Spinal radiosurgery: technology and clinical outcomes - Springer Link

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

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 guidance has allowed stereotactic radiosurgery and radiotherapy to be freed from the constraints imposed by the stereotactic frames once required for intracranial radiosurgery. This freedom has led to the application of radiosurgery to targets outside the brain. In this paper, we briefly review the technologies, treatment parameters, and clinical outcomes of radiosurgical treatment for spinal pathology, including metastatic tumors and rare but challenging lesions such as arteriovenous malformations and benign tumors. A special emphasis is put on the newest development, fiducial-less robotic radiosurgery. Spinal radiosurgery is associated with excellent rates of tumor control and pain relief with a good dose sparing of the highly sensitive spinal cord. Further research is required to optimize treatment strategies and to assess clinical benefits and toxicity in the long term. Keywords Spine . Spinal cord . Radiosurgery . Robotic . Image guidance

M. Avanzo Department of Medical Physics, Centro di Riferimento Oncologico, Via F. Gallini 2, 33081 Aviano, Italy e-mail: [email protected] P. Romanelli IRCCS Neuromed, Via Atinense 18, 86077 Pozilli, Italy P. Romanelli (*) Functional Neurosurgery, IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, Italy e-mail: [email protected]

Introduction Radiosurgery is the delivery, in a single or a few fractions, of a concentrated dose of radiation to diseased tissue with a steep dose fall off outside the treatment volume. The technique was first developed in the late 1940s, when the Swedish neurosurgeon Lars Leksell used X-rays to ablate dysfunctional loci of the brain [41]. High spatial accuracy of dose delivery to intracranial targets was achieved with the use of a rigid frame designed by Leksell. The frame, attached to patients’ skulls, served both to immobilize the head and provide external reference points for target localization. Radiosurgery has proven effective for controlling brain lesions with widely variable histologies, including arteriovenous 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 of some of these lesions (arteriovenous malformations, acoustic neuromas, cavernous sinus meningiomas, and brain metastases), radiosurgery is now the treatment of choice. Furthermore, functional indications such as trigeminal neuralgia [26, 36, 58, 66, 67] are becoming increasingly important. Spine and brain are affected by a comparable histopathological range of lesions, which suggests that radiosurgery may also be effective for the treatment of spinal lesions. Several factors, primary among them being concern about the precision with which highly focused, high-dose irradiation can be wielded in proximity to the delicate spinal cord, have delayed the application of radiosurgery to the spine. Historically, lesions of the spine have been treated with surgery, external photon beam radiotherapy, or both. Conventional photon irradiation of spinal neoplasms with the use of a single posterior field or opposed fields often cannot deliver a therapeutic dose to the tumor without

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exceeding the spinal cord’s radiation tolerance. Concerns about spinal cord dose limitations lead to suboptimal treatment not only of truly spinal lesions but also of many paraspinal tumors, which leads to high recurrence rates. Initial attempts at spinal radiosurgery involved a stereotactic frame that was fixated to the spine with bone screws under general anesthesia [27, 71]. This frame was invasive and uncomfortable for the patient and could introduce image artefacts in CT. The development of a more flexible and less painful approach, called image-guided or frameless radiosurgery, has allowed the principles of radiosurgery to be applied to the treatment of spinal lesions. Image guidance uses intraoperative imaging to locate the tumor during a treatment session and redirect the radiation source or reposition the patient based on these measurements. The accuracy of dose delivery using image-guided radiosurgery is comparable to that of radiosurgery performed with a stereotactic frame [8, 51, 52]. Furthermore, the removal of the invasive frame allows radiosurgical treatment to be delivered in more than one fraction, which has the potential to reduce toxicity to healthy tissue and organs at risk. Technologies for delivering radiation have evolved rapidly in the last decade, and with these new tools a conformal dose distribution can be effectively delivered to targets of irregular shape, thus allowing better control of the lesion and sparing of healthy tissue. Here we will describe image-guided stereotactic radiosurgery devices that can be used to treat the spine, briefly review clinical data showing the efficacy of these systems, and discuss concerns about and consequences of radiation toxicity induced by spinal radiosurgery.

Technologies for spinal radiosurgery Three image-guided LINAC devices are currently used to deliver spinal radiosurgery: the Novalis (Brainlab, Ammerthalstrabe, Germany), an intensity-modulated gantry-based system, Tomotherapy HI-ART (TomoTherapy, Inc., Madison, WI, USA), and the CyberKnife (Accuray, Inc., Sunnyvale, CA, USA), an innovative device providing robotic beam delivery. 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 neurosurgeons and radiation oncologists on the definition of radiosurgery. While a single, large-dose treatment is usually referred as radiosurgery, a treatment delivered in more than one fraction is called either radiosurgery [i.e., 17, 24, 68] or stereotactic radiotherapy [i.e., 7, 63]. In this paper, we adopt a definition of the term “radiosurgery” as the stereotactic application in one to five fractions of high-dose radiation to a target with ablative intent, where “high dose” means more than 2–3 Gy, fractional doses commonly used in conventional radiotherapy.

Neurosurg Rev (2009) 32:1–13

Intensity-modulated radiosurgery In intensity modulation radiosurgery (IMRS), the photon beams, typically five to nine, are divided into segments, and different doses are delivered with every segment [18]. In this way, dose distributions that conform very well to complicated targets while sparing the neighboring healthy tissues can be produced. In addition, the treatment plan is generated with an inverse planning process [25, 42] in which the weight of each segment is optimized to fulfill the constraints requested by the planner. Various image guidance solutions have been exploited to achieve the necessary spatial accuracy required to perform frameless IMRS, including online X-ray or in room CT imaging [7]. The Novalis system [77] is a 6 MV linear accelerator (LINAC) dedicated for image-guided IMRS (see Fig. 1), in which intensity modulation is achieved with a micro multileaf collimator (mMLC). Radiation can also be delivered through circular cone arcs or fixed-shape conformal beams using the mMLC. The image-guidance system is called Exactrac (Brainlab, AG, Heimstetten, Germany), a combination of two infrared cameras and kilovoltage X-ray tubes with amorphous silicon detectors mounted on the LINAC couch (Fig. 1). Pre-treatment CT scanning is acquired with infrared-sensitive markers placed on the patient’s skin. At the beginning of the treatment, the infrared cameras detect the markers with a precision of 0.3 mm [74] and their location is compared with that on the planning CT. The couch is then moved automatically to adjust the patient’s position. Then a pair of radiographs is taken and fused with digitally reconstructed radiographs (DRRs) generated from the pre-treatment CT scan to determine the deviation of the patient’s position from the pre-treatment CT [16]. Finally, two radiographs are acquired with portal films to verify patient position before irradiation. During treatment, the infrared system is used to monitor external patient motion, and isocenter deviations are measured and corrected. A non-invasive immobilization system (vacuum cushion and plastic film wrapped tightly to the patient’s body) stabilizes the patient in a comfortable position. The precision of this system for spinal radiosurgery, defined as the degree of variation between the isocenters of the CT simulation and the portal film radiography, is within 1.36±0.11 mm [61, 77]. Average deviation between estimated dose and measured dose with a microion chamber was 2%.

Robotic radiosurgery In most techniques, coplanar radiation beams are directed at isocentric targets. Non-coplanar and non-isocentric treatments using conventional LINACs can be achieved by


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

rotation (non-coplanarity) or translation (non-isocentricity) of the couch, as attempted successfully for stereotactic radiosurgery of the brain [1], but this can lead to a considerably longer treatment time. The CyberKnife [1] is a robotic radiosurgery system that achieves these goals differently. A highly mobile, image-guided robotic arm moves a small LINAC in the three-dimensional space. Beams can be pointed in virtually every direction, leading to non-isocentric, non-coplanar beams coursing through the target region. The beams are emitted through circular collimators with diameters ranging from 5 to 60 mm. This large number of beams, beam directions, and beam diameters allow the treating surgeon targeting and dosing possibilities that far exceed those offered by conventional systems (see Fig. 2). The combination of image guidance and robotics allows the system to measure and track target motion in any direction, an advantage over other available approaches [34, 45]. The precision in dose delivery necessary for radiosurgery is therefore obtained without rigid patient restraints. Image guidance is based on a pair of intra-treatment orthogonal radiographs acquired from two X-ray sources and amorphous silicon detectors positioned on either side of the target anatomy. The images are automatically registered to DRRs constructed from pre-treatment CT scans. This registration process allows the position of the treatment site

to be translated to the coordinate frame of the LINAC. This process is done to position the patient before starting treatment, and then typically every two to three beams to check the patient’s position in real time during the treatment. If the patient moves, the change is detected during the next imaging cycle and the beam is adjusted and realigned with the target [60]. Until recently, image guidance for spine treatments with the CyberKnife was based on fiducials [59], typically three to five stainless steel screws surgically placed in the lamina of the vertebra. Spatial accuracy of spinal radiosurgery with fiducial tracking has been determined to be 0.7±0.3 mm [78]. Even if minimally invasive, the placement of fiducials is a surgical procedure that introduces surgical risks and reduces the patient’s comfort. Furthermore, fiducial tracking assumes a rigid motion of the treatment site, which may not always be the case for the spine. Vertebrae can move one relative to another, thus deforming the surrounding soft tissue, therefore correct assessing of position, orientation, and deformation of the treatment site for tracking requires estimating of local displacements of spinal anatomy. These problems have been overcome with the introduction of XsightTM software (Accuray, Inc.). In Xsight, a 2D–3D local image registration is performed to register each pair of enhanced X-ray images to the corresponding enhanced DRRs. Local displacements of spinal anatomy are estimat-

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Fig. 2 The CyberKnife radiosurgery system (image used with permission from Accuray, Inc.)

ed and used for repositioning of the robotic manipulator during treatment. The Xsight fiducial-free spinal radiosurgery process has been recently described [20, 21, 32, 50]. A thin-slice CT scan is acquired with the patient in supine position. In some cases, the CT scan is not sufficient for correct contouring of the target and organs at risk and subsidiary image studies, such as gadolinium-enhanced magnetic resonance or a rotational angiography, are acquired and registered with the CT. After delineation of the target and organs at risk on the fused images, dose constraints are set for inverse planning. These typically include minimum and maximum dose to the target, and maximum dose and dose volume constraints to organs at risk. The treatment is planned by neurosurgeons, radiation oncologists, and medical physicists using Multiplan software (Accuray, Inc.), which uses an inverse planning algorithm to find an optimal set of beams and beam intensities to fulfill the dose constraints. When the optimization process is complete, the resulting dose distribution is calculated on CT images and evaluated. In Xsight treatments, a sharp dose gradient between the target region and the surrounding structures is achievable, an important factor for spinal tumors given their proximity to the spinal cord. As a consequence, the prescribed dose closely follows the target margin and dose to the spinal cord is effectively limited (see Fig. 3). The treatment begins with the patient placed on the treatment couch without immobilization devices. Two orthogonal X-ray images are acquired for the initial setup. Pre-treatment CT scan and X-ray images undergo an image enhancement process consisting of three steps [20]. In the

first, an exponential transformation of attenuation coefficients is applied to the CT scan. As a result, skeletal structures are emphasized relative to soft tissue. Then DRRs are generated by integration of CT attenuation coefficients through each ray connecting the X-ray source and the image plane. Finally, gamma correction and top-hat filtering applied to DRRs and radiographs produce images with better contrast of bony anatomy. A region of interest (ROI) surrounding the target volume is initially selected by the user and then refined to contain the maximum bony anatomical information by an algorithm that maximizes image entropy within the ROI. The resulting optimal ROI typically includes one to two vertebral bodies which form the basis of patient tracking and alignment. A 2D–2D local image registration is performed to register each pair of Xray images to the corresponding DRRs using the pattern intensity function [54] as a similarity measure and multiresolution block matching [21]. An ROI surrounding the target that includes substantial bony information is selected on the DRRs. A mesh laid over the ROI defines the points (nodes) at which local displacements are estimated. The pattern intensity function is calculated as a function of displacements in the X and Y axes between the two blocks surrounding the nodes in the DRR and the radiograph. Local displacement is identified as the vector that corresponds to the maximum of the pattern intensity function. To save computational time, the search is done with a multiresolution method: starting at low image resolution, and then with increasing resolution. With every step, some candidates of displacement vectors are discarded so that local optima are eliminated. Displacement vectors are


a

b

c

Fig. 3 Xsight fiducial-less radiosurgery for a thoracic vertebral body metastasis receiving 18 Gy prescribed to the 80% isodose. Isodose lines of 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 region is outlined in red and the spinal cord is in green. The prescription dose is 80% of the maximum and the spinal cord is spared by the 30% isodose curve. It can be appreciated the remarkable sparing of spinal cord irradiation (a spinal cord volume of about 3.8 cm3 receives a dose of 4 Gy)

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calculated for every node in the two DRR images, thus forming two displacement fields. Mismatching is possible for regions where skeletal structures are lacking. To solve this problem, the displacement fields are interpolated under the constraint of displacement smoothness, so that displacement vectors with a high difference from the surrounding are replaced by interpolated values. Displacements in the three-dimensional space are calculated by back projecting the 2D displacement fields. The tumor is localized in the three-dimensional space during treatment and a rotational and translational correction is applied to the robotic manipulator to obtain the planned LINAC orientation toward and distance from the target points. If a large movement of the treatment site is detected, the position of the patient is corrected with an automatic movement of the couch. The process of image acquiring, tumor localization and eventual LINAC or couch repositioning is repeated for each LINAC position until the end of the treatment. Accuracy of fiducial-less spinal radiosurgery has been measured by Ho et al. [32]. They took radiographs and DRRs of 11 patients treated with fiducial tracking and used fiducials as target points of known position to test the accuracy of registration. Each patient had four implanted fiducials. Fiducials were removed from DRRs to simulate the fiducial-less tracking, and their position in the CT was reconstructed from X-ray radiographs by application of the new registration method. The tracking system error is defined as the distance between the fiducial position on the CT scan and the position calculated from registration. The error in identifying the fiducials’ position, averaged over all the fiducials in the patient group, was measured to be 0.49 mm. In two different studies [32, 50], the spatial accuracy of the global spinal radiosurgical procedure, from preplanning CT scanning to spine tracking and dose delivery, was assessed. In both studies, an anthropomorphic head and cervical spine phantom loaded with radiochromic film was CT scanned. An isocentric radiosurgery treatment was planned and delivered, producing a spherical dose distribution. The position of the center of the dose distribution measured from film annealing was compared with that on the treatment plan. With a slice thickness of 1.5 mm, the accuracy 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 the only option; given the enormous number of possibilities for beam directions, placing beams by hand would not be practical. In the inverse planning process, the software attempts to find directions and doses for each beam to achieve the desired dose distribution. In the special case of robotic radiosurgery, first a number of equally spaced beam intersect points is generated on the target surface and a small number (typically two to four) of beam directions

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with random orientation in space is placed through every one of these points. Second, the optimization algorithm computes beam weights such that the dose constraints are fulfilled [64].

Tomotherapy A promising technique for spinal radiosurgery is helical tomotherapy [44], even if clinical published data are still limited. It is performed with a dedicated device, the HIART Tomotherapy System (TomoTherapy, Inc.). This is an intensity-modulated, image-guided radiation therapy system, in which a 6 MV LINAC rotates as in a computed tomography (see Fig. 4). At the same time, the couch moves continuously so that irradiation is delivered in oblique transverse planes through the patient. The beam is shaped by 64 binary multi-leaf collimators, and intensity modulation is achieved by opening every collimator for the appropriate length of time during irradiation. An inverse planning algorithm provides the optimal sequence of collimator openings. The same LINAC producing the therapeutic beam, coupled with megavoltage CT detectors, is the main component of the image guidance system. After initial patient positioning, a megavoltage CT scan is acquired and fused with the CT used in treatment planning to verify patient position and determine couch adjusting. Mahan and co-workers [47] did a feasibility study of radiosurgery of spinal metastases with the HI-ART. They Fig. 4 The HI-ART helical tomotherapy system at the C.R.O. in Aviano (PN)—Italy


simulated irradiation of a vertebral metastasis close to the spinal cord on a cylindrical phantom, evaluated sparing of the spinal cord with films, and obtained a dose gradient of 10% per millimeter while maintaining acceptable uniformity in the PTV. Patient setup error measured on the phantom was ±1.2 mm superior–inferior and ±0.6 mm anterior– posterior. The authors concluded that dose conformality and setup accuracy were sufficient to allow the treatment of targets adjacent to the spinal cord with this system. CT scan is currently used only for initial patient setup, but in the future it is planned to develop an optical position monitoring system to track patient position in real time during treatment delivery.

Spinal radiosurgery: clinical outcomes Spinal arteriovenous malformations The efficacy of stereotactic radiosurgery for arteriovenous malformations (AVMs) of the brain is well known, but only recently has radiosurgery emerged as a therapeutic alternative for spinal AVMs, specifically intramedullary AVMs [68]. These are AVMs with the nidus between an artery and a vein partially or totally located within the spinal cord parenchyma [6]. First symptoms of intramedullary AVMs happen during childhood, and include hemorrhage or acute medullary syndrome. With time, they can lead to deterioration of spinal cord function and recurrent hemorrhage. Therapies include


embolization or surgery, or a combination of both, but embolization requires feeding arteries of sufficient caliber, and surgery is not always possible because of the intramedullary location of the AVM. As a result, radiosurgery could be the only option left for these patients. Between 1997 and 2005, 15 cases of intramedullary AVMs were treated with the CyberKnife at Stanford Hospital [70]. Seven patients had received embolization before radiosurgery. A mean dose of 20.5 Gy was delivered to the margin of the nidus in two to five fractions to decrease the risk of radiation-related damage to spinal cord. Up to 3 years of post-radiosurgery follow-up was available. One patient showed complete angiographic obliteration after radiosurgery; four patients showed evidence of residual AVM on angiography, although AVM volumes were significantly reduced. The other patients did not undergo a final angiography, but showed significant AVM volume reduction on MRI. None of the patients demonstrated evidence of hemorrhage following CyberKnife treatment or any neurological deterioration attributable to SRS. Benign tumors of the spine Benign spinal tumors include schwannomas, meningiomas, and neurofibromas. They are slow growing tumors that can cause local and radicular pain and myelopathic symptoms of weakness and numbness from compression of nerve root and spinal cord. Although limited by short follow-up, some studies have shown outcomes of radiosurgery of spinal benign lesions. Three patients with benign spinal tumors were treated with the Novalis system [16]. A patient with a C3–4 foramina neurofibroma was treated with intensity-modulated radiosurgery at 12 Gy in a single fraction after prior surgical resection. Pre-treatment paresthesias of the hand were unchanged. A second patient had a T4 meningioma causing pain, weakness, and paresthesias of the back and was also treated with 12 Gy in a single fraction. All symptoms improved. A patient was treated for an L2 schwannoma to 15 Gy in a single fraction; pre-treatment thigh pain was unchanged after radiosurgery. All tumors were unchanged in follow-up imaging. In the most extensive clinical study of radiosurgery for benign spinal tumors to date [4], 59 benign lesions, 47 of which were located in the spine (25 cervical, four thoracic, 14 lumbar, and two sacral), were treated using the CyberKnife. Twenty-three lesions initially were surgically resected, and ten lesions received prior external beam radiation with a median dose of 48 Gy (range 40–54 Gy). Most treatments were administered in a single fraction with a median prescribed dose of 16 Gy to the 80% dose line. Improvement in pre-treatment symptoms was experienced by 78% of patients, with only one patient experiencing

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symptom progression. Of the 26 patients who underwent follow-up imaging, the local control rate was 96% after a median follow-up of 8 months. In another institution, the CyberKnife was used to treat 16 patients with 19 benign tumors of different histologies and spinal locations. Median prescribed dose was 21 Gy in three fractions. Tumor response after median follow-up of 25 months, documented by MRI, was progression in 2/18, regression in 3/18, and no change in 13/19 cases. No acute toxicity (grade 2–5) and no myelopathy were observed after treatment. Dodd et al. [17] reported about CyberKnife spinal radiosurgery on a group of 51 patients with 55 intradural extramedullary benign tumors (30 schwannomas, nine neurofibromas, and 16 meningiomas). The majority of patients were symptomatic, with symptoms including pain, radicular or myelopathic weakness, and sensory loss. Radiosurgery was administered because microsurgical resection was not indicated or refused or after subtotal or total gross tumor resection. Dose ranged from 16 to 30 Gy in one to five fractions. During follow-up interval (mean 36 months, range 24–73 months), 39% of the lesions decreased in size. Pain relief was observed in 50% of the initially symptomatic patients with meningioma and 70% of the patients with schwannoma. Symptoms did not improve in the patients with neurofibroma. Only three patients experienced worsening of symptoms and required surgical tumor resection. Lesions appeared stable (61%) or smaller (39%) after a mean follow-up of 36 months. One patient developed myelopathy that resulted in posterior column dysfunction, presumably as a consequence of treatment. Metastases of the spine The spine is a common site of metastatic disease that generally compromises a patient’s quality of life. Symptoms are caused by spinal cord or cauda equina compression and include back pain and myelopathy. Left untreated, many eventually become paraplegic, an event that strongly decreases life expectancy [73]. The goals of therapy include local tumor control, pain relief, prevention of neurological decline, and restoration of function. Bony instability and its neurological consequences are also concerns with these patients. Treating prior to the development of neurologic deficits improves the functional outcome for these patients [29]. Many clinical studies have demonstrated the safety, feasibility, and effectiveness of spinal radiosurgery for metastases. A summary of available clinical data for the treatment of many tumors is shown in Table 1. In a single-institution, phase I/II trial, 63 patients (with 74 tumors) were treated with IMRS integrated with near simultaneous CT scan for image guidance [7]. Some patients (55.6%) had been previously irradiated and some (46%) had received surgery. Treatment doses were 30 Gy in five

Metastatic

49 (61)

93 (103)

Metastatic

10 (10)

Yamada et al. [76]

Metastatic

8 (8)

15 (15)

Metastatic

74 (102)

Sinclair et al. [68]

Metastatic

336 (500)

Metastatic

AVM

Benign

Benign

51 (55)

16 (19)

Primary, metastatic

14 (22)

Primary and metastatic

51 (72)

Sahgal et al. [63]

De Salles et al. [16] Dodd et al. [17] Gerszten et al. [23] Gibbs et al. [24] Kim et al. [33] Ryu et al. [61] Ryu et al. [62]

Metastatic

63 (74)

Primary and metastatic

31 (35)

Chang et al. [7] Degen et al. [15]

Benign

44 (59)

Bhatnagar et al. [3] Benzil et al. [2]

Pathology

No. of patients (lesions)

Study, year, reference

10–24 Gy single fraction

15–25 Gy/2–5 sessions

Median 21 Gy, 3 fractions

15–30 Gy/1–5 fractions 6–8 Gy single fraction 10–16 Gy single fraction

30 Gy in 5 fx, 27 Gy in 3 fx Mean 21.16 Gy–6.45 Gy, mean 3.46 fractions 8–21 Gy single fraction 16–30 in 1–5 fractions 12–25 single fraction 16–25 in 1–5 fx

16 Gy median, single fraction 6 Gy–10 Gy/1–2 fractions

Dose/fraction(s)

Table 1 Selected published clinical results of image-guided spinal radiosurgery

IMRT with near simultaneous CT

Cyberknife

Cyberknife

Novalis

Novalis

Tomotherapy

Cyberknife

Cyberknife

Cyberknife

Novalis

Cyberknife

IMRT

Novalis

Cyberknife

Technique

Median 15 months

Median 17.9 months

Median 25 months

Median 6 months Median 6 months

Mean 9 months Not reported

Median 21

Mean 6.1 months Median 23

Mean 1 year

Median 21.3

Median 8 months Not reported

Follow-up

Complete pain relief 46%, partial 18.9%, no change 16.2% 3 (16%) tumors progressed, 2 (11%) regressed, 13 (68%) unchanged 1 complete angiographical obliteration, 6 significant reduction 90% local control

Pain relief in 100% patients

100% radiographic control

84% symptom improvement

61% stable, 39% smaller, 50% unchanged 88% local control

70% pain improved

100% in patients with metastatic disease

78% symptoms improvement, 96% local control Pain relief in 32/34 tumors causing pain 84% local control

Outcome

0

0

0

0

0

0

3 severe myelopathy

0

1 severe myelopathy

0

0

0

2 transient radiculitis, 1 neurological deterioration

0

Spinal cord complications

8 Neurosurg Rev (2009) 32:1–13


fractions or 27 Gy in three fractions. After a median followup of 21.3 months, actuarial 1-year local control rate was 84%. No cases of grade 3 or 4 neurological toxicity occurred. X-ray imaging for initial patient positioning and infrared markers to check intrafraction movement was used by Yamada et al. [76] for IMRS on 93 patients with 103 lesions. Treatments were delivered in a single fraction of 10–24 Gy to the tumor margin. Local control rate was 90%. Ryu and co-workers [61] reported results of a clinical feasibility study in ten patients of radiosurgery of spinal metastases with the Novalis system. Radiosurgery (6–8 Gy single fraction) was administered as a boost after external beam radiotherapy (25 Gy in ten fractions). After median follow-up of 6 months, all patients had some pain relief, five leading to medication reduction. Two patients with paraplegia before treatment recovered completely or partially after treatment. In another study [2], 31 patients with symptoms of pain and/or neurological deficits were treated with the same technique for 35 tumors, 26 of them spinal metastases. External-beam radiotherapy (25 Gy in ten fractions) was followed by a single-fraction radiosurgical boost of 6 to 8 Gy to the 90% isodose. Patients who had previously received 30 Gy with external radiotherapy were treated with 10 Gy in two fractions. Thirty-two patients experienced pain relief within 72 h and 22 showed durable neurological improvement. The incidence of complications related to radiosurgery was fairly low, with two patients developing transient radiculitis, and one showing severe neurological deterioration. The Novalis system has been used for radiosurgery on patients that had not been irradiated [62]. In this study, 49 patients with 61 spinal lesions were treated with singlefraction doses ranging from 10 to 16 Gy, with pain control as the primary endpoint. They reported complete pain relief in 37.7%, partial pain relief in 47.6%, and stable symptoms in 16.2% of cases at 8 weeks after treatment. No complication to spinal cord related to irradiation occurred. In many centers, robotic radiosurgery with the CyberKnife is used to treat spinal metastases, often as the primary treatment modality [15, 23, 24]. At the University of Pittsburgh Medical Center, the largest clinical series to date has been treated with single-fraction radiosurgery [23]. The study involved 500 lesions in 393 patients with metastases of various histologies, mostly renal cell, breast, lung, and melanoma. Goals of therapy included tumor control, palliation of symptoms, and restoring of neurological function. The average maximum dose to the tumor was 19 Gy in a single fraction. Sixty-seven patients had not been previously irradiated. In 48 of these cases, a significant decrease in pain was observed during the follow-up period of 6–48 months (median 16 months). Authors reported longterm radiographic control in 88% of all cases, and 100% for breast and lung and renal cell carcinoma when radiosurgery

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was the primary treatment. An overall long-term improvement in pain was obtained in 290 of the 336 cases that presented with pain as a primary indication (86%). Similar local control results were obtained in a series of 58 patients treated at the Georgetown University Hospital for various metastatic lesions [15]. A local control rate of 100% was achieved in patients who had not been previously irradiated, but there were three recurrences among the patients who had undergone irradiation before radiosurgery. Only minor and transient side effects of radiosurgery were observed during a 3-month follow-up period. CyberKnife, with Xsight tracking system for patients treated after Sept. 2004, was used by Gibbs et al. [24] on 74 patients with 102 lesions. Doses ranged between 16 and 25 Gy in one to five fractions. Two thirds of the patients had been previously irradiated. Symptoms, including pain and neurological deficits, improved in 84% of cases. Severe myelopathy related to radiosurgery occurred in three patients after a mean of 7 months from treatment. The HI-ART helical tomotherapy system has been used by Kim et al. [33] for fractionated radiosurgery of spinal metastases. A series of eight patients were treated with doses of 15–30 Gy, in one to five fractions. Two patients were treated in a single dose of 15 Gy. A non-invasive immobilization system that utilizes vacuum technology (Bodyfix. Medical Intelligence, Swabmunchen, Germany) was used. All the treated patients experienced complete radiographic control. Pain control was achieved in all the four patients who had follow-up with regard to pain control. Three patients experienced toxicity related to treatment, including nausea and dysphagia requiring medication and diarrhea that did not require medication. In general, then, clinical studies have shown that stereotactic delivery of radiation to metastatic lesions near the spinal cord can result in good tumor control, rapid and durable pain relief, and in some cases recovery of neurologic function, with little evidence of radiation-related side effects or radiation necrosis. While the role of spinal radiosurgery as a salvage treatment, i.e., for reirradiation after conventional radiotherapy, is well established, the superiority of this treatment modality as a primary treatment modality has still to be demonstrated. A metaanalysis of randomized trials [75] failed to demonstrate any advantage of single-fraction therapy over low doseper-fraction radiation therapy, but in this study the singlefraction dose was limited to 8 Gy and the only clinical endpoint was palliation. Image-guided RS, when used as the primary treatment modality, has shown the potential to treat spinal metastases with higher doses. This is reasonably expected to increase local control and palliation of symptoms. A randomized phase III study will be needed to ultimately demonstrate if radiosurgery is the primary treatment modality of choice for spinal metastases.

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Conclusions By eliminating the need for the invasive frame, image guidance has made it possible to use spinal radiosurgery to its full potential. The first clinical studies show good results in terms of tumor control of spinal metastasis and benign tumors, and angiographic obliteration of spinal AVMs. Single-fraction spinal radiosurgery using fiducial-free tumor tracking software is of particular value for patients with malignant disease and limited life expectancy because it improves the quality of life without significant physical stress. Furthermore, it is as safe and effective a treatment method as its counterpart that uses fiducials, in control of local tumor growth and associated pain syndromes. Given the very low incidence of unwanted effects, clinical results also show that in some cases higher doses can be used. Considerable research is required to determine optimal dose and fractionation, and the limits for radiosurgery around the radiosensitive spinal cord. More information from prospective evaluations that take into account clinical, imaging, and quality of life data are desirable for definitive conclusions and final treatment recommendations.

References 1. Adler JR Jr, Chang SD, Murphy MJ, Doty J, Geis P, Hancock SL (1997) The Cyberknife: a frameless robotic system for radiosurgery. Stereotact Funct Neurosurg 69:124–128 2. Benzil DL, Saboori M, Mogilner AY, Rocchio R, Moorthy CR (2004) Safety and efficacy of stereotactic radiosurgery for tumors of the spine. J Neurosurg 101(Suppl 3):413–418 3. Bhatnagar A, Gerszten P, Ozhasaglu C, Vogel WJ, Kalnicki S, Welch WC, Burton SA (2005) Cyberknife frameless radiosurgery for the treatment of extracranial benign tumors. Tech Canc Res Treat 4(5):571–576 4. Bhatnagar AK, Flickinger JC, Kondziolka D, Lunsford LD (2006) Stereotactic radiosurgery for four or more intracranial metastases. Int J Radiat Oncol Biol Phys 64(3):898–903 5. Bollet MA, Anxionnat R, Buchheit I, Bey P, Cordebar A, Jay N, Desandes E, Marchal C, Lapeyre M, Aletti P, Picard L (2004) Efficacy and morbidity of arc-therapy radiosurgery for cerebral arteriovenous malformations: a comparison with the natural history. Int J Radiat Oncol Biol Phys 58(5):1353–1363 6. Caragine Louis P Jr, Halbach Van V, Perry P, Dowd CF (2002) Vascular myelopathies—vascular malformations of the spinal cord: presentation and endovascular surgical management. Semin Neurol 22(2):123–131 7. Chang EL, Shiu AS, Mendel E, Matthews LA, Mahajan A, Allen PK, Weinberg JS, Brown BW, Wang XS, Woo SY, Cleeland C, Maor MH, Rhines LD (2007) Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine 7:151–160 8. Chang SD, Main W, Martin DP, Gibbs IC, Heilbrun MP (2003) An analysis of the accuracy of the Cyberknife: a robotic frameless stereotactic radiosurgical system. Neurosurgery 52(1):140–146 9. Chopra R, Morris CG, Friedman WA, Mendenhall WM (2005) Radiotherapy and radiosurgery for benign neurofibromas. Am J Clin Oncol 28(3):317–320

Neurosurg Rev (2009) 32:1–13 10. Chuang CC, Chang CN, Tsang NM, Wei KC, Tseng CK, Chang JT, Pai PC (2004) Linear accelerator-based radiosurgery in the management of skull base meningiomas. J Neurooncol 66 (1–2):241–249 11. Colombo F, Benedetti A, Pozza F, Marchetti C, Chierego G (1989) Linear accelerator radiosurgery of arteriovenous malformations. Neurosurgery 24:833–840 12. Combs SE, Volk, S, Schultz-Ertner DJ, Huber PE, Thilmann C, Debus J (2005) Management of acoustic neuromas with fractionated stereotactic radiosurgery (FSRT): long-term results in 106 patients treated in a single institution. Int J Radiat Oncol Biol Phys 63(1):75–81 13. Combs SE, Widmer V, Thilmann C, Holger H, Debus J, Schultz-Ertner D (2005) Stereotactic radiosurgery (SRS): treatment option for recurrent glioblastoma multiforme (GBM). Cancer 104(10):2168–2173 14. Dade Lunsford L, Niranjan A, Flickinger JC, Maitz A, Kondziolka D (2005) Radiosurgery of vestibular schwannomas: summary of experience in 829 cases. J Neurosurg 102(Suppl):195–199 15. Degen JW, Gagnon GJ, Voyadzis JM, McRae DA, Lunsden M, Dieterich S, Molzahn I, Henderson FC (2005) CyberKnife stereotactic radiosurgical treatment of spinal tumors for pain control and quality of life. J Neurosurg Spine 2:540–549 16. De Salles AF, Pedroso AG, Medin P, Agazaryan N, Solberg T, Cabatan-Awang C, Espinosa DM, Ford J, Selch MT (2004) Spinal lesions treated with Novalis shaped beam intensity modulated radiosurgery and stereotactic radiotherapy. J Neurosurg 101: 435–440 17. Dodd RL, Ryu MR, Kamnerdsupaphon P, Gibbs IC, Chang SD Jr, Adler JR Jr (2006) Cyberknife radiosurgery for benign intradural extramedullary spinal tumors. Neurosurgery 58(4):674–685 18. Ezzell GA, Galvin JM, Low D, Jatinder RP, Rosen I, Sharpe MB, Xia P, Xiao Y, Xing L, Yu CX, IMRT subcommittee, AAPM Radiation Therapy Committee (2003) Guidance document on delivery, treatment planning, and clinical implementation of IMRT: report of the IMRT subcommittee of the AAPM radiation therapy committee. Med Phys 30(8):2089–2115 19. Flickinger JC, Lunsford LD, Coffey RJ, Linskey ME, Bissonette DJ, Maitz AH, Kondziolka D (1991) Radiosurgery of acoustic neurinomas. Cancer 67:345–353 20. Fu D, Kuduvalli G (2006) Enhancing skeletal features in digitally reconstructed radiographs. Proc of SPIE Vol. 6144, 61442M 21. Fu D, Kuduvalli G, Maurer CR, Allision JW, Adler JR (2006) 3D target localization using 2D local displacements of skeletal structures in orthogonal X-ray images for image-guided spinal radiosurgery. Int J CARS 1:198–200 22. Fuentes S, Delsanti C, Metellus P, Peragut JC, Grisoli F, Regis H (2006) Brainstem metastases: management using gamma knife radiosurgery. Neurosurgery 58(1):37–42 23. Gerszten PC, Burton SA, Ozhasoglu C, Vogel WJ (2007) Radiosurgery for spinal metastases. Clinical experience in 500 cases from a single institution. Spine 32(2):193–199 24. Gibbs IC, Kamnerdsupaphon P, Ryu MR, Dodd R, Kiernan M, Chang SD, Adler JR Jr (2007) Image-guided robotic radiosurgery for spinal metastases. Radiother Oncol 82:185–190 25. Goitein M (1991) The inverse problem. Int J Rad Oncol Biol Phys 18:489–491 26. Goss BW, Frighetto L, De Salles AA, Smith Z, Solberg T, Selch M (2003) Linear accelerator radiosurgery using 90 gray for essential trigeminal neuralgia: results and dose volume histogram analysis. Neurosurgery 53(4):823–828 27. Hamilton AJ, Lulu BA, Fosmire H, Stea B, Cassidy JR (1995) Preliminary experience with linear accelerator based spinal radiosurgery. Neurosurgery 36:311–319 28. Hasegawa T, Fujitani S, Katsumata S, Kida Y, Yoshimoto M, Koike J (2005) Stereotactic radiosurgery for vestibular schwanno-


29.

30. 31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41. 42.

43.

44.

45.

46.

47.

mas: analysis of 317 patients followed more than 5 years. Neurosurgery 57(2):257–265, Aug Helweg-Larsen S (1996) Clinical outcome in metastatic spinal cord compression: a prospective study of 153 patients. Acta Neurol Scand 94:269–275 Heppner PA, Sheehan JP, Steiner LE (2005) Gamma knife surgery for low-grade gliomas. Neurosurgery 57(6):1132–1139 Hsieh PH, Chandler JP, Bhangoo S, Panagiotopoulos K, Kalapural JA, Marymont MH, Cozzens JW, Levy RM, Salehi S (2005) Adjuvant gamma knife stereotactic radiosurgery at the time of tumor progression potentially improves survival for patients with glioblastoma multiforme. Neurosurgery 57(4):684–692 Ho AK, Fu D, Cotrutz C, Hancock SL, Chang SD, Gibbs IC, Maurer CR Jr, Adler JR Jr (2007) A study of the accuracy of Cyberknife spinal radiosurgery using skeletal structure tracking. Neurosurgery 60:147–156 Kim B, Soisson ET, Duma C, Chen P, Hafer R, Cox C, Cubellis J, Minion A, Plunkett M, Mackintosh R (2008) Image-guided helical Tomotherapy for treatment of spine tumors. Clin Neurol Neurosurg 110(4):357–362 Keall PJ, Mageras GS, Balter JM, Emery RS, Forster KM, Jiang SB, Kapatoes JM, Low DA, Murphy MJ, Murray BR, Ramsey CR, Van Herk MB, Vedam SS, Wong JW, Yorke E (2006) The management o f respiratory motion in radiation oncology report of AAPM Task Group Report No 76. Med Phys 33 (10):3874–3900 Kobayashi T, Kida Y, Mori Y, Hasegawa T (2005) Long-term results of gamma knife surgery for the treatment of craniopharyngioma in 98 consecutive cases. J Neurosurg 103(6 Suppl):482–488 Kondziolka D, Flickinger JC, Lunsford LD, Habeck M (1996) Trigeminal neuralgia radiosurgery: the University of Pittsburgh experience. Stereotact Funct Neurosurg 66(1):343–348 Kondziolka D, Flickinger JC, Bissonette DJ, Bozik M, Lunsford LD (1997) Survival benefit of stereotactic radiosurgery for patients with malignant glial neoplasms. Neurosurgery 50:41–46 Kondziolka D, Lunsford LD, Coffey RJ, Flickinger JC (1991) Stereotactic radiosurgery of meningiomas. J Neurosurg 74 (4):552–559 Kreil W, Luggin J, Fuchs I, Weigl V, Eustacchio S, Papaefthymiou G (2005) Long term experience of gamma knife radiosurgery for benign skull base meningiomas. J Neurol Neurosurg Psychiatry 76 (10):1425–1430 Lavine SD, Petrovich Z, Cohen-Gadol AA et al (1999) Gamma knife radiosurgery for metastatic melanoma: an analysis of survival, outcome, and complications. Neurosurgery 44(1):59–64 Leksell LT (1951) The stereotactic method and radiosurgery of the brain. Acta Chir Scand 102(4):316–319 Lind BK, Kallman P (1990) Experimental verification of an algorithm for inverse radiation therapy planning. Radiother Oncol 17:359–368 Lunsford LD, Kondziolka D, Flickinger JC, Bissonette DJ, Jungreis DA, Maitz AH, Horton JA, Coffey RJ (1991) Stereotactic radiosurgery for arteriovenous malformations of the brain. J Neurosurg 75(4):512–524 Mackie TR, Balog J, Ruchala K, Shepard D, Aldridge S, Fitchard E, Reckwerdt P, Olivera G, McNutt T, Mehta M (1999) Tomotherapy. Semin Radiat Oncol 9(1):108–117 Mageras GS, Yorke E, Jiang SB (2006) “4D” IMRT delivery. In: Bortfeld T, Schmidt-Ullrich R, De Neve W, Wazer DE (eds) Image-Guided IMRT. Springer, New York, pp 269–285 Mahajan A, McCutcheon IE, Suki D, Chang EL, Hassenbusch SJ, Weinberg JS, Shiu A, Maor MH, Woo SY (2005) Case–control study of stereotactic radiosurgery for recurrent glioblastoma multiforme. J Neurosurg 103(2):210–217 Mahan SL, Ramsey CR, Scaperoth DD, Chase DJ, Byrne TE (2005) Evaluation of image-guided helical tomotherapy for the

11

48. 49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

retreatment of spinal metastasis. Int J Radiation Oncol Biol Phys 63(5):1576–1583 McDermott MW, Sneed PK (2005) Radiosurgery in metastatic brain cancer. Neurosurgery 57(5):45–53, discussion S1–4 Miyawaki L, Dowd C, Wara W, Goldsmith B, Albright N, Gutin P, Halbach V, Hieshima G, Higashida R, Lulu B, Pitts L, Schell M, Smith V, Weaver K, Wilson C, Larson D (1999) Five year result of LINAC radiosurgery for arteriovenous malformations: outcome for large AVMs. Int J Radiat Oncol Biol Phys 44 (5):1089–1106 Muacevic A, Staehler M, Drexler C, Wowra B, Reiser M, Tonn JC (2006) Technical description, phantom accuracy, and clinical feasibility for fiducial-free frameless real-time image-guided spinal radiosurgery. J Neurosurg Spine 5(4):303–312 Murphy MJ, Cox RS (1996) The accuracy of dose localization for an image-guided frameless radiosurgery system. Med Phys 23 (12):2043–2049 Murphy MJ, Chang SD, Gibbs IC, Le QT, Hai J, Kim D, Martin DP, Adler JR Jr (2003) Patterns of patient movement during frameless image-guided radiosurgery. Int J Radiat Oncol Biol Phys 55 (5):1400–1408 Nataf F, Schlienger M, Lefkopoulos D, Merienne L, Ghoussob M, Foulquier JN, Deniaud-Alexandre E, Mammar H, Meder JF, Turak B, Huart J, Toubol E, Roux FX (2003) Radiosurgery of cerebral arteriovenous malformations in children: a series of 57 cases. Int J Radiat Oncol Biol Phys 57(1):184–195 Penny GP, Weese J (1998) A comparison of similarity measures for use in 2D–3D medical image registration. IEEE 1998; Med Imag 17:586–595 Poen JC, Golby AJ, Forster KM, Martin DP, Chinn DM, Hancock SL, Adler JR Jr (1999) Fractionated stereotactic radiosurgery and preservation of hearing in patients with vestibular schwannoma: a preliminary report. Neurosurgery 45(6):1299–1305 Pollock BE, Link MJ, Foote RL, Stafford SL, Brown PD, Schomberg PJ (2004) Radiosurgery as primary management for meningiomas extending into the internal auditory canal. Stereotact Funct Neurosurg 82(2–3):98–103 Pollock BE, Stafford SL (2005) Results of stereotactic radiosurgery for patients with imaging defined cavernous sinus meningiomas. Int J Radiat Oncol Biol Phys 62(5):1427–1431 Richards DM, Bradley KA, Tome WA, Bentzen SM, Resnick DK, Mehta MP (2005) Linear accelerator radiosurgery for trigeminal neuralgia. Neurosurgery 57(6):1193–200 Romanelli P, Chang SD, Koong A, Adler JR Jr (2003) Extracranial radiosurgery using the Cyberknife. Tech Neurosurg 9:226–231 Romanelli P, Schweikard A, Schlaefer A, Adler JR Jr (2006) Computer aided robotic radiosurgery. Comput Aided Surg 11 (4):161–174 Ryu S, Fang FY, Rock J, Zhu J, Chu A, Kagan E, Rogers L, Ajlouni M, Rosenblum M, Kim JH (2003) Image-guided and intensity-modulated radiosurgery for patients with spinal metastasis. Cancer 97(8):2013–2018 Ryu S, Jin R, Jin JY, Chen Q, Rock J, Anderson J, Movsas B (2008) Pain control by image-guided radiosurgery for solitary spinal metastasis. J Pain Symptom Manage 35:292–298 Sahgal A, Chou D, Ames C, Ma L, Lamborn K, Huang K, Chuang C, Aiken A, Petti P, Weinstein P, Larson D (2007) Imageguided robotic stereotactic body radiotherapy for benign spinal tumors: the University of San Francisco preliminary experience. Technol Cancer Res Treat 6(6):595–604, Dec Schweikard A, Bodduluri A, Adler JR (1998) Planning for camera-guided robotic radiosurgery. IEEE Trans Robot Autom 14:951–962 Sheehan JP, Niranjan A, Sheehan JM, Jane JA Jr, Laws ER, Kondziolka D, Flickinger J, Landolt AM, Loeffler JS, Lunsford

12

66.

67.

68.

69.

70.

71.

72.

73. 74.

75.

76.

77.

78.

79.

Neurosurg Rev (2009) 32:1–13 LD (2005) Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium. J Neurosurg 102 (4):678–691 Sheehan J, Pan HC, Stroila M, Steiner L (2000) Gamma knife radiosurgery for trigeminal neuralgia: outcomes and prognostic factors. J Neurosurg 102(3):434–441 Simth ZA, De Salles AA, Frighetto L, Goss B, Lee SP, Selch M, Wallace RE, Cabatan-Awang C, Solberg T (2003) Dedicated linear accelerator radiosurgery for the treatment of trigeminal neuralgia. Neurosurg 99(3):511–516 Sinclair J, Chang SD, Gibbs I, Adler JR Jr (2005) Cyberknife radiosurgery for intramedullary spinal cord arteriovenous malformations. In: Mould RF, Schultz RA (eds) Robotic Radiosurgery Volume I. The Cyberknife Society, Sunnyvale, pp 187–196 Steiner L, Lindquist C, Adler JR Jr, Torner JC, Alves W, Steiner M (1992) Clinical outcome of radiosurgery for cerebral arteriovenous malformations. J Neurosurg 77(1):1–8 Sinclair J, Chang SD, Gibbs IC, Adler JR Jr (2006) Multisession Cyberknife radiosurgery for intramedullary spinal cord arteriovenous malformations. Neurosurgery 58(6):1081–1089 Takacs I, Hamilton AJ (1999) Extracranial stereotactic radiosurgery: applications for the spine and beyond. Neurosurg Clin N Am 10:257–270 Torres RC, Frighetto L, DeSalles AA, Goss B, Medin P, Solberg T, Ford JM, Selch M (2003) Radiosurgery and stereotactic radiotherapy for intracranial meningiomas. Neurosurg Focus 14(5):e5 Vrionis FD, Miguel R (2003) Management of spinal metastases. Semin Pain Med 1(1):25–33 Wang LT, Solberg TD, Medin PM, Boone R (2001) Infrared patient positioning for stereotactic radiosurgery of spinal tumors. Comput Biol Med 31(2):101–111 Wu JS, Wong R, Johnston M et al (2003) Meta-analysis of dosefractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 55:594–605 Yamada Y, Blisky MH, Lovelock D, Venkatraman S, Toner S, Johnson J, Zatcky J, Zelefsky MJ, Fuks Z (2008) High-dose, single fraction image-guided intensity modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys Jan 28 2008. Epub ahead of print Yin FF, Ryu S, Ajlouni M, Zhu J, Yan H, Guan H, Faber K, Rock J, Abdulhak M, Rogers L, Rosenblum M, Kim JH (2002) A technique of intensity modulated radiosurgery (IMRS) for spinal tumors. Med Phys 29:2815–2822 Yu C, Main W, Kuduvalli G, Apuzzo ML, Adler JR Jr (2004) An anthropomorphic phantom study of the accuracy of spinal radiosurgery. Neurosurgery 55(5):1138–1149 Zabel Du-Bois A, Milker-Zabel S, Huber P, Schlegel W, Debus J (2006) Stereotactic linac-based radiosurgery in the treatment of cerebral arteriovenous malformations located deep, involving corpus callosum, motor cortex or brainstem. Int J Radiat Oncol Biol Phys 64 (4):1044–1048

Comments Eugen B Hug, Villigen, Switzerland In the present issue, M. Avanzo and P. Romanelli review equipment, techniques, and published clinical outcomes on extracranial, spinal radiosurgery. I congratulate the authors to an excellent presentation of currently available radiosurgery and stereotactic body radiotherapy (SBRT) equipment, as well as the concise update and discussion of the literature.

Prior to the advent of this technology and other image-guidancebased precision technologies, physicians essentially had to choose between treatment modalities to accomplish either symptom management (mainly pain control) or tumor control and preservation of functional stability of the spine. The realities were as such that radiotherapy would be able to control pain since only moderate amounts of radiation dosages are needed for short- to mid-term pain control. However, radiation dose levels required for actual tumor control, i.e., arresting progressive destruction and preserving spinal column stability in case of vertebral body involvement, routinely exceeded spinal cord tolerance. Hence, surgical resection including stabilization was frequently the only realistic treatment of choice for tumor control. Specifically in palliative situations, surgery with its related morbidity, hospitalization, and rehabilitation impacted significantly on quality of life within a patient’s residual lifespan. Innovative, non-invasive radiosurgical techniques, as presented in this article, finally overcame this dilemma and are holding the promise for many patients of accomplishing both symptom reduction as well as tumor control with low risks of spinal cord injury. Although acquisition costs and operating expenses are generally higher compared to conventional radiation equipment, most technologies have versatile, curative applications for tumors outside the spinal or paraspinal region. In addition, avoidance of surgical procedures and hospitalization, lack of progressive neurologic disability, and reduction of chronic medication will result in significant savings for society. Extrapolating from incidence numbers, patients with either solitary or few bony metastases to vertebral bodies will likely emerge as the dominant patient cohort. For patients with diffuse metastatic spread and/or life expectancy measured in weeks only, single dose conventional photon irradiation will likely remain a suitable and locally readily available radiation modality (1). As to the application in primary intraspinal or paraspinal neoplasms, the authors acknowledge the presently limited clinical data. However, one can reasonably expect within the coming years publications from major institutions with larger patient numbers and more mature follow-up. For radioresistant mesenchymal tumors, i.e., sarcomas of the axial skeleton, particle therapy and specifically proton therapy have demonstrated their success in high-dose tumor control next to critical structures (2 and 3). Despite an approximate 30-year history of clinical patient treatments, the high costs of particle facilities have in the past prohibited a more widespread use. It will be most interesting to compare evolving photon-based radiosurgery data with outcomes after particle therapy. In Fig. 3, the authors demonstrate an example of the isodose distribution using fiducial-less radiosurgery for a thoracic vertebral body metastasis. With a dose prescription to the 80% isodose line and the spinal cord being covered by the ≤30% isodose curve, this example elucidates both the possibilities as well as limitations of photon-based spinal radiosurgery. The ultimate goal of any high-dose radiotherapy is complete 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 accomplishes this goal, it is notable that the target volume does not appear to include the posterior bony portion of the vertebral body. This essentially created an added distance between target volume and spinal cord. In the clinic, many patients present with a scenario, where only CSF separates target volume from spinal cord; when posterior portions of the vertebral body are eroded by tumor, a soft tissue tumor component bulges into the spinal canal or involves nerve roots with extension into the spinal canal. Taking the isodose fall-off distance in Fig. 3 as representative for photon-based radiosurgery and applying it to those other, frequent clinical scenarios, the authors would have to choose between significant underdosage of tumor components closest to the spinal cord and/or overdosage of the spinal cord. Since dosages beyond spinal cord

Neurosurg Rev (2009) 32:1–13 tolerance are clinically unacceptable, the logical result will be an underdosage of posterior tumor components. In summary, photon-based radiosurgery represents a tremendous advancement in technology and has created promising opportunities for non-invasive tumor and symptom control for many patients with spinal and paraspinal diseases. The issue of treating tumors in immediate proximity to the spinal cord, specifically tumors with radioresistant histology, remains and will provide a continued challenge for the coming years.

13 References 1. Chow E, Harris K, Fan G, Tsao M, Sze WM. Palliative radiotherapy trials for bone metastasis: a systematic review. J Clin Oncol, 25(11):1423–1436, 2007 2. Hug EB, Munzenrider JE. Skull Base and Cervical Spine. In: Proton and Charged Particle Radiotherapy. Delaney and Kooy, Eds. Lippincott Williams and Wilkins, Philadelphia, 2008 3. Munzenrider JE, Liebsch NJ. Proton therapy for tumors of the skull base. Strahlenther Onkol 175 (Suppl 2):57–63, 1999