s104236800800003x.pdf

Neurosurg Clin N Am 19 (2008) 345–365

LINAC Radiosurgery and Radiotherapy

Treatment of Acoustic Neuromas

Ilya Likhterov, BA a , Robert M. Allbright, MD b ,

Samuel H. Selesnick, MD c , d , e , *

a Weill Cornell Medical College, 1305 York Avenue; 5th ﬂoor, New York, NY 10021, USA

Department of Radiation Oncology, Weill Cornell Medical College,

Stich Radiation Center, 525 East 68th Street, New York, NY 10021, USA

Department of Otorhinolaryngology, Weill Cornell Medical College,

1305 York Avenue, 5th ﬂoor, New York, NY 10021, USA

Department of Neurological Surgery, Weill Cornell Medical College,

1305 York Avenue, 5th ﬂoor, New York, NY 10021, USA

e Department of Neurology and Neuroscience, Weill Cornell Medical College,

1305 York Avenue, 5th ﬂoor, New York, NY 10021, USA

Acoustic neuromas (ANs) are benign, slow-

growing tumors that arise from the Schwann cells

of the vestibulocochlear nerve. Although these

tumors are benign, their expansion in the internal

auditory canal and cerebellopontine angle com-

presses the cranial nerves and the brainstem [1] .

Once diagnosed, the tumors are commonly resected

microsurgically, managed conservatively with ra-

diologic surveillance, or treated with radiation

therapy [2] . This article focuses on the eﬀectiveness

of linear accelerator (LINAC) stereotactic radio-

surgery and radiotherapy in AN treatment.

ionizing X-rays and gamma rays lies in their

ability to compromise the integrity of DNA and

other important biologic molecules of the target

cell. Speciﬁcally, excitation of electrons in mole-

cules exposed to radiation produces reactive, free

radicals, which in turn degrade structures that are

important for cell survival. Double strand breaks

in the DNA are most detrimental to the cell.

Eﬀective mechanisms for ﬁxing the double strand

breaks, which include nonhomologous end joining

and a more precise homologous recombination,

are often inadequate to deal with the overwhelm-

ing damage to the genetic material, especially in

highly mutated tumor cells. These lesions prevent

the cell from completing the replication cycle and

arrest the growth of the tumor. Excessive radia-

tion damage to DNA and the arrest of mitosis

lead to induction of the apoptoticdor pro-

grammeddcell death pathway. Radiation damage

to phospholipids in the membrane of the cell also

acts to trigger cascades that lead to cell death [3,4] .

There are two types of ionizing radiation:

electromagnetic, which consists of photons or

packets of energy, and particulate radiation. The

common feature of these forms of radiation is

ionization, a process that ejects an excited electron

from the target atom. This process occurs when

a photon or particle transfers its energy to

the target tissue. X-rays and gamma rays are

Radiation biology

Radiation-induced damage to the cell machin-

ery has been used to control the proliferation of

tumors. Interruption of cell division is a desired

eﬀect in cells that have lost the ability to respond

to appropriate internal and external surveillance

because of mutation. The therapeutic role of

A version of this article originally appeared in

Otolaryngologic Clinics of NA, volume 40, issue 3.

* Corresponding author. Department of Otorhino-

laryngology, Weill Cornell Medical College, 1305 York

Avenue; 5th ﬂoor, New York, NY 10021.

E-mail address: shselesn@med.cornell.edu

(S.H. Selesnick).

doi:10.1016/j.nec.2008.02.001

neurosurgery.theclinics.com

346

LIKHTEROV et al

indirectly ionizing, whereas charged particles are

directly ionizing. X-rays and gamma rays are

types of electromagnetic radiation and diﬀer in

that an X-ray is a result of a collision between an

electron and a target, whereas gamma rays are

produced when the contents of the nucleus of an

atom return to their initial energy state from an

excited level, a process known as gamma decay.

As these electromagnetic waves pass through

tissue, they are absorbed and produce fast recoil

electrons. As this occurs, they lose intensity.

Protons are heavy charged particles that cause

damage directly. They have an opposite charge

from electrons and have considerably more mass.

When a proton beam strikes a target, it deposits

almost all of its energy at the end of its range. This

characteristic, known as the Bragg peak, can be

exploited to deliver high doses to tumors with

almost no fall-oﬀ of radiation. Helium ions act

similarly. Neutrons have no charge and are equiv-

alent to a proton in mass. They are not aﬀected by

an electric ﬁeld. They are also indirectly ionizing,

and after interacting with matter they produce

recoil protons and alpha particles. Although all

other radiation modalities work best on parts of

tumors in which oxygen is available, neutron

radiation provides an opportunity to target the

center of large tumors that are oxygen deﬁcient and

types of tumors known to be poorly aerated [5] .

Radiosurgery (RS) is a term used for the

delivery of ionizing radiation to an intracranial

target with the use of stereotactic technique. The

exposure of normal, healthy tissues to radiation

should be limited, yet signiﬁcant doses must be

delivered to the tumor to have a therapeutic eﬀect.

Stereotactic technique facilitates the accomplish-

ment of these goals through accurate localization

and targeting of the lesion. The target volume is

represented in a three-dimensional space with the

use of markers on a ﬁxed frame, the location of

which is electronically linked with either CT or

MRI scans. Fig. 1 shows the planning of a treat-

ment based on the MRI of a patient with AN. Spe-

cial care must be taken to isolate and protect the

brainstem, which is in close proximity to the target

volume. The three-dimensional target created is ir-

radiated from several angles; beams all meet and

deliver a high cumulative dose of radiation to a sin-

gle isocenter. For irregularly shaped targets, more

than one isocenter can be used. Three modalities

are used to deliver radiation in stereotactic RS [6] .

As of 2003, approximately 200,000 patients

were treated with gamma knife technology.

Gamma knife contains 201 cobalt 60 sources

Fig. 1. This computerized treatment plan reveals MRI deﬁning the target (encircled in red) and the area of concern to be

isolated, the brainstem encircled by an oblong shape. The mock treatment plan shows the eyes and the brainstem, which are

isolated from the target. The radiation beams are shown converging on the target, in this case an intracanalicular AN.

RADIOSURGERY AND RADIOTHERAPY TREATMENT OF ACOUSTIC NEUROMAS

347

that are collimated using a helmet ﬁtted for

patients. Once the treatment is planned using the

three-dimensional representation of the target,

a patient’s head is ﬁxed and the beams from the

sources align on multiple isocenters [6] .

LINAC is a tool that has long been used to

generate X-rays. LINAC uses electromagnetic

waves of microwave frequency to accelerate elec-

trons. This ﬁrst became possible with technology

borrowed from high-energy microwave generators

used in military radars during World War II.

LINAC was ﬁrst used for radiotherapy in 1953

[7] . More recently, in the early 1980s, it was

adapted for use in stereotactic RS. Many LINAC

units have been modiﬁed for RS, whereas others

are designed speciﬁcally for this use. It is esti-

mated that more than 30,000 people have

undergone LINAC-based RS. LINAC delivers

a photon beam of high-energy X-rays through

a series of arcs or ﬁxed static ﬁelds. Conformality

is maximized with the use of micro-multileaf colli-

mators. Conformality can be enhanced further

with the use of intensity modulated RS, which

varies the intensity of dose within a ﬁeld to treat

tumor and spare normal tissue.

Another modality that has been used in RS

over the past 40 years is particle beam irradiation.

Two to six beams of charged particles are focused

on the target. One example is the use of protons in

radiation of intracranial tumors. As in the other

two modalities used for RS, the radiation dose

that reaches structures outside the target volume

is minimized by the eﬀect of the Bragg peak [6] .

Stereotactic radiotherapy, or fractionated ste-

reotactic radiotherapy (FSRT), is an alternative to

RS. It diﬀers in that the full radiation dose is not

administered at one time but is instead divided

into several doses. The accuracy of irradiation is

reproduced with the use of a head frame, such as

the GTC (Gill Thomas Cosman) ( Fig. 2 ), which

ensures that the treatment is consistently targeted

each time. A bite plate may be used to individual-

ize the frame for each patient and achieve repro-

ducibility with multiple treatments (see Fig. 2 ;

Fig. 3 ). Using smaller doses over many fractions

reduces late side eﬀects, such as hearing loss,

when compared with single fraction RS [8] .

Fig. 2. A removable and reusable stereotactic device us-

ing an oral bite plate to ensure placement reproducibility.

ANs is radiologic surveillance of the tumors with

repeat MRI scans. Since the introduction of

gadolinium-enhanced MRI, tumors of smaller

size can be detected and followed over time. A

signiﬁcant amount of data on the natural history

of AN tumors has been collected from patients

who choose this conservative option.

A review of studies on the surveillance of ANs

was published by Selesnick and Johnson [9] in

1998. The authors presented a meta-analysis of

13 studies on the topic published between 1985

and 1997. In all, 571 patients across the studies

Natural history of acoustic neuromas

When evaluating the eﬀect of radiation therapy

on the growth of ANs, the natural history of these

tumors must be considered. One of the options

used in the management of patients who have

Fig. 3. This patient has been placed in the removable

reusable stereotactic device using an oral bite plate to

ensure placement reproducibility. The patient is posi-

tioned for treatment.

348

LIKHTEROV et al

evaluated were followed for an average of

36 months. The mean diameter of tumors at the

beginning of the surveillance was 11.8 mm, and

54% of the tumors (range 14%–74%) grew at

an average rate of 1.8 mm per year. Slightly less

than half of the patients included in the meta-

analysis had no AN growth at a mean follow-up

of 3 years. Among the patients whose tumor size

increased (n ¼ 178), the growth rate was 4 mm

per year. Initial size of the tumors and the age

of the patients were not found to be predictive

of growth of AN.

A more recent meta-analysis published by

Yoshimoto [10] in 2005 reviewed 26 studies examin-

ing the natural course of AN growth published be-

tween 1991 and 2002. In the 1340 patients included,

the mean initial tumor diameter was 11 mm,

and 46% (range 15%–85%) had an increase in

tumor size during the mean follow-up period

of 38 months (range 6–64 months). A mean

growth rate of 1.2 mm per year was calculated

from the 16 studies (n ¼ 964) that contained

this information. Eight percent of patients had

a spontaneous decrease in tumor size. The au-

thor also analyzed a subgroup of 12 studies

that used only MRI and not CT for tumor sur-

veillance. In this group, 39% of tumors in-

creased in size in the mean follow-up time of

33 months.

Since the Yoshimoto’s review, Stangerup and

colleagues [11] reported on 552 patients from a sin-

gle institution who had ANs not associated with

neuroﬁbromatosis type 2 (NF2) and who under-

went radiologic surveillance of tumors with re-

peated MRI scans. The data were collected for

the patient population managed from 1975 to

June 2005, and the mean follow-up was 43 months

(range 12–180 months). Tumors were character-

ized as either intrameatal or extrameatal and

were analyzed separately. Of the 230 intrameatal

tumors, 17% grew to extend extrameatally.

Growth occurred 64% of the time during the ﬁrst

year (growth rate, 10.32 mm/y), 23% during the

second year (growth rate, 3.83 mm/y), 5% during

the third year (growth rate, 2.17 mm/y), and 8%

during the fourth year of observation (growth

rate, 0.92 mm/y). Extrameatal tumors observed

in 322 patients were deﬁned as growing when

the largest diameter increased by 2 mm and were

deﬁned as shrinking when the diameter decreased

by 2 mm. In total, 70.2% of tumors remained

stable, 28.9% grew, and 0.9% shrank. Sixty-two

percent of growth occurred during the ﬁrst year

(growth rate, 4.90 mm/y), 26% occurred during

the second year (growth rate, 2.79 mm/y), 10%

occurred during the third year (growth rate,

1.15 mm/y), and 2% occurred during fourth

year of follow-up (growth rate, 0.75 mm/y). The

diﬀerence between growth of intrameatal and ex-

trameatal ANs of 17% and 28.9%, respectively,

was reported to be statistically signiﬁcant. Intra-

meatal or extrameatal tumor growth was not

observed after the fourth year of follow-up.

It is dicult to compare AN growth rates with

and without radiosurgical intervention because of

diﬀerences in follow-up time and methods used to

report tumor size and control. Battaglia and

colleagues [12] addressed the issue by comparing

111 patients followed radiologically for an aver-

age of 38 months at a single institution with

data reported in the literature on radiosurgical

treatment of AN. Only patients treated with the

maximum marginal dose of 12 to 13 Gy adminis-

tered in a single treatment with any radiosurgical

modality were included in the analysis. Mainly,

data from studies in which gamma knife surgery

was used were represented. Only studies that re-

ported a mean or median follow-up of 24 months

were used for comparison. The natural tumor

growth rate reported by the authors was 0.7 mm/y,

with 18% of tumors growing faster than

1 mm/y and 13% growing faster than 2 mm/y.

On average, change in size was noted at 2.2 years

after surveillance was initiated. No growth dur-

ing the follow-up period was noted in 50.5%

of the patients. Tumor control in RS studies se-

lected by the authors was deﬁned as no growth

more than 2 mm/y or more than 1 mm in two

dimensions. Using this same deﬁnition, 87% of

ANs were controlled by conservative manage-

ment, a result not signiﬁcantly diﬀerent from

when the tumors were treated with radiation.

There is some indication that AN tumors do

not grow in a linear fashion. In 2000, Tschudi and

colleagues [13] reported growth followed by stabi-

lization in some of the patients whose tumors were

observed over time. Charabi and colleagues [1] de-

scribed a group of cases in which the tumor size

was stable for an average of 19 months and then

experienced a period of growth. This irregularity

in the natural progression of the tumors suggests

that a period of stability does not necessarily

predict long-term control, whereas a period of

growth does not predict continuous enlargement.

The fact that the natural history of AN growth

undergoes periods of quiescence is important

when trying to judge the impact of radiation

therapy on these tumors.

RADIOSURGERY AND RADIOTHERAPY TREATMENT OF ACOUSTIC NEUROMAS

349

Tumor size measurement

This ﬁnding is important when judging the

eﬀect of radiation on acoustic tumors, because

small changes in size may not be appreciated or

may be overread.

The current, preferred method for measuring

the size of AN tumors involves the use of MRI.

Accuracy and precision are important in determin-

ing the initial size of the tumor at presentation and

evaluating tumor changes. The consistency of these

measurements and the precision with which tumor

progression can be followed have limitations.

In 2003, Slattery and colleagues [14] addressed

the issue of reliability of MRI-based measure-

ment. Factors that contribute to the quality of

the scan include the MRI machine used, how the

image is acquired, the training of the technician

and the radiologist, whether contrast is adminis-

tered, what dimension is used to measure the

size of the tumor, and how much the patient

moves during the scan.

A large source of variability could originate in

the method of measurement. The radiologist can

measure a distance by eye or use computer

software. (The latter approach is considered

more precise.) Studies evaluated in our review

varied with respect to what constitutes the size of

the tumor. Greatest diameter of the AN was

commonly used. The American Academy of

Otolaryngology–Head and Neck Surgery recom-

mends that two measurements be taken: one

parallel and one perpendicular to the petrous

ridge. Computer algorithms allow tumor volume

to be calculated to evaluate size. Each of these

methods varies in its accuracy and precision.

To answer a question of how much consistency

there is among data obtained fromMRI scans and

what is the minimum amount of change that can

be detected in tumor size, Slattery and colleagues

[14] performed six scans on three diﬀerent MRI

machines (two consecutive scans on each) for

seven patients with NF2. T1-weighted post-

gadolium-enhanced gradient three-dimensional

sequences were used in this study. In total, 20

meningiomas and ANs were used to evaluate

inter- and intrascanner reliability. The volume

and the greatest diameter were measured using

computer software. The authors reported that cal-

culated tumor size was consistent across the two

studies conducted on one machine and across

the three machines used. They concluded that

the minimal diﬀerence in tumor diameter that

can be detected on an MRI is 1.1 mm, whereas

the minimum reliable volume diﬀerence is

0.15 mL. The authors suggested that a more

consistent protocol be used to measure tumor

size in patients with AN.

Methods

For the purpose of this article, MEDLINE was

searched for studies using LINAC for AN treat-

ment. The terms ‘‘vestibular schwannoma,’’ ‘‘acous-

tic neurilemmoma,’’ ‘‘acoustic neurinoma,’’

‘‘acoustic neurilemoma,’’ ‘‘acoustic schwannoma,’’

and ‘‘acoustic neuroma’’ were crossed with ‘‘radio-

surger*,’’ ‘‘stereotactic radiosurger*,’’ ‘‘linear ac-

celerator,’’ ‘‘LINAC,’’ ‘‘linear accelerator-based

surger*,’’ and ‘‘X knife.’’ (The use of [*] after

a word indicates that all possible endings of the

word were incorporated in the search.) Only arti-

cles published in English since 1996 were consid-

ered for analysis. The abstracts were screened to

exclude articles pertaining to the use of gamma

knife and other stereotactic radiation modalities.

The references of selected articles were reviewed

for additional relevant sources. Articles from a sin-

gles institution reporting on redundant patient

populations were identiﬁed, and the more recent

and complete studies were chosen for analysis.

Radiosurgery

In one of the earliest publications on LINAC

RS for ANs, Chakrabarti [15] presented 11 pa-

tients in whom surgery failed to control the

tumors and who were treated with stereotactic ra-

diation. The diameter of the tumors ranged from

15 to 35 mm (mean 26 mm), and the lesions

were targeted with 12.5 to 20 Gy administered

to the 90% isodose contour. Ten patients were fol-

lowed radiologically with repeat CT or MRI scans

or both for 3 to 36 months (mean 15 months).

Seven of the patients had observable necrosis in

the center of the tumor 6 months after RS. During

the period of 7 to 20 months after treatment, tu-

mors decreased in size in 4 patients. No change

was observed in four cases, and 1 mm increase

was seen in 2 patients. Hearing was diminished

in 7 patients before treatment; it was stabilized

or improved in 5 of these patients, whereas 2 pa-

tients became completely deaf. Although no new

facial palsy was found after RS, 4 patients experi-

enced it before treatment. In 2 patients, their pre-

existing facial palsy was unchanged; it improved

in 1 patient at 14 months after RS; it deteriorated

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