s1042368008000041.pdf

Neurosurg Clin N Am 19 (2008) 367–377

Stereotactic Radiation Techniques in the Treatment

of Acoustic Schwannomas

Steven Abram, MD * , Paul Rosenblatt, MD, Stephen Holcomb, MS

Neuroscience Institute of Saint Thomas Hospital, Nashville, TN, USA

Medical decision-making is based on beneﬁt-

to-cost analysis. Optimally, treatment obtains

a high degree of beneﬁt while minimizing the

physical, social, and ﬁnancial costs. The goals of

the treatment of acoustic schwannomas are pro-

hibiting tumor growth and alleviation of symp-

toms caused by damage to local structures. These

symptomsdtinnitus, ataxia, and hearing lossd

secondary to eighth nerve dysfunction, as well as

symptoms arising from damage to adjacent struc-

tures such as the facial nerve, trigeminal nerve, or

pons, can be caused by tumor growth or treat-

ment. Determination of optimal therapy must

also take into account an understanding of the

natural history of the disease, because acoustic

schwannomas are slow-growing benign tumors

that when left untreated, usually enlarge over

time and cause problems.

operation, was able to go home and give birth to

a healthy child [1] .

During the twentieth century, diﬀerent surgical

approaches (suboccipital, translabrynthine, and

middle fos) were developed for the resection of

eighth-nerve tumors. Each sought to diminish the

inherent anatomic issues associated with total

removal. In addition to the obvious hearing loss

associated with eighth nerve resection, there was

also the risk of seventh nerve damage, cerebro-

spinal ﬂuid leak, and hemorrhage. Because of

diculties with early diagnosis before modern

imaging tests, the pattern of slow intermittent

growth, and the morbidity of resection, observa-

tion instead of immediate intervention became

a frequent consideration.

In 1951, Dr. Lars Leksell, a neurosurgeon, and

Borje Larsonn, a physicist, using the Uppsala

University cyclotron, ion Uppsala, Sweden, de-

veloped an approach to treating small brain

lesions with multiple proton beams, using a ﬁxed

rigid Cartesian coordinate system to locate the

target. Their idea was to develop a noninvasive

therapy system to deliver ablative doses of radi-

ation to a geometrically deﬁned discrete volume of

tissue, using multiple small beams of radiation.

This concept evolved into the Gamma Knife

(Elekta, Stockholm, Sweden) stereotactic radio-

surgery. The Gamma Knife unit consists of 201

cobalt radiation sources placed in a helmet, within

which lie shuttered channels directed toward the

center of the helmet. The target lesion is placed at

that center position of the helmet by using

a stereotactic frame axed to the patient’s skull.

Diﬀerent dose patterns with sharp dose gradients

can be obtained using multiple isocenters designed

to match the shape of the tumor (Appendix).

Historical perspective

Archeological ﬁndings from 2500 BC provide

evidence that acoustic nerve tumors have been

present since antiquity. These tumors, called

acoustic neuromas or, more properly, schwanno-

mas, were diagnosed based on a recognized pro-

gression from deafness to death as early as 1810.

The ﬁrst documented successful removal of an

acoustic schwannoma was performed by Thomas

Annandale in 1896 in Edinburgh, Scotland. The

patient, who was pregnant at the time of the

A version of this article originally appeared in

Otolaryngologic Clinics of NA, volume 40, issue 3.

* Corresponding author.

E-mail address: sabram@howellallen.com

(S. Abram).

doi:10.1016/j.nec.2008.02.003

neurosurgery.theclinics.com

368

ABRAM et al

Dr. Leksell and his team working at the

Karolinska Institute in Stockholm, Sweden were

the ﬁrst to treat acoustic neuromas with stereo-

tactic radiosurgery (SRS). Their initial series

(1969–1974) reported initial tumor control in eight

of the nine cases; however, hearing loss was

reported in the majority of patients treated [2] .In

these early studies, high doses (25–35 Gray) were

employed; targeting was crude compared with im-

aging studies available today. The ﬁrst Gamma

Knife unit in the United States was installed at

the University of Pittsburgh in Pittsburgh, Penn-

sylvania under the direction of Dr. Dade Lunsford.

Many of the early results involving radiosurgery

for acoustic neuromas in North America were

published by the University of Pittsburgh group.

An alternate stereotactic delivery platform was

developed using linear accelerators (linacs).

Linacs were already available in most modern

radiation centers. Instead of multiple sources

aimed at a central designated target, the linac

systems rotated the treatment beam of the unit

around the target in a varying number of rota-

tional arcs. Betti and Colombo initially developed

this technique in South America. Because the linac

systems involve moving sources of radiation,

special devices are needed to limit positional

variation in beam delivery.

Both of these techniques require some method

to limit patient and target movement. Fixation of

target position in a geometric coordinate system

can be achieved with metal frames screwed into

the skull, which can obtain submillimetric accu-

racy, or with thermoplastic molded mask systems,

which allow for more fractionated schedules,

whereby treatment can be administered over

several days without placing ﬁxation screws into

a patient’s skull.

Increased tumor volumes and irregularly

shaped tumor volumes are associated with in-

creased integral dose (energy deposition) within

the tumor for Gamma Knife and cone-based linac

SRS systems. Gamma Knife doses are prescribed

to the tumor periphery. These peripheral doses are

frequently 50% of the peak dose delivered within

the central volume treated. This dose proﬁle with

areas of very high dose within the target volume

(hot spots) is less a problem with single isocenter

treatment plans using a multileaf collimator,

where dose is more uniform. Shaped-beam pe-

ripheral doses are usually prescribed to the 90%

to 95% isodose line. Central hot spots are 10% to

20% higher than the dose prescribed to the tumor

periphery; however, the multileaf collimated treat-

ment plans do not produce dose patterns that are

as conformal or tightly ﬁtting as the multiple

isocenter systems or Gamma Knife systems.

Single isocenter treatment techniques typically

treat a small rim of normal tissue surrounding

an irregularly shaped tumor.

Stereotactic radiosurgery

The initial studies from Pittsburgh demon-

strated the ability of stereotactic radiosurgery to

achieve control rates of 95% or more with doses

of 16 to 20 Gray; however, these doses were

associated with an increased risk of trigeminal

nerve injury, seventh nerve injury, and decreased

hearing. Before 1992, when using these higher

doses, reports of treatment results in patients who

were in the Pittsburgh patient cohort receiving

stereotactic radiation demonstrate that 34%

developed facial nerve weakness, although one

half of these were transient. Thirty-two percent

developed new trigeminal neuropathy. Useful

hearing could be preserved in 38% at 1 year [3] .

Foote and colleagues [4] reported similar side-

eﬀect proﬁles from the University of Florida in

Gainesville, Florida when higher doses were used,

with fewer side eﬀects when doses lower than

13 Gray were prescribed to the tumor margin.

Reduced toxicity to the trigeminal and facial

nerves was accomplished by decreasing the mar-

ginal SRS dose given to the tumor. Rates of

morbidity decreased from 29% to 5% for facial

neuropathy, and similarly, to 2% or less for

trigeminal neuropathy. Tumor control rates did

not appear to be compromised until the marginal

dose was decreased to 10 Gray or less [4] . Doses

to the tumor margin of 12 to 13 Gray were

Treatment goals

The goal of treatment is to eradicate the eﬀects

of a tumor with the fewest side eﬀects. In surgical

series, the means of achieving this goal is the

removal of the oﬀending tumor. In most reports

of radiation ecacy, the objective is to achieve

tumor reduction; however, in slow-growing tu-

mors such as acoustic schwannomas, the achiev-

able goal in studies with shorter duration of

follow-up is the prevention of both tumor growth

and symptom progression. Tumor shrinkage as-

sessed by radiographic size may take years before

a complete response can be evaluated. Addition-

ally, relapses might be late occurrences.

STEREOTACTIC RADIATION TECHNIQUES FOR SCHWANNOMAS

369

associated with 5-year tumor control rates of 92%

to 98% [4–6] . Maximum doses were 20 to 26

Gray. Useful hearing was noted in 56% to 78%

after treatment.

Optimal dose prescription balances tumor kill

and normal tissue survival. Radiation oncologists

have long recognized the limited tolerance of

cranial nerves to radiation. The best-delineated

toxicity data for stereotactic radiation relate to the

optic nerves and chiasm. Limits of 8 Gray in one

fraction and 50 Gray using standard fractionation

(1.8 to 2 Gray per day), serve as dose restraints for

this nerve. Radiation toxicity must also take into

consideration the length of nerve radiated as well as

the dose absorbed. The idea of volume at risk may

be a function of vascular damage or of repopula-

tion limits. The dose given to the tumor margin and

more plausibly, the maximal dose within the

volume treated reﬂect the degree of tissue damage.

A group from Seoul, Korea related hearing

loss in relationship to the cochlear dose received

during radiosurgery [7] . The mean dose to the co-

chlea in those maintaining useful hearing was 6.9

Gray. When the mean dose was greater than 11

Gray, hearing declined. Massager and colleagues

[8] also found cochlear dose to be lower in patients

retaining useful hearing. They found a signiﬁcant

relationship regarding intracanalicular tumor vol-

ume (!100 mm 3 versus 100 mm 3 ) as well as intra-

canalicular integrated dose as determinants of

hearing loss. Their paper postulates that ‘‘hearing

worsening after the gamma knife radiosurgery

(GKR) procedure can be attributed to cochlear

injury inside the internal acoustic canal caused

by the enlargement of the intracanalicular part

of the vestibular schwannomas during the inﬂam-

matory edema phase after radiosurgery through

an increase of the intracanalicular pressure.’’

2.0 Gray per day given daily for 25 to 30

treatments. A total dose to tumors as measured

at their periphery is 45 to 60 Gray. Central portions

of the tumor volume receive 5% to 10%more than

the periphery. This regimen has been used for

decades in the treatment of malignant tumors to

maximize soft tissue repair from radiation damage.

Several institutions have reported their results

for fractionated radiotherapy using radiosurgical

techniques in the treatment of acoustic schwan-

nomas, with excellent tumor control rates and

with minimal toxicity. Relocatable, molded face

masks have been used for skull immobilization.

These treatments have been delivered using linac-

based therapy, with tumor doses prescribed to

a peripheral dose encompassing the tumor, plus

a small margin (2 mm) to account for the small

amount of movement that occurs between daily

fractions and any movement within the face mask

during treatment.

Chan and colleagues [9] , from Massachusetts

General Hospital-Harvard in Boston, Massachu-

setts, report a 5-year tumor control rate of 98%

using a regimen of 54 Gray given in 1.8 Gray frac-

tions as prescribed to the 95% isodose line. They

note a distinct relationship between tumor sizes

and tumor control. Surgical resection was re-

quired for three patients with larger tumors and

increasing symptoms at a median of 37 months.

At 5-year follow-up, freedom from any surgical

intervention was 97% for tumors smaller than

8cm 3 , and 47% for tumors greater than 8 mm 3 .

Selch and colleagues [10] from the University

of California, Los Angeles (UCLA), using a simi-

lar radiation regimend54 Gray in 30 treatments

as prescribed to the 90% isodose linedreported

a local control rate of 100% at 36-month median

follow-up in 50 patients. Useful hearing was pre-

served in 93%, with a median follow-up of

36 months. Facial numbness occurred in 1 patient

(2.2%) and 1 patient experienced the new onset of

facial palsy. Twelve of their patients experienced

tumor growth. In 6 of the 12, the growth was tran-

sient, and was felt to represent a treatment eﬀect.

The transient type of enlargement shows subse-

quent shrinkage within 2 years, and is frequently

associated with loss of central enhancement on

MRI. The phenomenon of transient enlargement

has also been a common ﬁnding in other institu-

tions for both SRS and fractionated stereotactic

radiation therapy (FSRT) [11,12] .

A Heidelberg, Germany group treated 106

patients who had acoustic neuromas using stan-

dard fractionation, given to a total dose of

Fractionated stereotactic radiation therapy

Whereas some centers were investigating low-

ering the marginal peripheral dose with single dose

treatment regimens, others investigated using frac-

tionated radiation therapy. The theory behind

fractionated or multiple treatment radiation ther-

apy is that multiple smaller doses of radiation can

achieve a similar tumor eﬀect (cell death) while

allowing normal tissue time to repair between each

dose, and thereby limit toxicity. This approach

involves a greater total dose of radiation than

a single-dose treatment to overcome whatever

repairs the tumor has been able to achieve.

Standard fractionation involves doses of 1.8 to

370

ABRAM et al

57.6 Gray. Local control at 5 years was 93%.

Trigeminal and facial toxicity were 3.4% and

2.3%, respectively. Useful hearing was preserved

in 94% [13] . In a more recent publication by that

same group, Combs and colleagues [14] report

that hearing preservation in patients who had use-

ful or serviceable hearing before radiation therapy

was 55% at 9 years after SRS, compared with 94%

showing serviceable hearing 5 years after FSRT.

Attempts to decrease toxicity by decreasing

total tumor dose for ractionated stereotactic

radiotherapy have also been described. Thomas

Jeﬀerson University in Philadelphia, Pennsylvania

presented a retrospective analysis showing no

tumor control diﬀerence in two cohorts of pa-

tients treated with either 50.4 Gray or 46.8 Gray.

Although tumor control rates were equivalent

(98% versus 100%) with a median follow-up of

3 years, hearing preservation was better in the

lower dose group. Hearing preservation was

measured by pure tone averages and speech

discrimination. Corrected for follow-up and initial

hearing, the rate of preservation was 93% for the

low-dose group versus 67% for the higher-dose

cohort. The median follow-up time for the low-

dose group was 29 months [15] . A group at

Hokkaido, Japan used 40 to 50 Gray in 20 to 25

fractions. Their actuarial tumor control rate at

5 years was 91%, with no new permanent facial

weakness. The rate of useful hearing preservation

(Gardner-Robertson Class I or II) was 71%.

Complications were milddtransient facial nerve

palsy was 4%, trigeminal neuropathy was 14%,

and balance disturbance occurred in 17% of pa-

tients [16] .

In another low-dose FSRT study, Shirato and

colleagues [17] matched a group of patients who

had vestibular schwannoma who underwent ob-

servation only against a cohort of patients treated

with fractionated radiotherapy delivering 36 to

44 Gray in 20 to 22 treatments. The conclusion

of the study was that there were no diﬀerences

in the actuarial Gardner/Robertson hearing class

preservation curves after the initial presentation.

The rate of hearing deterioration in the treated

arm was comparable to that of untreated patients.

The mean growth of the tumor in the observation

arm was 3.87 mm per year, whereas there was

tumor reduction in the radiated cohort.

daily radiation treatments, a third alternatived

hypofractionationdhas also been studied. Using

biological modeling to provide theoretically

equivalent results as standard fractionation, hy-

pofractionation gives higher doses per treatment

for fewer treatments than standard fractionation

schemes, but less dosage per day than single-dose

prescriptions. Hypofractionation regimens use

doses in the range of 3 to 7 Gray per day for 3

to 10 days, for total doses in the range of 21 to

30 Gray.

Meijer and colleagues [18] from Vrije Univer-

siteit University Medical Center in Amsterdam

used a hypofractionation schedule of 4 to

5 Gray for 5 days as measured at the 80% iso-

dose line. The 20 to 25 Gray was delivered in

1 week. Five-year local control in 80 patients

was 94%. Facial nerve function was preserved

in 97%. The study authors compared these pa-

tients to a group of 49 patients treated at the

same institution with a single fraction of 10 to

12.5 Gray, and found no signiﬁcant diﬀerences

in outcome in regard to tumor control or facial

nerve damage. Five-year hearing preservation fa-

vored the fractionated group (75% versus 61%).

At Johns Hopkins in Baltimore, Maryland, a sim-

ilar rate (70%) of hearing preservation was also

achieved using 5 Gray for 5 days for smaller

tumors or 3 Gray for 10 treatments for larger

tumors [19] .

Large tumors

Tumor size can aﬀect control. Foster and

colleagues [20] showed that tumors larger than

3 cm had a control rate of 33%, whereas tumors

of 2 to 3 cm had a control rate of 86%, and

tumors of 2 cm or less could be controlled in

89% of their SRS series. Chan [9] also showed

a relationship between increasing tumor volume

and the need for surgical intervention (shunt or

resection) following FSRT.

Park and colleagues [21] reviewed 50 cases of

acoustic neuromas measuring over 3 cm on

MRI. Microsurgery was performed on all

patients. Among eight patients who underwent

subtotal resection followed by radiosurgery, all

had tumor control with a median follow-up of

113 months (9.4 years). Gross total resection

alone resulted in failure in one patient, and subto-

tal resection without radiation resulted in a 32%

recurrence rate. The facial nerve preservation

rate was inversely proportional to the extent of

tumor removal.

Hypofractionation

In an attempt to maximize hearing preserva-

tion rates without the need for several weeks of

STEREOTACTIC RADIATION TECHNIQUES FOR SCHWANNOMAS

371

Neuroﬁbromatosis-2

tumor growth is controlled. At the doses currently

used, the majority of patients do not develop new

symptoms. A minority of patients experience an

improvement in symptoms, and a minority expe-

rience worsening symptoms.

Approximately 5% of patients who have

acoustic neuromas have neuroﬁbromatosis type 2

(NF-2). These patients present a special manage-

ment problem, because their tumors are often

bilateral, placing them at risk for total hearing

loss. Both microsurgical techniques and stereotac-

tic radiosurgery have been associated with poorer

rates of hearing preservation in NF-2 patients.

Tumor control rates following single-dose stereo-

tactic radiosurgery are reported as 50% to 98%,

with preservation of functional hearing being

achieved in 40% to 50% [22–25] . This decrease in

functional hearing following therapy is also noted

in some fractionated stereotactic radiotherapy se-

ries. Combs and colleagues [14] saw hearing preser-

vation rates fall from 98% in sporadic vestibular

schwannoma cases treated with 57.6 Gray given

in 1.8 Gray fractions to 64% in NF-2 patients

treatedwith the same regimen. Chan and colleagues

[9] saw no diﬀerences in results between their NF-2

and sporadic cases in regard to tumor control or

hearing preservation rates, using a fractionated

schedule. The Stanford, California CyberKnife

(Accuray, Sunnyvale, California) group obtained

hearing preservation rates of 67% at 2 years, using

a hypofractionated technique of 21 Gray delivered

in three fractions of 7 Gray, with 90% tumor

control at a mean follow-up of 26 months. Nine

percent developed trigeminal nerve injury [24] .

Hydrocephalus

Hydrocephalus in the absence of progressive

tumor growth has been described as occurring in

3% to 11% of patients in both SRS and FSRT

series [26,27] . The hydrocephalus occurs at a me-

dian of 1 year. Hydrocephalus is believed to be

the result of tumor necrosis, with proteinaceous

debris blocking cerebrospinal ﬂuid (CSF) ﬂow.

The development of hydrocephalus is more com-

mon following treatment of larger (O25 mm)

tumors. The hydrocephalus sometimes resolves

spontaneously [10] . Shunting may be required if

hydrocephalus becomes symptomatic.

Tinnitus

Pittsburgh radiosurgery experience describes

symptoms of tinnitus resolving in approximately

one half of patients, whereas the UCLA FSRT

experience with stereotactic fractionated radio-

therapy provided improvement in 6 of 50 patients,

whereas two patients experienced worsening [9] .

Karpinos and colleagues [27] , in comparing mi-

crosurgery and radiosurgery, found more tinnitus

at long-term follow-up in patients undergoing

radiosurgery. In their radiosurgery group, 26%

reported increase in tinnitus, whereas 10% re-

ported decreased tinnitus.

Radiographic follow-up

MRI scans should be obtained at regular in-

tervals following therapy. Loss of central enhance-

ment is a common ﬁnding, usually associated with

enlargement and capsular thickening. A group at

UCLA reported the loss of central tumor enhance-

ment in two thirds of their patients at a median of

6 months following stereotactic radiotherapy [9] .

The increase in tumor size was less than 2 mm.

Radiographic enlargement occurring after 2 years,

or growth 3 mm or greater, is indicative of tumor

regrowth. Resection can be performed after radia-

tion therapy; however, some authors feel it is more

dicult than resection as initial treatment.

Conversely, radiation therapy following resection

has a higher complication rate as well.

Vertigo

Karpinos and colleagues [27] noted no signiﬁ-

cant diﬀerence in experiencing postprocedural im-

balance between microsurgery and Gamma Knife

radiosurgery: 22% worsened, whereas 14% im-

proved. Niranjan and colleagues [28] describe ep-

isodic vertigo continuing following radiosurgery

in 3 of 11 patients presenting with this symptom.

Balance disturbances worsened in 17% of patients

treated in Hokkaido using a low-dose, fraction-

ated stereotactic radiation scheme [16] .

Malignant transformation

Malignant transformation can occur, but the

risk is estimated to be very rare. Bari and colleagues

[29] , in a literature review of malignancy in

vestibular schwannomas, describe malignant de-

generation in both radiated and unirradiated

eighth-nerve tumors. In their literature review,

Clinical follow-up

Most patients undergoing treatment for acous-

tic neuromas tolerate their treatments well, and

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