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R S Weil, J M Cohen, I Portarena, M Brada (2006) Optimal dose of stereotactic radiosurgery for acoustic neuromas: a systematic review, British Journal of Neurosurgery, Vol. 20(4), 195-202

Optimal dose of stereotactic radiosurgery for acoustic neuromas: a

systematic review

Weil RS2*, Cohen JM**, Portarena I2***, Brada M1,2

Academic Unit of Radiotherapy and Oncology1, The Institute of Cancer Research and Neuro-Oncology Unit2, The Royal Marsden NHS Foundation Trust, London and Sutton, UK

Present address: * National Hospital for Neurology and Neurosurgery, Queen Square, London ** Barnet General Hospital, Wellhouse Lane, Barnet, EN5, *** Dipartimento di Neuroscienze, Universiti di Roma Tor Vergata, Via Montepellier

1, 00133 Roma Italy Abbreviations AN Acoustic Neuroma, Gy Gray, GK Gamma knife, LINAC linear accelerator, NF2 Neurofibromatosis type 2, PFS Progression-Free Survival,

Corresponding author

Prof Michael Brada The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust Downs Road Sutton Surrey SM2 5PT tel: 44 (0)20 8661 3272 fax: 44 (0)20 8661 3127 e-mail: michael.brada@icr.ac.uk

2

Abstract Purpose: Radiosurgery is increasingly employed in the treatment of acoustic neuroma

but the optimal dose in terms of long-term tumour control and minimal adverse effects

has not been established. We performed a systematic review of the published literature

of radiosurgery of acoustic neuroma to assess whether the use of low dose radiosurgery

is as effective as high dose treatment.

Methods and Materials: Reports of radiosurgery for acoustic neuroma were identified

through a Medline search. Studies with at least 15 patients and a median follow-up

longer than 12 months were included. The relationship between actuarial 5 year

progression-free survival (PFS) and tumour and treatment parameters was examined.

Results: 42 studies were included. Tumour control following lower radiosurgery doses

was similar to that reported following high doses. Only 12 studies reported actuarial

outcomes at 5 years. There was no relationship between PFS at five years and dose to

the tumour margin. Radiosurgery of larger tumours was associated with lower 5 year

PFS (p < 0.05).

Conclusion: Although on initial inspection radiosurgery of acoustic neuroma with doses

of 12-13 Gy seems to be as effective as higher dose treatment, the available reports are

subject to a number of confounding factors, are not sufficiently statistically powered and

there is only limited long-term actuarial outcome data. Currently, available studies do not

provide sufficient confidence to support the claim that low dose radiosurgery is equally

effective as higher doses in the long term control of acoustic neuroma.

Acoustic neuroma, vestibular schwannoma, radiosurgery

3

Introduction

The treatment options for patients with acoustic neuroma (AN) are microsurgical

resection, radiotherapy, expectant observation or any combination of these modalities.

Surgical resection, including sub-occipital, trans-labyrinthine and middle fossa

approaches, allows for the removal of the AN in most cases. However, even with recent

technological advances, considerable morbidity remains, including hearing loss and

facial nerve weakness, particularly in patients with large tumours 1. Furthermore, almost

half the tumours that are incompletely excised recur 2.

Conservative management was initially reserved for patients unsuitable for surgery. As

imaging has improved and understanding of this slow-growing tumour has increased,

expectant observation has become accepted as an initial treatment option for selected

patients 3. However, many untreated AN will progress within 2 years 4 and even in those

without radiological progression, hearing has been shown to deteriorate 5.

Focal irradiation as either single fraction radiosurgery or fractionated stereotactic

radiotherapy is increasingly employed as an alternative to microsurgery for the treatment

of acoustic neuromas. It produces excellent local control rates with enhanced

preservation of function 6-8.

Over the past two decades, treatment planning techniques have improved. Magnetic

resonance imaging and sophisticated 3D radiation planning, combined with increasingly

conformal treatment delivery, allow radiation to be given in a more localised manner

achieving good tumour control. Alongside definitive tumour management, preservation

of cranial nerve function has also become a significant aim. Larger radiotherapy doses

are associated with higher risk of hearing loss and other cranial nerve damage 9. This

damage increases with proximity of each nerve to the region of high dose radiation.

Toxicity has also been shown to be associated with increasing length of cranial nerve

irradiated 10 .

Initial reports of radiosurgery in the 1980s used a marginal dose of more than 20Gy 11.

More recent studies with doses of 16-18 Gy were associated with high rates of facial

nerve palsy and hearing loss 12 . Since these preliminary results, lower doses were

4

used with documented reduction in complication rates, particularly in terms of cranial

nerve dysfunction and a lower incidence of hearing loss 7 13 14 15 16 9.

Although dose reduction results in fewer side effects, there is limited data to show that

such low radiation doses are as effective in achieving long-term disease control as

higher doses. Despite this, reassuring statements have been made about the efficacy of

low dose radiosurgery 17. To ascertain whether low dose radiosurgery is indeed

effective, we performed a systematic review of the published literature to examine the

long term tumour control in patients treated with stereotactic radiosurgery in differing

doses. We also examined whether other variables affect outcome after radiosurgery.

Materials and Methods Search strategy and inclusion criteria

A MEDLINE literature search was conducted using PubMed from 1966 to March 2005.

The search used all variations and combinations of the keywords “acoustic neuroma”

and “vestibular schwannoma”. This was combined with a search of all variations of the

keywords “radiosurgery”, “gamma knife” and “LINAC”. The search was limited to

English language journals and those concerned with human subjects. The abstracts of

all articles were examined, and those reporting trials or case series of patients treated

with radiosurgery for acoustic neuromas were included. Reports from abstracts or

conference proceedings were excluded. Case series of less than 15 patients and those

with a median follow-up of 12 months or less were not included as they did not provide

sufficient data to assess long term outcome. To avoid duplication of data, earlier reports

and overlapping patient subsets from the same centre were also excluded.

Data analysis

The number of patients in the study and the number followed up for the stated time

period were extracted from full publications. Patient population characteristics including

age, the number of patients with type 2 Neurofibromatosis (NF2), the proportion who

had undergone previous surgery and the size of the tumour (median volume and

diameter) were recorded. Radiosurgery doses to the tumour margin (minimum,

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maximum and median) were noted. Where median doses were not reported, the mean

was recorded or calculated from the available data. As a summary figure, the mean of

the reported median values was calculated.

Outcome data was recorded as percentage tumour control and as progression-free

survival (PFS) if available. If outcomes were reported as resection free survival (RFS)

and PFS on imaging, only the radiological PFS was used for analysis as other factors

may have influenced the decision to surgically resect a progressing tumour. Duration of

follow-up from radiosurgery was noted. As a summary figure, the mean of the reported

median follow-up, corrected for the number of patients in each study was calculated.

Relationship between dose to tumour margin, tumour control and and 5 year PFS were

analysed using linear regression. Other comparisons were made on actuarial data only.

Factors affecting PFS were analysed using linear regression or t-tests as appropriate.

In all tests, p < 0.05 indicated significance.

Results Study characteristics

42 studies from 32 centres were identified. These were published between 1993 and

2005. Ten studies were from one centre. There were no prospective controlled trials.

Full details of the studies are shown in Table 1.

Patient characteristics

3721 patients were included in the 42 studies, although the actual number is likely to be

less due to multiple reporting (Table 1). The number of patients in individual reports

ranged from 20 18 to 313 19 with a median of 69 patients per study. Patients were aged

from 7 18 to 92 years 16 20 21 with a corrected summary median of 58 years. Twelve

studies excluded patients with NF2 14 22 23 and three studies looked exclusively at the

radiosurgical management of patients with NF2 18 24 25. Fifteen reports included a mix of

patients with and without NF2 and 12 studies did not provide details of NF2 status. The

studies differed in the proportion of patients who had undergone previous surgery. One

6

reported only patients with tumours recurrent after previous surgery 26, while others 6

excluded such patients.

Tumour Characteristics

Where tumour volume was reported, the tumours varied in size from a minimum volume

of 0.02cm3 27 28 to a maximum of 36.7 cm3 29. 23 out of 42 studies reported median

volumes and the summary median tumour volume was 2.96 cm3. 12 studies reported

median diameters of tumours which ranged from 3mm 15 to 50mm 15 with a summary

median of 21 mm. One study reported only intracanalicular tumours 30 .

Radiosurgery

7 studies reported linear accelerator (LINAC) based radiosurgery 21 31 32 33 34 35 12 and

35 reported gamma knife radiosurgery. The dose to the tumour margin ranged from

7.5Gy 15 to 25 Gy 24 36. The summary median marginal dose was 13.6 Gy and the

weighted mean dose was 14.1Gy.

Follow-up data

Follow-up ranged from 1.2 months 16 to 154 months 24. Only 16 of 24 studies had a

median follow-up greater than 3 years, with only 6 studies having a median follow-up of

5 years or more. 27 13 29 37 38 39. The summary weighted mean of the median follow-up

was 42 months.

Many reports quoted a larger number of patients treated than were included in the

follow-up of the study, suggesting exclusions and loss to follow-up 40 41 23 42 43.

Outcome data

All studies reported “tumour control”, defined as lack of progression on neuroimaging

without information on the duration of follow-up. Tumour control, as assessed by

neuroimaging, ranged from 86% 13 to 100% 18 20 21 30. The summary weighted median

tumour control was 94.7%. Relationship of “tumour control” at an unspecified time and

dose for all studies is shown in Figure 1. There was no correlation between tumour

control and median dose to tumour margin.

7

Only 13 of the studies (33%) reported actuarial outcome. Of these, only 12 reported

progression-free survival at 5 years or more (Table 2). In these studies, five year

progression-free survival ranged from 87% 29 32 to 100% 31 with a weighted mean of

92%. There was no correlation between 5 year PFS and median dose, median age,

gender, NF2, previous surgery and treatment technique (GK or LINAC).

The relationship between dose to the tumour margin and 5 year PFS is shown in Figure

2 for the twelve studies where this information was available. Only seven studies

reported both five year PFS and tumour volumes (Table 2). For these studies, median

tumour volume was negatively correlated with 5 year PFS (r2 = 0.74, p< 0.05). For

every 1 cm3 increase in tumour volume, 5 year PFS fell by 1.52% (95% confidence

interval 1.11-1.93%) (Figure 3).

Discussion We report a systematic review of the published literature of radiosurgery for acoustic

neuroma reported in the past 39 years in English language journals. All published

experience of radiosurgical treatment of acoustic neuroma is from retrospective data

with no prospectively designed Phase I, II or III clinical trials. Only 42 studies were

published reporting series of patients who have undergone radiosurgery for AN with a

median follow-up of more than 12 months and at least 15 patients. The original series

describing early experience with radiosurgery in acoustic neuroma were excluded due to

the small numbers of patients involved. A quarter of the studies stem from one centre.

As they contain large numbers of patients, it is likely that this may have

disproportionately influenced the opinion and practice of radiosurgery.

We have not evaluated hearing preservation in radiosurgery as this has been done in

other reports 44 45 and is beyond the scope of this review.

Neurofibromatosis type II

Comparison between reports is difficult due to considerable heterogeneity in the

acoustic neuroma patient population, radiosurgery details and reporting of results.

8

In particular, patients with NF2 are likely to represent a sub-group which is particularly

difficult to treat. They are at increased risk of complete deafness due to bilateral

tumours, many patients also have other intracranial neoplasms, which may complicate

radiosurgical regimens and the concern of malignant transformation is greater. These

patients are more likely to suffer cranial nerve damage as well as other complications

during radiosurgical treatment, than patients with sporadic AN. Tumour control rates are

also recognised to be lower in all treatment modalities in patients with NF2, with an

estimated local tumour control rate of 50% at 5 years 24. Furthermore, tumour control is

often more difficult to define due to increased loss to follow-up and higher mortality in

NF2. It may also be difficult to distinguish recurrence of a previously treated tumour from

a new lesion. For these reasons, the assessment of radiosurgery for the treatment of

acoustic neuroma should best be carried out separately for patients with and without

NF2 and studies combining these patient groups may not reflect the true outcome of

either of the groups alone.

Post-resection studies and differences in tumour size

Some studies reported post-resection cohorts, where tumours had recurred despite

surgery 26. This could result in selection of patients with unfavourable prognosis. The

variation in tumour size between series also makes comparison difficult. Doses of

radiosurgery had been adjusted to tumour size, which does not allow for an independent

assessment of the influence of dose. Furthermore, we have shown that large tumour

volume is associated with a worse outcome, supporting previous findings 29, which may

make it difficult to compare PFS at equivalent doses in cohorts with differing tumour

volumes.

Follow-up data

Acoustic neuromas are benign, slow growing tumours, where surveillance is considered

a reasonable management option. In a recent meta-analysis of conservative

management of acoustic neuromas with a mean follow-up of 3.2 years, 57% of tumours

showed no growth and some regressed in size 4. In conditions where more than half of

tumours do not progress even without treatment, it is critical that follow-up is of sufficient

9

duration to identify change in size which may occur over many years. Long term follow-

up is also required for assessment of treatment associated morbidity which may take

years to manifest 46.

Many studies suffered from limited follow-up information. More than half the studies had

a median follow-up of less than 3 years. Only six reported a median follow-up of five

years or more 27 13 29 37 38 39 . In addition, a number of studies excluded rather than

censored patients lost to follow-up 40 41 32 42 which leads to bias, particularly if the

estimates of tumour control are not quoted as actuarial outcome.

Outcome data

In the first 12 months following radiosurgery, tumours may transiently increase in size

before shrinkage. This occurs most frequently around 6 months after treatment but may

be seen for up to 2 years 43. As the enlargement is temporary, this is likely to represent

a reactive process. The incidence of this phenomenon may be related to the dose

delivered and could account for early reports of tumour progression associated with high

radiation doses 47. The recognition of this phenomenon may have lead to an apparent

improvement in tumour control in more recent reports, coinciding with the use of lower

radiation doses.

When examining the efficacy of a treatment over time with variable length of follow-up,

the only accepted measure of local tumour control is actuarial PFS. Tumour control

figures without an indication of the timing of measured outcome provide a highly

unreliable outcome measure due to wide variation in the duration of follow-up.

Only twelve studies reported PFS at 5 years (Table 2), with values ranging between 87-

100% and most studies reporting 5 PFS in the region of 91-96%.

The 5 year PFS seems on initial inspection independent of radiation dose with similar

control rates for doses of <14Gy 13 15 38 22 and ≥14Gy 34 12. However, results are

confounded by potential patient selection, with smaller tumours treated with radiosurgery

in more recent years and the recognition that transient increase in tumour size does not

reflect tumour progression, both of which lead to apparent improvement in local tumour

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control in sequential studies. The small size of patient cohorts and the small proportion

of patients at the 5 year time point provide for large confidence intervals with

considerable uncertainty about the equivalence of the results. The available

retrospective data is not sufficiently powered to reliably detect such a difference.

Furthermore, a recent study with longer follow up 22 suggests worse actuarial tumour

control in patients treated with a marginal dose less than 12Gy compared to doses

≥12Gy. There is, therefore, insufficient data to substantiate the claim that the use of

lower dose radiosurgery in the treatment of AN is as effective as higher doses.

Technical improvements

In the time that radiosurgery doses have declined both the technique of radiosurgery

and selection criteria for treatment have evolved. Earlier studies were more liberal in

selection of patients, essentially treating all who were unsuitable for surgery 48 49. More

recent series have selected patients with better overall prognosis. The introduction of

MRI for the delineation of AN has also been associated with improved outcome 7 and

techniques of conformal radiosurgery in the form of multiple isocentre (gamma-knife)

and conformal fixed field treatment (linear accelerator) have also progressed. Improved

delivery of radiation may have also affected outcome. All such changes influence

outcome regardless of radiosurgery dose and may account for unchanged tumour

control rates, despite lower doses.

Fractionated Stereotactic Radiotherapy

An alternative way to preserve hearing and reduce complication rates whilst achieving

comparable local tumour control rates to radiosurgery is to deliver radiation in

fractionated manner. A recent study of fractionated stereotactic radiotherapy for AN

reported an actuarial 5 year PFS rate of 93% and only mild toxicity with 98% actuarial

hearing preservation at 5 years in patients without NF2 44. Previous studies referred

similarly good preservation of cranial nerve function with maintained tumour control 50 51 52. Fractionation which is associated with low risk of irradiation-induced nerve toxicity

offers an alternative treatment option for AN of all sizes.

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Summary

Radiosurgery as an effective treatment for AN has evolved and improved over the last

decade, leading to a reduction in side effect profile and improvement in outcome. The

toxicity of higher dose radiosurgery has led to dose reduction which has resulted in a

decline in complication rates 13 19 although a recent study 53 using a median marginal

dose of 12Gy showed low rates of hearing preservation. While low dose radiosurgery

may be the correct approach, there is currently insufficient data to substantiate the claim 17 that lower doses are as effective in achieving long-term tumour control as higher

doses. There are too few studies, inadequate follow-up, limited actuarial data and

results are confounded by changing patterns of care and technology. Ideally, a

randomised multi-centre trial with follow-up of at least 8-10 years would provide

sufficient information for an evidence based choice. For the moment, we have to await

the long term follow-up of existing studies reported in an actuarial manner to have full

confidence in the efficacy of the low-dose approach.

Acknowledgment This work was supported in part by the Neuro-Oncology Research fund, The Royal

Marsden NHS Foundation Trust and Cancer Research UK. The work was undertaken by

the Royal Marsden NHS Trust who received a proportion of its funding from the NHS

Executive; the views expressed are those of the authors and not necessarily those of the

NHS Executive.

Table 1

Characteristics of 42 studies of radiosurgery for acoustic neuroma

Study (first author)

Number of

patients Median

age (yrs)

Patients with NF2

(%)

Previous surgical

treatment (%)

Median Volume

cm3 Unit

Median dose to tumour

margin (Gy)

Median follow-up (months)

5Yr PFSa (%)

Tumour controlb

(%) Van Eck 54 78 58* nd nd 2.3* GK 13.7 22* 87

Wowra 38 111 nd 9 33 1.6 GK 13 84 95 nd

Chung 22 187 51* 0 37.4 4.1* GK 13 30 93.3 93.6

Hasegawa 29 71 52* 0 26 6.3* GK 14.6* 135 87 88

Landy55 34 58* 0 25 nd GK 12 37 94 97

Wackym56 29 nd 0 nd nd GK 13.5* nd 93.1

Flickinger 17 313 56 nd nd 1.1 GK 13 24 93.5 96.5

Litvack 57 121 55* nd 13.4 nd GK 12* 32* 96.7

Chung 21 45 62 6.7 22.2 2.4 LINAC 12 27 100

Rowe 58 212 56* 0 25 3.7* GK 15 34 92

Rowe 24 122 29* 100 20.5 nd GK 15.2* 50* nd

Delbrouk 40 48 nd 0 20.8 nd GK 12.3 nd 97.9

kondziolkap 39 157 60* nd 25.5 nd GK 16.7* 109 98.1

Meijer 31 49 63* nd nd nd LINAC 12.5 30 100 nd

Iwai 13 51 55* nd 17.6 3.6 GK 12 60 92 86

Unger 27 100 58 4 40 3.8 GK 12 76 96

Karpinos 41 75 62.5 0 13.7 nd GK 14.5* 48 90.9

Ottaviani 59 30 55* nd nd 1.6* GK 13.4* 24† 86.6

Petit 15 47 59 1 8.5 nd GK 12 43 96 95.4

Foote KD 32 149 64* 5.4 28.2 4.8* LINAC 14* 34 87 92.4

Bertalanffy 60 40 65* 2.5 51 nd GK 12 54* 90.6

Andrews 50 69 61* 7.2 24.6 3.0* GK 12‡ 28* 98

13

Spiegelman 33 44 57* nd 23 3.8* LINAC 14.6* 32* 97.7

Yu 43 126 Nd nd nd nd GK 12 22* 94.5

Moller 37 69 nd nd 21.7 nd GK 12† 78* 92.5

Suh34 29 67 13.8 31 2.1 LINAC 16 49 94 96.5

Kida 18 20 38* 100 70 nd GK 13* 34* 100

Lee35 42 nd nd 7.1 nd LINAC 12 25 97.6

Niranjanp 30 29 nd 0 3.4 nd GK 14* 33 100

Prasad 28 153 65* 0 37.3 2.8* GK 13.2* 51* 92.2

Subachp 25 40 35* 100 32.5 4.8* GK 15.1* 36 97.8

Millermf 16 82 66 9.8 25.6 3.2 GK 16 28 96.2

Pollockp+mc 26 76 58 10 100 2.8 GK 15 37 93.6

Kondziolkap 14 162 60* 0 25.9 nd GK 16.6* 36 94.4

Kwon 42 88 44* 8 40.9 7.6* GK 12.6* 52 95.2

Ito 36 46 54 4.3 10.9 1.6* GK 16.8* 39 95.6

Mendenhall 12 56 nd 7.1 37.5 nd LINAC 15 21 95 96.3

Flickingerp 61 273 nd nd nd nd GK 15.3* 24 91 96.7

FooteRLmf+mc 20 36 68 13.9 22.2 3.14 GK 18 16 100

Pollockp 6 47 62* 0 0 nd GK 16.3* 24 93.6

Ogunrindep 23 31 55 0 3.2 0.6 GK 16.9* 24* 90

Flickingerp 48 134 60 14.2 35 2.75 GK 17 24 97.1

GK- gamma knife, LINAC – linear accelerator a 5yr PFS - 5 year Progression-Free Survival b Tumour control - percentage of tumours that have not increased in size on neuro-imaging * Where median is not reported, the mean was recorded or calculated from the available data † All patients underwent this treatment dose ‡ “Almost all” patients underwent this treatment dose “nd” no data available In centres reporting more than one study: p Pittsburgh, mc Mayo Clinic, mf Mayo Foundation

14

Table 2

Characteristics of twelve studies reporting 5 year Progression-Free Survival after stereotactic radiosurgery for acoustic neuroma

Study (first author)

Number of

patients Patients with

NF2 (%) Median

Volume (cm3)

Median dose to tumour

margin Gy)

5 year Progression-Free Survival

(%) Wowra 38 111 9 1.6 13 95

Chung 22 187 0 4.1* 13 93.3

Hasegawa 29 71 0 6.3* 14.6* 87

Landy 55 34 0 nd 12 94

Flickinger 19 313 nd 1.1 13 93.5

Meijer 31 49 nd nd 12.5 100

Iwai 13 51 nd 3.6 12 92

Petit 15 47 1 nd 12 96

Foote KD 32 149 5.4 4.8* 14* 87

Suh 34 29 13.8 2.1 16 94

Mendenhall 12 56 7.1 nd 15 95

Flickinger 61 273 nd nd 15.3 91

* Where median is not reported, the mean was recorded or calculated from the available data Nd – not documented

Figure 1

84

86

88

90

92

94

96

98

100

10 12 14 16 18 20

Median Dose (Gy)

Tum

our C

ontro

l (%

)

Figure 2

85

90

95

100

10 11 12 13 14 15 16 17

Dose (Gy)

5 yr

PFS

(%)

16

Figure 3

8687888990919293949596

0 1 2 3 4 5 6 7

median volume of tumour (cm3)

5 ye

ar P

FS (%

)

17

18

Figure Legends

Figure 1

Relationship between overall tumour control (at unspecified time point) and median radiosurgery

dose to tumour margin in the treatment of acoustic neuroma. 39 studies included; 2 studies

reported only PFS, 1 study 24(Rowe 2003 on NF2) unable to report neuroimaging tumour control

due to loss to follow-up and death in patients with NF2.

Regression coefficient by linear regression r2 = 0.007, p = 0.61.

Gy - Gray

Figure 2

Actuarial 5 year Progression-Free Survival following radiosurgery for acoustic neuroma,

according to median dose to tumour margin. 12 studies included. The size of the symbol ( ) is

scaled to the number of patients in the study.

The paler symbols represent two studies 19 61 from the same centre which may have included

some overlap of patients. Regression coefficient by linear regression r2 = 0.13 p = 0.24.

5 yr PFS - 5 year Progression-Free Survival

Gy - Gray

Figure 3

Actuarial 5 year Progression-Free Survival in 7 studies* against median tumour volume.

Regression coefficient by linear regression r2 = 0.74 p = 0.013 (< 0.05).

* 5 year Progression-Free Survival and tumour volume data only available for 7 studies.

19

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