REVIEW

Spinal radiosurgery: technology and clinical outcomes

M. Avanzo & P. Romanelli

Received: 5 September 2007 /Revised: 23 May 2008 /Accepted: 26 July 2008 / Published online: 24 September 2008# Springer-Verlag 2008

Abstract The development of computer-based image guid-ance has allowed stereotactic radiosurgery and radiotherapyto be freed from the constraints imposed by the stereotacticframes once required for intracranial radiosurgery. Thisfreedom has led to the application of radiosurgery to targetsoutside the brain. In this paper, we briefly review thetechnologies, treatment parameters, and clinical outcomesof radiosurgical treatment for spinal pathology, includingmetastatic tumors and rare but challenging lesions such asarteriovenous malformations and benign tumors. A specialemphasis is put on the newest development, fiducial-lessrobotic radiosurgery. Spinal radiosurgery is associated withexcellent rates of tumor control and pain relief with a gooddose sparing of the highly sensitive spinal cord. Furtherresearch is required to optimize treatment strategies and toassess clinical benefits and toxicity in the long term.

Keywords Spine . Spinal cord . Radiosurgery . Robotic .

Image guidance

Introduction

Radiosurgery is the delivery, in a single or a few fractions, of aconcentrated dose of radiation to diseased tissue with a steepdose fall off outside the treatment volume. The technique wasfirst developed in the late 1940s, when the Swedishneurosurgeon Lars Leksell used X-rays to ablate dysfunction-al loci of the brain [41]. High spatial accuracy of dosedelivery to intracranial targets was achieved with the use of arigid frame designed by Leksell. The frame, attached topatients’ skulls, served both to immobilize the head andprovide external reference points for target localization.Radiosurgery has proven effective for controlling brainlesions with widely variable histologies, including arteriove-nous malformations [5, 11, 43, 49, 53, 69, 79], meningiomas[10, 38, 39, 56, 57, 72], acoustic neuromas [12, 14, 19, 28,55] and other benign lesions [9, 35, 65], gliomas [13, 30, 31,37, 46], and metastases [4, 22, 40, 48]. For selected cases ofsome of these lesions (arteriovenous malformations, acousticneuromas, cavernous sinus meningiomas, and brain metas-tases), radiosurgery is now the treatment of choice. Further-more, functional indications such as trigeminal neuralgia [26,36, 58, 66, 67] are becoming increasingly important.

Spine and brain are affected by a comparable histopath-ological range of lesions, which suggests that radiosurgerymay also be effective for the treatment of spinal lesions.Several factors, primary among them being concern aboutthe precision with which highly focused, high-dose irradi-ation can be wielded in proximity to the delicate spinalcord, have delayed the application of radiosurgery to thespine. Historically, lesions of the spine have been treatedwith surgery, external photon beam radiotherapy, or both.Conventional photon irradiation of spinal neoplasms withthe use of a single posterior field or opposed fields oftencannot deliver a therapeutic dose to the tumor without

Neurosurg Rev (2009) 32:1–13DOI 10.1007/s10143-008-0167-z

DO00167; No of Pages

M. AvanzoDepartment of Medical Physics,Centro di Riferimento Oncologico,Via F. Gallini 2,33081 Aviano, Italye-mail: mavanzo@cro.it

P. RomanelliIRCCS Neuromed,Via Atinense 18,86077 Pozilli, Italy

P. Romanelli (*)Functional Neurosurgery, IRCCS Neuromed,Via Atinense 18,86077 Pozzilli, Italye-mail: radiosurgery2000@yahoo.com

exceeding the spinal cord’s radiation tolerance. Concernsabout spinal cord dose limitations lead to suboptimaltreatment not only of truly spinal lesions but also of manyparaspinal tumors, which leads to high recurrence rates.Initial attempts at spinal radiosurgery involved a stereotac-tic frame that was fixated to the spine with bone screwsunder general anesthesia [27, 71]. This frame was invasiveand uncomfortable for the patient and could introduceimage artefacts in CT. The development of a more flexibleand less painful approach, called image-guided or framelessradiosurgery, has allowed the principles of radiosurgery tobe applied to the treatment of spinal lesions. Imageguidance uses intraoperative imaging to locate the tumorduring a treatment session and redirect the radiation sourceor reposition the patient based on these measurements.

The accuracy of dose delivery using image-guided radio-surgery is comparable to that of radiosurgery performedwith astereotactic frame [8, 51, 52]. Furthermore, the removal ofthe invasive frame allows radiosurgical treatment to bedelivered in more than one fraction, which has the potentialto reduce toxicity to healthy tissue and organs at risk.Technologies for delivering radiation have evolved rapidly inthe last decade, and with these new tools a conformal dosedistribution can be effectively delivered to targets of irregularshape, thus allowing better control of the lesion and sparingof healthy tissue. Here we will describe image-guidedstereotactic radiosurgery devices that can be used to treatthe spine, briefly review clinical data showing the efficacy ofthese systems, and discuss concerns about and consequencesof radiation toxicity induced by spinal radiosurgery.

Technologies for spinal radiosurgery

Three image-guided LINAC devices are currently used todeliver spinal radiosurgery: the Novalis (Brainlab, Ammer-thalstrabe, Germany), an intensity-modulated gantry-basedsystem, Tomotherapy HI-ART (TomoTherapy, Inc., Madison,WI, USA), and the CyberKnife (Accuray, Inc., Sunnyvale,CA, USA), an innovative device providing robotic beamdelivery. The CyberKnife is the most-used device worldwide,with several hundreds cases reported in peer-reviewed papers.

There is not yet a general agreement among neuro-surgeons and radiation oncologists on the definition ofradiosurgery. While a single, large-dose treatment is usuallyreferred as radiosurgery, a treatment delivered in more thanone fraction is called either radiosurgery [i.e., 17, 24, 68] orstereotactic radiotherapy [i.e., 7, 63]. In this paper, weadopt a definition of the term “radiosurgery” as thestereotactic application in one to five fractions of high-doseradiation to a target with ablative intent, where “high dose”means more than 2–3 Gy, fractional doses commonly usedin conventional radiotherapy.

Intensity-modulated radiosurgery

In intensity modulation radiosurgery (IMRS), the photonbeams, typically five to nine, are divided into segments, anddifferent doses are delivered with every segment [18]. In thisway, dose distributions that conform very well to complicat-ed targets while sparing the neighboring healthy tissues canbe produced. In addition, the treatment plan is generated withan inverse planning process [25, 42] in which the weight ofeach segment is optimized to fulfill the constraints requestedby the planner. Various image guidance solutions have beenexploited to achieve the necessary spatial accuracy requiredto perform frameless IMRS, including online X-ray or inroom CT imaging [7].

The Novalis system [77] is a 6 MV linear accelerator(LINAC) dedicated for image-guided IMRS (see Fig. 1), inwhich intensity modulation is achieved with a micro multi-leaf collimator (mMLC). Radiation can also be deliveredthrough circular cone arcs or fixed-shape conformal beamsusing the mMLC. The image-guidance system is calledExactrac (Brainlab, AG, Heimstetten, Germany), a combi-nation of two infrared cameras and kilovoltage X-ray tubeswith amorphous silicon detectors mounted on the LINACcouch (Fig. 1). Pre-treatment CT scanning is acquired withinfrared-sensitive markers placed on the patient’s skin. Atthe beginning of the treatment, the infrared cameras detectthe markers with a precision of 0.3 mm [74] and theirlocation is compared with that on the planning CT. Thecouch is then moved automatically to adjust the patient’sposition. Then a pair of radiographs is taken and fused withdigitally reconstructed radiographs (DRRs) generated fromthe pre-treatment CT scan to determine the deviation of thepatient’s position from the pre-treatment CT [16]. Finally,two radiographs are acquired with portal films to verifypatient position before irradiation.

During treatment, the infrared system is used to monitorexternal patient motion, and isocenter deviations aremeasured and corrected. A non-invasive immobilizationsystem (vacuum cushion and plastic film wrapped tightly tothe patient’s body) stabilizes the patient in a comfortableposition. The precision of this system for spinal radio-surgery, defined as the degree of variation between theisocenters of the CT simulation and the portal filmradiography, is within 1.36±0.11 mm [61, 77]. Averagedeviation between estimated dose and measured dose with amicroion chamber was 2%.

Robotic radiosurgery

In most techniques, coplanar radiation beams are directed atisocentric targets. Non-coplanar and non-isocentric treat-ments using conventional LINACs can be achieved by

2 Neurosurg Rev (2009) 32:1–13

rotation (non-coplanarity) or translation (non-isocentricity)of the couch, as attempted successfully for stereotacticradiosurgery of the brain [1], but this can lead to aconsiderably longer treatment time. The CyberKnife [1] isa robotic radiosurgery system that achieves these goalsdifferently. A highly mobile, image-guided robotic armmoves a small LINAC in the three-dimensional space.Beams can be pointed in virtually every direction, leadingto non-isocentric, non-coplanar beams coursing through thetarget region. The beams are emitted through circularcollimators with diameters ranging from 5 to 60 mm. Thislarge number of beams, beam directions, and beamdiameters allow the treating surgeon targeting and dosingpossibilities that far exceed those offered by conventionalsystems (see Fig. 2).

The combination of image guidance and robotics allowsthe system to measure and track target motion in anydirection, an advantage over other available approaches [34,45]. The precision in dose delivery necessary for radio-surgery is therefore obtained without rigid patient restraints.Image guidance is based on a pair of intra-treatmentorthogonal radiographs acquired from two X-ray sourcesand amorphous silicon detectors positioned on either side ofthe target anatomy. The images are automatically registeredto DRRs constructed from pre-treatment CT scans. Thisregistration process allows the position of the treatment site

to be translated to the coordinate frame of the LINAC. Thisprocess is done to position the patient before startingtreatment, and then typically every two to three beams tocheck the patient’s position in real time during thetreatment. If the patient moves, the change is detectedduring the next imaging cycle and the beam is adjusted andrealigned with the target [60].

Until recently, image guidance for spine treatments withthe CyberKnife was based on fiducials [59], typically threeto five stainless steel screws surgically placed in the laminaof the vertebra. Spatial accuracy of spinal radiosurgery withfiducial tracking has been determined to be 0.7±0.3 mm[78]. Even if minimally invasive, the placement of fiducialsis a surgical procedure that introduces surgical risks andreduces the patient’s comfort. Furthermore, fiducial track-ing assumes a rigid motion of the treatment site, which maynot always be the case for the spine. Vertebrae can moveone relative to another, thus deforming the surrounding softtissue, therefore correct assessing of position, orientation,and deformation of the treatment site for tracking requiresestimating of local displacements of spinal anatomy. Theseproblems have been overcome with the introduction ofXsightTM software (Accuray, Inc.). In Xsight, a 2D–3Dlocal image registration is performed to register each pair ofenhanced X-ray images to the corresponding enhancedDRRs. Local displacements of spinal anatomy are estimat-

Fig. 1 The Novalis system(image used with permissionfrom Brainlab AG)

Neurosurg Rev (2009) 32:1–13 3

ed and used for repositioning of the robotic manipulatorduring treatment.

The Xsight fiducial-free spinal radiosurgery process hasbeen recently described [20, 21, 32, 50]. A thin-slice CTscan is acquired with the patient in supine position. In somecases, the CT scan is not sufficient for correct contouring ofthe target and organs at risk and subsidiary image studies,such as gadolinium-enhanced magnetic resonance or arotational angiography, are acquired and registered with theCT. After delineation of the target and organs at risk on thefused images, dose constraints are set for inverse planning.These typically include minimum and maximum dose to thetarget, and maximum dose and dose volume constraints toorgans at risk. The treatment is planned by neurosurgeons,radiation oncologists, and medical physicists using Multi-plan software (Accuray, Inc.), which uses an inverseplanning algorithm to find an optimal set of beams andbeam intensities to fulfill the dose constraints. When theoptimization process is complete, the resulting dosedistribution is calculated on CT images and evaluated. InXsight treatments, a sharp dose gradient between the targetregion and the surrounding structures is achievable, animportant factor for spinal tumors given their proximity tothe spinal cord. As a consequence, the prescribed doseclosely follows the target margin and dose to the spinalcord is effectively limited (see Fig. 3).

The treatment begins with the patient placed on thetreatment couch without immobilization devices. Twoorthogonal X-ray images are acquired for the initial setup.Pre-treatment CT scan and X-ray images undergo an imageenhancement process consisting of three steps [20]. In the

first, an exponential transformation of attenuation coeffi-cients is applied to the CT scan. As a result, skeletalstructures are emphasized relative to soft tissue. ThenDRRs are generated by integration of CT attenuationcoefficients through each ray connecting the X-ray sourceand the image plane. Finally, gamma correction and top-hatfiltering applied to DRRs and radiographs produce imageswith better contrast of bony anatomy. A region of interest(ROI) surrounding the target volume is initially selected bythe user and then refined to contain the maximum bonyanatomical information by an algorithm that maximizesimage entropy within the ROI. The resulting optimal ROItypically includes one to two vertebral bodies which formthe basis of patient tracking and alignment. A 2D–2D localimage registration is performed to register each pair of X-ray images to the corresponding DRRs using the patternintensity function [54] as a similarity measure and multi-resolution block matching [21]. An ROI surrounding thetarget that includes substantial bony information is selectedon the DRRs. A mesh laid over the ROI defines the points(nodes) at which local displacements are estimated. Thepattern intensity function is calculated as a function ofdisplacements in the X and Y axes between the two blockssurrounding the nodes in the DRR and the radiograph.Local displacement is identified as the vector that corre-sponds to the maximum of the pattern intensity function. Tosave computational time, the search is done with a multi-resolution method: starting at low image resolution, andthen with increasing resolution. With every step, somecandidates of displacement vectors are discarded so thatlocal optima are eliminated. Displacement vectors are

Fig. 2 The CyberKniferadiosurgery system (imageused with permission fromAccuray, Inc.)

4 Neurosurg Rev (2009) 32:1–13

calculated for every node in the two DRR images, thusforming two displacement fields. Mismatching is possiblefor regions where skeletal structures are lacking. To solvethis problem, the displacement fields are interpolatedunder the constraint of displacement smoothness, so thatdisplacement vectors with a high difference from thesurrounding are replaced by interpolated values. Displace-ments in the three-dimensional space are calculated by backprojecting the 2D displacement fields. The tumor islocalized in the three-dimensional space during treatmentand a rotational and translational correction is applied to therobotic manipulator to obtain the planned LINAC orienta-tion toward and distance from the target points. If a largemovement of the treatment site is detected, the position ofthe patient is corrected with an automatic movement of thecouch. The process of image acquiring, tumor localizationand eventual LINAC or couch repositioning is repeated foreach LINAC position until the end of the treatment.

Accuracy of fiducial-less spinal radiosurgery has beenmeasured by Ho et al. [32]. They took radiographs andDRRs of 11 patients treated with fiducial tracking and usedfiducials as target points of known position to test theaccuracy of registration. Each patient had four implantedfiducials. Fiducials were removed from DRRs to simulatethe fiducial-less tracking, and their position in the CT wasreconstructed from X-ray radiographs by application of thenew registration method. The tracking system error isdefined as the distance between the fiducial position on theCT scan and the position calculated from registration. Theerror in identifying the fiducials’ position, averaged overall the fiducials in the patient group, was measured to be0.49 mm.

In two different studies [32, 50], the spatial accuracy ofthe global spinal radiosurgical procedure, from pre-planning CT scanning to spine tracking and dose delivery,was assessed. In both studies, an anthropomorphic head andcervical spine phantom loaded with radiochromic film wasCT scanned. An isocentric radiosurgery treatment wasplanned and delivered, producing a spherical dose distribu-tion. The position of the center of the dose distributionmeasured from film annealing was compared with that onthe treatment plan. With a slice thickness of 1.5 mm, theaccuracy measured in the two reports was of 0.52 mm±0.22 mm [50] and 0.61±0.27 mm [32].

For most robotic radiosurgery, inverse planning is theonly option; given the enormous number of possibilities forbeam directions, placing beams by hand would not bepractical. In the inverse planning process, the softwareattempts to find directions and doses for each beam toachieve the desired dose distribution. In the special case ofrobotic radiosurgery, first a number of equally spaced beamintersect points is generated on the target surface and asmall number (typically two to four) of beam directions

a

b

c

Fig. 3 Xsight fiducial-less radiosurgery for a thoracic vertebral bodymetastasis receiving 18 Gy prescribed to the 80% isodose. Isodose linesof 20% (blue), 30% (cyan), 50% (purple), 70% (white), 80% (orange),and 90% (red) of maximum dose are shown on the axial (a), coronal(b), and sagittal (c) view of the pre-treatment CT scan. The target regionis outlined in red and the spinal cord is in green. The prescription doseis 80% of the maximum and the spinal cord is spared by the 30%isodose curve. It can be appreciated the remarkable sparing of spinalcord irradiation (a spinal cord volume of about 3.8 cm3 receives a doseof 4 Gy)

Neurosurg Rev (2009) 32:1–13 5

with random orientation in space is placed through everyone of these points. Second, the optimization algorithmcomputes beam weights such that the dose constraints arefulfilled [64].

Tomotherapy

A promising technique for spinal radiosurgery is helicaltomotherapy [44], even if clinical published data are stilllimited. It is performed with a dedicated device, the HI-ART Tomotherapy System (TomoTherapy, Inc.). This is anintensity-modulated, image-guided radiation therapy sys-tem, in which a 6 MV LINAC rotates as in a computedtomography (see Fig. 4). At the same time, the couchmoves continuously so that irradiation is delivered inoblique transverse planes through the patient. The beam isshaped by 64 binary multi-leaf collimators, and intensitymodulation is achieved by opening every collimator for theappropriate length of time during irradiation. An inverseplanning algorithm provides the optimal sequence ofcollimator openings. The same LINAC producing thetherapeutic beam, coupled with megavoltage CT detectors,is the main component of the image guidance system. Afterinitial patient positioning, a megavoltage CT scan isacquired and fused with the CT used in treatment planningto verify patient position and determine couch adjusting.

Mahan and co-workers [47] did a feasibility study ofradiosurgery of spinal metastases with the HI-ART. They

simulated irradiation of a vertebral metastasis close to thespinal cord on a cylindrical phantom, evaluated sparing ofthe spinal cord with films, and obtained a dose gradient of10% per millimeter while maintaining acceptable uniformi-ty in the PTV. Patient setup error measured on the phantomwas ±1.2 mm superior–inferior and ±0.6 mm anterior–posterior. The authors concluded that dose conformality andsetup accuracy were sufficient to allow the treatment oftargets adjacent to the spinal cord with this system. CT scanis currently used only for initial patient setup, but in thefuture it is planned to develop an optical positionmonitoring system to track patient position in real timeduring treatment delivery.

Spinal radiosurgery: clinical outcomes

Spinal arteriovenous malformations

The efficacy of stereotactic radiosurgery for arteriovenousmalformations (AVMs) of the brain is well known, but onlyrecently has radiosurgery emerged as a therapeutic alternativefor spinal AVMs, specifically intramedullary AVMs [68].These are AVMs with the nidus between an artery and a veinpartially or totally located within the spinal cord parenchyma[6]. First symptoms of intramedullary AVMs happen duringchildhood, and include hemorrhage or acute medullarysyndrome. With time, they can lead to deterioration of spinalcord function and recurrent hemorrhage. Therapies include

Fig. 4 The HI-ART helicaltomotherapy system at theC.R.O. in Aviano (PN)—Italy

6 Neurosurg Rev (2009) 32:1–13

embolization or surgery, or a combination of both, butembolization requires feeding arteries of sufficient caliber,and surgery is not always possible because of the intra-medullary location of the AVM. As a result, radiosurgerycould be the only option left for these patients.

Between 1997 and 2005, 15 cases of intramedullary AVMswere treated with the CyberKnife at Stanford Hospital [70].Seven patients had received embolization before radiosur-gery. A mean dose of 20.5 Gy was delivered to the marginof the nidus in two to five fractions to decrease the risk ofradiation-related damage to spinal cord. Up to 3 years ofpost-radiosurgery follow-up was available. One patientshowed complete angiographic obliteration after radiosur-gery; four patients showed evidence of residual AVM onangiography, although AVM volumes were significantlyreduced. The other patients did not undergo a finalangiography, but showed significant AVM volume reductionon MRI. None of the patients demonstrated evidence ofhemorrhage following CyberKnife treatment or any neuro-logical deterioration attributable to SRS.

Benign tumors of the spine

Benign spinal tumors include schwannomas, meningiomas,and neurofibromas. They are slow growing tumors that cancause local and radicular pain and myelopathic symptomsof weakness and numbness from compression of nerve rootand spinal cord. Although limited by short follow-up, somestudies have shown outcomes of radiosurgery of spinalbenign lesions.

Three patients with benign spinal tumors were treated withthe Novalis system [16]. A patient with a C3–4 foraminaneurofibroma was treated with intensity-modulated radio-surgery at 12 Gy in a single fraction after prior surgicalresection. Pre-treatment paresthesias of the hand wereunchanged. A second patient had a T4 meningioma causingpain, weakness, and paresthesias of the back and was alsotreated with 12 Gy in a single fraction. All symptomsimproved. A patient was treated for an L2 schwannoma to 15Gy in a single fraction; pre-treatment thigh pain wasunchanged after radiosurgery. All tumors were unchangedin follow-up imaging.

In the most extensive clinical study of radiosurgery forbenign spinal tumors to date [4], 59 benign lesions, 47 ofwhich were located in the spine (25 cervical, four thoracic,14 lumbar, and two sacral), were treated using the Cyber-Knife. Twenty-three lesions initially were surgicallyresected, and ten lesions received prior external beamradiation with a median dose of 48 Gy (range 40–54 Gy).Most treatments were administered in a single fraction witha median prescribed dose of 16 Gy to the 80% dose line.Improvement in pre-treatment symptoms was experiencedby 78% of patients, with only one patient experiencing

symptom progression. Of the 26 patients who underwentfollow-up imaging, the local control rate was 96% after amedian follow-up of 8 months. In another institution, theCyberKnife was used to treat 16 patients with 19 benigntumors of different histologies and spinal locations. Medianprescribed dose was 21 Gy in three fractions. Tumorresponse after median follow-up of 25 months, documentedby MRI, was progression in 2/18, regression in 3/18, andno change in 13/19 cases. No acute toxicity (grade 2–5) andno myelopathy were observed after treatment.

Dodd et al. [17] reported about CyberKnife spinalradiosurgery on a group of 51 patients with 55 intraduralextramedullary benign tumors (30 schwannomas, nineneurofibromas, and 16 meningiomas). The majority ofpatients were symptomatic, with symptoms including pain,radicular or myelopathic weakness, and sensory loss.Radiosurgery was administered because microsurgicalresection was not indicated or refused or after subtotal ortotal gross tumor resection. Dose ranged from 16 to 30 Gyin one to five fractions. During follow-up interval (mean36 months, range 24–73 months), 39% of the lesionsdecreased in size. Pain relief was observed in 50% of theinitially symptomatic patients with meningioma and 70% ofthe patients with schwannoma. Symptoms did not improvein the patients with neurofibroma. Only three patientsexperienced worsening of symptoms and required surgicaltumor resection. Lesions appeared stable (61%) or smaller(39%) after a mean follow-up of 36 months. One patientdeveloped myelopathy that resulted in posterior columndysfunction, presumably as a consequence of treatment.

Metastases of the spine

The spine is a common site of metastatic disease thatgenerally compromises a patient’s quality of life. Symp-toms are caused by spinal cord or cauda equina compres-sion and include back pain and myelopathy. Left untreated,many eventually become paraplegic, an event that stronglydecreases life expectancy [73]. The goals of therapy includelocal tumor control, pain relief, prevention of neurologicaldecline, and restoration of function. Bony instability and itsneurological consequences are also concerns with thesepatients. Treating prior to the development of neurologicdeficits improves the functional outcome for these patients[29]. Many clinical studies have demonstrated the safety,feasibility, and effectiveness of spinal radiosurgery formetastases. A summary of available clinical data for thetreatment of many tumors is shown in Table 1.

In a single-institution, phase I/II trial, 63 patients (with 74tumors) were treated with IMRS integrated with nearsimultaneous CT scan for image guidance [7]. Some patients(55.6%) had been previously irradiated and some (46%) hadreceived surgery. Treatment doses were 30 Gy in five

Neurosurg Rev (2009) 32:1–13 7

Tab

le1

Selectedpu

blishedclinical

results

ofim

age-gu

ided

spinal

radiosurgery

Study,year,

reference

No.

ofpatients

(lesions)

Patho

logy

Dose/fractio

n(s)

Techn

ique

Follow-up

Outcome

Spinalcord

complications

Bhatnagar

etal.[3]

44(59)

Benign

16Gymedian,

sing

lefractio

nCyb

erkn

ife

Median

8mon

ths

78%

symptom

sim

prov

ement,

96%

localcontrol

0

Benzil

etal.[2]

31(35)

Primaryandmetastatic

6Gy–

10Gy/1–

2fractio

nsNov

alis

Not

repo

rted

Painreliefin

32/34tumors

causingpain

2transientradiculitis,

1neurolog

ical

deterioration

Chang

etal.[7]

63(74)

Metastatic

30Gyin

5fx,27

Gy

in3fx

IMRT

Median21

.384

%localcontrol

0

Degen

etal.[15]

51(72)

Primaryandmetastatic

Mean21

.16

Gy–

6.45

Gy,

mean3.46

fractio

ns

Cyb

erkn

ife

Mean1year

100%

inpatientswith

metastatic

disease

0

DeSalles

etal.[16]

14(22)

Primary,

metastatic

8–21

Gysing

lefractio

nNov

alis

Mean

6.1mon

ths

70%

pain

improv

ed0

Dod

det

al.[17]

51(55)

Benign

16–3

0in

1–5

fractio

nsCyb

erkn

ife

Median23

61%

stable,39

%sm

aller,

50%

unchanged

1severe

myelopathy

Gerszten

etal.[23]

336(500

)Metastatic

12–2

5sing

lefractio

nCyb

erkn

ife

Median21

88%

localcontrol

0

Gibbs

etal.[24]

74(102

)Metastatic

16–2

5in

1–5fx

Cyb

erkn

ife

Mean

9mon

ths

84%

symptom

improv

ement

3severe

myelopathy

Kim

etal.

[33]

8(8)

Metastatic

15–3

0Gy/1–

5fractio

nsTom

otherapy

Not

repo

rted

100%

radiog

raph

iccontrol

0

Ryu

etal.

[61]

10(10)

Metastatic

6–8Gysing

lefractio

nNov

alis

Median

6mon

ths

Painreliefin

100%

patients

0

Ryu

etal.

[62]

49(61)

Metastatic

10–1

6Gysing

lefractio

nNov

alis

Median

6mon

ths

Com

pletepain

relief

46%,partial18

.9%,

nochange

16.2%

0

Sahgal

etal.[63]

16(19)

Benign

Median21

Gy,

3fractio

nsCyb

erkn

ife

Median

25mon

ths

3(16%

)tumorsprog

ressed,

2(11%

)regressed,

13(68%

)un

changed

0

Sinclair

etal.[68]

15(15)

AVM

15–2

5Gy/2–

5sessions

Cyb

erkn

ife

Median

17.9

mon

ths

1completeangiog

raph

ical

obliteration,

6sign

ificant

redu

ction

0

Yam

ada

etal.[76]

93(103

)Metastatic

10–2

4Gysing

lefractio

nIM

RTwith

near

simultaneou

sCT

Median

15mon

ths

90%

localcontrol

0

8 Neurosurg Rev (2009) 32:1–13

fractions or 27 Gy in three fractions. After a median follow-up of 21.3 months, actuarial 1-year local control rate was84%. No cases of grade 3 or 4 neurological toxicity occurred.

X-ray imaging for initial patient positioning and infraredmarkers to check intrafraction movement was used byYamada et al. [76] for IMRS on 93 patients with 103lesions. Treatments were delivered in a single fraction of10–24 Gy to the tumor margin. Local control rate was 90%.

Ryu and co-workers [61] reported results of a clinicalfeasibility study in ten patients of radiosurgery of spinalmetastases with the Novalis system. Radiosurgery (6–8 Gysingle fraction) was administered as a boost after externalbeam radiotherapy (25 Gy in ten fractions). After medianfollow-up of 6 months, all patients had some pain relief,five leading to medication reduction. Two patients withparaplegia before treatment recovered completely or par-tially after treatment.

In another study [2], 31 patients with symptoms of painand/or neurological deficits were treated with the sametechnique for 35 tumors, 26 of them spinal metastases.External-beam radiotherapy (25 Gy in ten fractions) wasfollowed by a single-fraction radiosurgical boost of 6 to 8 Gyto the 90% isodose. Patients who had previously received30 Gy with external radiotherapy were treated with 10 Gy intwo fractions. Thirty-two patients experienced pain reliefwithin 72 h and 22 showed durable neurological improvement.The incidence of complications related to radiosurgery wasfairly low, with two patients developing transient radiculitis,and one showing severe neurological deterioration.

The Novalis system has been used for radiosurgery onpatients that had not been irradiated [62]. In this study, 49patients with 61 spinal lesions were treated with single-fraction doses ranging from 10 to 16 Gy, with pain controlas the primary endpoint. They reported complete pain reliefin 37.7%, partial pain relief in 47.6%, and stable symptomsin 16.2% of cases at 8 weeks after treatment. Nocomplication to spinal cord related to irradiation occurred.

In many centers, robotic radiosurgery with the CyberKnifeis used to treat spinal metastases, often as the primarytreatment modality [15, 23, 24]. At the University ofPittsburgh Medical Center, the largest clinical series to datehas been treated with single-fraction radiosurgery [23]. Thestudy involved 500 lesions in 393 patients with metastases ofvarious histologies, mostly renal cell, breast, lung, andmelanoma. Goals of therapy included tumor control,palliation of symptoms, and restoring of neurologicalfunction. The average maximum dose to the tumor was19 Gy in a single fraction. Sixty-seven patients had not beenpreviously irradiated. In 48 of these cases, a significantdecrease in pain was observed during the follow-up period of6–48 months (median 16 months). Authors reported long-term radiographic control in 88% of all cases, and 100% forbreast and lung and renal cell carcinoma when radiosurgery

was the primary treatment. An overall long-term improve-ment in pain was obtained in 290 of the 336 cases thatpresented with pain as a primary indication (86%).

Similar local control results were obtained in a series of58 patients treated at the Georgetown University Hospitalfor various metastatic lesions [15]. A local control rate of100% was achieved in patients who had not beenpreviously irradiated, but there were three recurrencesamong the patients who had undergone irradiation beforeradiosurgery. Only minor and transient side effects ofradiosurgery were observed during a 3-month follow-upperiod. CyberKnife, with Xsight tracking system forpatients treated after Sept. 2004, was used by Gibbs et al.[24] on 74 patients with 102 lesions. Doses ranged between16 and 25 Gy in one to five fractions. Two thirds of thepatients had been previously irradiated. Symptoms, includ-ing pain and neurological deficits, improved in 84% ofcases. Severe myelopathy related to radiosurgery occurredin three patients after a mean of 7 months from treatment.

The HI-ART helical tomotherapy system has been usedby Kim et al. [33] for fractionated radiosurgery of spinalmetastases. A series of eight patients were treated withdoses of 15–30 Gy, in one to five fractions. Two patientswere treated in a single dose of 15 Gy. A non-invasiveimmobilization system that utilizes vacuum technology(Bodyfix. Medical Intelligence, Swabmunchen, Germany)was used. All the treated patients experienced completeradiographic control. Pain control was achieved in all thefour patients who had follow-up with regard to pain control.Three patients experienced toxicity related to treatment,including nausea and dysphagia requiring medication anddiarrhea that did not require medication.

In general, then, clinical studies have shown thatstereotactic delivery of radiation to metastatic lesions nearthe spinal cord can result in good tumor control, rapid anddurable pain relief, and in some cases recovery ofneurologic function, with little evidence of radiation-relatedside effects or radiation necrosis. While the role of spinalradiosurgery as a salvage treatment, i.e., for reirradiationafter conventional radiotherapy, is well established, thesuperiority of this treatment modality as a primarytreatment modality has still to be demonstrated. A meta-analysis of randomized trials [75] failed to demonstrate anyadvantage of single-fraction therapy over low dose-per-fraction radiation therapy, but in this study the single-fraction dose was limited to 8 Gy and the only clinicalendpoint was palliation. Image-guided RS, when used asthe primary treatment modality, has shown the potential totreat spinal metastases with higher doses. This is reasonablyexpected to increase local control and palliation ofsymptoms. A randomized phase III study will be neededto ultimately demonstrate if radiosurgery is the primarytreatment modality of choice for spinal metastases.

Neurosurg Rev (2009) 32:1–13 9

Conclusions

By eliminating the need for the invasive frame, imageguidance has made it possible to use spinal radiosurgery toits full potential. The first clinical studies show good resultsin terms of tumor control of spinal metastasis and benigntumors, and angiographic obliteration of spinal AVMs.Single-fraction spinal radiosurgery using fiducial-free tu-mor tracking software is of particular value for patients withmalignant disease and limited life expectancy because itimproves the quality of life without significant physicalstress. Furthermore, it is as safe and effective a treatmentmethod as its counterpart that uses fiducials, in control oflocal tumor growth and associated pain syndromes. Giventhe very low incidence of unwanted effects, clinical resultsalso show that in some cases higher doses can be used.Considerable research is required to determine optimal doseand fractionation, and the limits for radiosurgery around theradiosensitive spinal cord. More information from prospec-tive evaluations that take into account clinical, imaging, andquality of life data are desirable for definitive conclusionsand final treatment recommendations.

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Comments

Eugen B Hug, Villigen, SwitzerlandIn the present issue, M. Avanzo and P. Romanelli review

equipment, techniques, and published clinical outcomes on extracra-nial, spinal radiosurgery. I congratulate the authors to an excellentpresentation of currently available radiosurgery and stereotactic bodyradiotherapy (SBRT) equipment, as well as the concise update anddiscussion of the literature.

Prior to the advent of this technology and other image-guidance-based precision technologies, physicians essentially had to choosebetween treatment modalities to accomplish either symptom manage-ment (mainly pain control) or tumor control and preservation offunctional stability of the spine. The realities were as such thatradiotherapy would be able to control pain since only moderateamounts of radiation dosages are needed for short- to mid-term paincontrol. However, radiation dose levels required for actual tumorcontrol, i.e., arresting progressive destruction and preserving spinalcolumn stability in case of vertebral body involvement, routinelyexceeded spinal cord tolerance. Hence, surgical resection includingstabilization was frequently the only realistic treatment of choice fortumor control. Specifically in palliative situations, surgery with itsrelated morbidity, hospitalization, and rehabilitation impacted signif-icantly on quality of life within a patient’s residual lifespan.

Innovative, non-invasive radiosurgical techniques, as presented inthis article, finally overcame this dilemma and are holding the promisefor many patients of accomplishing both symptom reduction as well astumor control with low risks of spinal cord injury. Although acquisitioncosts and operating expenses are generally higher compared toconventional radiation equipment, most technologies have versatile,curative applications for tumors outside the spinal or paraspinalregion. In addition, avoidance of surgical procedures and hospital-ization, lack of progressive neurologic disability, and reduction ofchronic medication will result in significant savings for society.

Extrapolating from incidence numbers, patients with either solitaryor few bony metastases to vertebral bodies will likely emerge as thedominant patient cohort. For patients with diffuse metastatic spreadand/or life expectancy measured in weeks only, single dose conven-tional photon irradiation will likely remain a suitable and locallyreadily available radiation modality (1).

As to the application in primary intraspinal or paraspinal neo-plasms, the authors acknowledge the presently limited clinical data.However, one can reasonably expect within the coming yearspublications from major institutions with larger patient numbers andmore mature follow-up.

For radioresistant mesenchymal tumors, i.e., sarcomas of the axialskeleton, particle therapy and specifically proton therapy havedemonstrated their success in high-dose tumor control next to criticalstructures (2 and 3). Despite an approximate 30-year history of clinicalpatient treatments, the high costs of particle facilities have in the pastprohibited a more widespread use. It will be most interesting tocompare evolving photon-based radiosurgery data with outcomes afterparticle therapy.

In Fig. 3, the authors demonstrate an example of the isodosedistribution using fiducial-less radiosurgery for a thoracic vertebral bodymetastasis. With a dose prescription to the 80% isodose line and thespinal cord being covered by the ≤30% isodose curve, this exampleelucidates both the possibilities as well as limitations of photon-basedspinal radiosurgery. The ultimate goal of any high-dose radiotherapy iscomplete target coverage with minimum dose to critical organs at risk.The technical ability is determined by the steepness of the dose gradient,i.e., the physical fall-off distance in the patient from high to low isodose.Although the example chosen by the authors by and large accomplishesthis goal, it is notable that the target volume does not appear to includethe posterior bony portion of the vertebral body. This essentially createdan added distance between target volume and spinal cord. In the clinic,many patients present with a scenario, where only CSF separates targetvolume from spinal cord; when posterior portions of the vertebral bodyare eroded by tumor, a soft tissue tumor component bulges into thespinal canal or involves nerve roots with extension into the spinal canal.Taking the isodose fall-off distance in Fig. 3 as representative forphoton-based radiosurgery and applying it to those other, frequentclinical scenarios, the authors would have to choose between significantunderdosage of tumor components closest to the spinal cord and/oroverdosage of the spinal cord. Since dosages beyond spinal cord

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tolerance are clinically unacceptable, the logical result will be anunderdosage of posterior tumor components.

In summary, photon-based radiosurgery represents a tremendousadvancement in technology and has created promising opportunitiesfor non-invasive tumor and symptom control for many patients withspinal and paraspinal diseases. The issue of treating tumors inimmediate proximity to the spinal cord, specifically tumors withradioresistant histology, remains and will provide a continuedchallenge for the coming years.

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