/F

8,068

Solid

3

non-serviceable

GK/12Gy

Cyst formation

64

20,968

STR

334 (98)

1/1

No-recur

SRS: stereotactic radiosurgery, GK: gamma-knife surgery, EOR: extent of resection, GTR: gross total resection, STR: subtotal resection

No competing interests reported.

supplementaryfile.zip

Fate of Residual Tumor After Subtotal-resected, Previously-irradiated Vestibular Schwannoma: Long-term Follow-up of a Single Institutional Series

Status:

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Abstract

Figures

Introduction

Materials And Methods

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 2