Image-Guided Radiosurgical Ablation of Intra- and Extra-Cranial Lesions

Technology in Cancer Research and Treatment ISSN 1533-0346 Volume 5, Number 4, August (2006) Adenine Press (2006) Image-Guided Radiosurgical Ablation of Intra- and Extra-Cranial Lesions www.tcrt.org For decades since its introduction, stereotactic radiosurgery (SRS) was used only to treat intracranial lesions because intracranial targets could be immobilized and located relative to a rigid metal frame affixed to the patient s head. Lesions outside the head were generally not treated with SRS because it is difficult to immobilize extracranial lesions and to attach stereotactic frames elsewhere on the body. Advances in computerized image guidance and robotics allowed the development of systems, such as the CyberKnife SRS System (Accuray, Inc, Sunnyvale, CA), that could target intracranial lesions without the stereotactic frame. Enhancements have resulted in a radiation delivery system that can accurately deliver high-dose, focal radiation to lesions in the spine, chest, and abdomen, even if they move during respiration. In this review we will describe the technical features of frameless SRS systems and briefly review their application to treating intracranial and extracranial lesions, focusing in particular on spinal lesions. Pantaleo Romanelli, M.D. 1,2,* David W. Schaal, Ph.D. 2 John R. Adler, M.D. 2 1 Department of Neurosurgery Neuromed IRCCS Pozzilli, IS, Italy 2 Department of Neurosurgery Stanford University Stanford, CA, USA Key words: Image-guided stereotactic radiosurgery, Intracranial, Extracranial, and Spine. Introduction Stereotactic radiosurgery (SRS) began with the introduction of the concept, and its embodiment in the Gamma Knife, by Lars Leksell in 1951 (1). The ability to deliver highly focused beams of radiation accurately to intracranial lesions without damaging healthy surrounding tissue was predicated on the fact that intracranial lesions do not move within the skull, and can therefore be localized precisely with reference to a stereotactic frame attached to the patient s head and fixed within the Gamma Knife apparatus. The problem of delivering radiation to a target defined in imaging was solved by arranging 201 individual radiation sources around the cranium and focused on a single point, the isocenter, within the patient s tumor. This highly successful technology was a treatment revolution in neurosurgery, and has been successfully applied to brain tumors, vascular malformations, and to neurological disorders such as trigeminal neuralgia and movement disorders. Advances in image guidance and robotics paved the way for the development of a second generation of SRS systems, such as the CyberKnife (Accuray, Inc., Sunnyvale, CA.) and the Novalis system (BrainLab AG, Heimstetten, Germany), that have devised alternative methods for targeting lesions, thereby eliminating the stereotactic frame. This review will deal mostly with the CyberKnife, with which we have first-hand experience. CyberKnife frameless SRS is based on * Corresponding Author: Pantaleo Romanelli, M.D. Email: radiosurgery2000@yahoo.com Abbreviations: SRS, Stereotactic radiosurgery; LINAC, Linear accelerator; CT, Computed tomography; MRI, Magnetic resonance imaging; DRRs, Digitally reconstructed radiographs; TN, Trigeminal neuralgia; 5-FU, 5-fluorouracil; IMRT, Intensity-modulated radiotherapy. 421

422 Romanelli et al. noninvasive image-guided manipulation of a lightweight high-energy linear accelerator (LINAC) by a dexterous robotic arm (2, 3). Solving the frame problem in this way has allowed users of the CyberKnife to fractionate treatment of intracranial lesions and to treat lesions anywhere in the body with generally excellent results (4-11). After briefly reviewing the CyberKnife system, outcomes of CyberKnife SRS to treat targets throughout the body will be reviewed. CyberKnife SRS The CyberKnife is characterized by a localization system that is based on the patient s anatomy [for a more extensive technical review see (2, 3)]. The target reference coordinates are provided by the skull contour for intracranial treatments and by implanted fiducials elsewhere. A real-time control loop between the imaging and beam delivery systems allows the beams to follow a moving target (8, 12-15), which was the key to the elimination of the rigid frame fixation. In contrast to the Gamma Knife, the beam delivery of the CyberKnife can be non-isocentric, thanks to the high degree of mobility of the robotic arm. As illustrated in Figure 1, this allows the highly conformal treatment of large, non-spherical targets without the use of multiple overlapping isocenters. Real-time Image Guidance The essential characteristic of image-guided SRS is the capacity to check the target position and adjust the treatment accordingly if the patient moves. Continuous image guidance during treatment is a critical feature of frameless SRS. Image guidance is made possible by the repeated determination of target position using bony landmarks or implanted fiducials. The position of the target is determined pre-operatively on computed tomography (CT), often supplemented with angiography or functional imaging (e.g., PET or fmri), obtained while the patient is comfortably and minimally restrained. Real-time imaging during surgery is provided by X-ray devices. The images are registered by computer to the model derived from the treatment planning CT, thereby allowing the position of the treatment site to be translated to the coordinate frame of the LINAC. If the patient moves adjustments are made to assure accurate targeting. Robotic Adjustments Image-guided SRS requires an interface between treatment execution software and robotic devices that are responsible for adjusting beam position depending on the treatment plan and patient movements. In the Novalis system the position of the patients themselves is modified by moving the table that they rest on during treatment. The CyberKnife employs a robotic arm to alter the position of its 6 MV LINAC, thus changing the beam target and trajectory (3, 12) (see Figure 2). Treatment Planning The localization method of the CyberKnife is based on digitally reconstructed scans obtained from a thin-slice (e.g., 1.25 mm) CT, usually acquired after intravenous injection of contrast. The patient s CT is transferred to the treatment planning station, where the target is delineated and the delivery of stereotactic irradiation is planned. CT-MR fusion can be employed to define targets that are not adequately delineated on CT. Single isocenters are used for spherical lesions. Irregularly shaped lesions are treated either with multiple overlapping isocenters or non-isocentrically. The latter is usually preferred because the treatment of irregular tumor volumes with multiple isocenters can result in reduced homogeneity and increased treatment time. The mobility of the robotic arm allows an array of overlapping beams to be delivered non-isocentrically to the target. The set of beam directions is chosen through an inverse planning process and can deliver homogeneous dose distributions that closely conform even to highly irregular volumes. Treatment Delivery A treatment for a typical patient begins in the days prior to the delivery of radiation. Patients are referred or self-refer for consideration for SRS. If it is agreed by a team of surgeons, medical oncologists, and radiation oncologists that SRS is a good option, the patient undergoes thin-slice CT acquisition to obtain planning CT images (some extracranial patients may require fiducial placement, which should be conducted far enough in advance of CT acquisition to allow edema to subside). The treatment is planned and the patient is brought into the CyberKnife suite and positioned on the treatment table, with minimal, comfortable restraints to limit excessive movement. The imaging system acquires a pair of alignment radiographs that are compared to digitally reconstructed radiographs (DRRs) obtained from the treatment planning CT. Once proper alignment is verified, the system can determine the initial location of the treatment site within the robotic coordinate system and the robot moves the LINAC to its initial position. The robotic arm then moves the LINAC through a sequence of preset points (nodes) surrounding the patient along a specific path. At each point (or after each treatment beam; this is a user-defined parameter) the LINAC stops and a new pair of x-ray images is acquired, from which the position of the target is redetermined and delivered to the robotic arm, which adapts the beam pointing so that patient movements up to 1 cm are compensated for. The LINAC then delivers the preplanned dose of radiation for that beam direction. This process of redetermination of target location is repeated for each node until all the planned beams are delivered and treatment is completed (roughly 30-60 min for intracranial, 60-120 min for extracranial). An average treatment requires about 100

Image-guided Radiosurgery 423 nodes, each allowing a set of 12 possible beam directions, for a total of 1200 trajectories available for a treatment. Dose Placement Precision Targeting error for conventional SRS using stereotactic frames is about 1.2 to 2.7 mm (16-18). The accuracy of image-guided SRS is influenced by the precision of beam delivery and the accuracy of target localization, and has been found to be sub-millimetric (19). Accuracy was measured in a study by Chang et al. (20) using head phantoms loaded with packs of radiochromic film. They found the mean error to be affected by CT slice thickness, and is reliably sub-millimetric using thin-slice CT. Errors based on the precision of the robotic arm (about 0.3 mm) and the tracking system plus the treatment planning precision are also less than a millimeter (3). Dose placement precision of the CyberKnife, therefore, approximates that of conventional frame-based radiosurgery systems. Extracranial Targets The ability to perform extracranial radiosurgery is a novel feature of the CyberKnife. In most cases the treatment of spinal lesions currently requires implantation of fiducials on the spinal laminae. Accuray recently introduced Xsight, software that is used to target and track lesions near the spine based on landmarks provided by the bony anatomy of the spine itself (21), thus making spinal SRS fiducial-free. The treatment of other extracranial lesions, such as those in the lung and pancreas, requires tracking of the target while it moves with respiration. Tracking is based on the combination of fiducial tracking (typically gold balls implanted near the lesion) and chest and abdominal wall tracking using infrared detectors (8, 9, 13, 22). Prior to beam delivery the system tracks both the internal and external markers and builds a correspondence model that is used to predict internal fiducial movement from the movement of the external markers. The model is updated throughout the procedure, and large errors stop the procedure until an accurate model is rebuilt. Aside from the nuances of target localization, treatment delivery for extracranial lesions follows the same modalities used for the treatment of intracranial lesions (8, 9). Figure 3 shows images of titanium screws implanted on the spinal laminae above and below the target. Clinical Experience Intracranial Lesions Vestibular Schwannomas: Gamma Knife single-stage radiosurgery for vestibular schwannomas is known to produce excellent rates of tumor control with a 50-73% likelihood of maintaining hearing at the pre-treatment level. Damage to the acoustic, facial, or trigeminal nerve can be detected in some patients, resulting in loss of hearing, facial weakness, or trigeminal dysesthesias [e.g., (23)]. The first report of CyberKnife SRS for the treatment of vestibular schwannomas (24) showed excellent rates of hearing preservation (93%) and tumor control (94%). A more recent paper (4), confirmed excellent control of tumor growth in association with remarkable rates of hearing preservation. Since 1999, the CyberKnife at Stanford University has been used to treat over 400 patients with vestibular schwannomas. A hypofractionated protocol was applied in which 18 Gy was delivered in three stages separated by 24 hours. Of the 61 patients with at least 36 months of follow-up (mean, 48 months), 74% with serviceable hearing prior to treatment (Gardner-Robinson Class 1-2) maintained these levels at the last follow-up, and no patient with at least some hearing before treatment lost all hearing on the treated side. Only one treated tumor (2%) progressed after radiosurgery; 29 out of 61 (48%) decreased in size and 31 out of 61 (50%) were stable. No treatment-related trigeminal or facial nerve dysfunction was observed. Pituitary Adenomas: Kajiwara and coworkers (25) recently described 21 patients with pituitary adenomas who were treated with image-guided SRS. These included 14 non-functioning adenomas, three prolactinomas, two GH-secreting adenomas, and two ACTH-secreting adenomas. The mean volume of the 14 non-functioning and the seven functioning adenomas was 13.3 cc and 7.5 cc, respectively. The mean marginal irradiation dose was 12.6 Gy for non-functioning adenomas and 17.5 Gy for functioning adenomas. The tumor control rate was 95.2% with a mean follow-up period of 35.3 months. Hormonal function improved in all of the seven functioning adenomas. In two cases, hypopituitarism occurred after the therapy. Visual damage was not detected except in one case, where the growth of a cystic lesion induced compression of the visual pathway requiring surgical decompression. Glomus Jugulare Tumors: In a paper reporting the results of stereotactic radiosurgery for glomus jugulare tumors, Lim et al. described three patients treated with the CyberKnife [and six other patients treated with conventional frame-based LINAC; (6)]. One patient was treated for bilateral tumors and received 18 Gy in three fractions. The other two patients received 18 Gy in a single fraction. Lesion volume ranged from 3.3 to 42.4 cc. Tumor control was achieved for all four lesions treated, without development of new neurological deficits. Trigeminal Neuralgia: Treatment of intractable pain, including that caused by trigeminal neuralgia (TN), went hand in hand with tumor ablation in the early development of the Gamma Knife (26), and Gamma Knife irradiation of the trigeminal nerve has repeatedly been shown to be effective, with a median time to achieve more than 50% pain relief of about two months (27). A more rapid onset of pain relief was

424 Romanelli et al. Figure 1: A brainstem pilocytic astrocytoma treated with CyberKnife radiosurgery. Doses of 21 Gy were prescribed to the 82% isodose line and delivered in three stages. The green line is the prescription isodose and is tightly adherent to the tumor margin. enced a recurrence of pain at a median of six months (range 2-8 months). Long-term response after a mean follow-up time of 11 months was found in 32 (78%) out of 41 patients. Twenty-one patients (51.2%) experienced numbness after treatment. The hypoesthesia rate was found to be related to the length of the trigeminal nerve treated. These data suggest that CyberKnife SRS results in higher rates of initial pain control and hypoesthesia and a shorter latency of pain relief despite a relatively low dose range. The early onset of pain relief may reflect the improved treatment conformality and dose homogeneity that is possible with the non-isocentric beam targeting of the CyberKnife. Figure 2: The CyberKnife LINAC is mounted on a robotic arm with six joints. One of the flat-panel amorphous silicon detectors can be seen on the side of the treatment table. reported following image-guided SRS for TN by Romanelli and coworkers (10), and a recent multi-institutional study has confirmed these results in a larger cohort of patients (7). Forty-one patients were treated for idiopathic TN. The retrogasserian region of the trigeminal nerve was treated with 60 to 70 Gy prescribed to the 80% isodose or more (see Figure 4). The median latency of pain relief onset after single-stage Cyberknife radiosurgery was seven days. Pain control was ranked as excellent in 36 patients (87.8%) and moderate in two (4.9%), and three patients (7.3%) reported no change. Six (15.8%) of the 38 patients with initial relief experi- Visual Pathway Tumors: Single-stage radiosurgery for lesions close to the optic pathways is frequently associated with loss of vision. Mehta et al. used image-guided SRS to treat 13 patients with tumors adjacent to the anterior visual pathways (28). In their hypofractionation procedure, 20-25 Gy was delivered in 2 to 5 fractions separated by 24 hours. Radiation was successfully limited to the lesions, with very little contacting the optic nerve. At a median follow up of 18 months (range 12 to 54), no tumor progression was observed, four patients had improvement in their vision, and in no case did vision deteriorate. Staged radiosurgery was also reported by Pham and co-workers to produce high rates of tumor control and preservation of visual function (29). In this retrospective study, 20 patients with meningiomas and 14 patients with pituitary adenomas within 2 mm of the optic apparatus were treated with CyberKnife radiosurgery. Several patients had previously been treated with conventional

Image-guided Radiosurgery Synthetic Image A Camera Image A 425 Overlay of Images A Couch Corrections Current Node RGT: 4.9mm ANT: 1.4mm INF: 2.8mm LFT: 2.0 deg Synthetic Image B Camera Image B Overlay of Images B H-DWN: 1.1 deg CW: 0.8 deg Figure 3: Six-dimensional fiducial tracking for spinal radiosurgery with the CyberKnife system. Tracking Mode Fiducial Tracking fractionated radiotherapy (five patients) or subtotal surgical resection (23 patients). Radiosurgery was delivered in 2 to 5 stages to a cumulative mean marginal dose of 20 Gy. Visual testing and clinical examinations were performed before treatment and at follow-up intervals beginning at six months after treatment. Thirty-two out of 34 patients (94%) experienced a reduction or stabilization of tumor size at a mean follow-up of 29 months; in two cases the tumor progressed. Pre- and post-treatment vision was unchanged in 20 patients, improved in ten, and worse in three. In two of the latter three cases, visual deterioration accompanied tumor progression. Overall tumor control was achieved in 94% and pre-surgical vision was preserved in 91% of the patients. Image-guided Radiosurgery in Children: The use of image-guided SRS in children, including infants, has recently been described by Giller and coworkers (30, 31). Infants can suffer devastating cognitive decline due to radiotherapy, but Figure 4: Treatment planning for a patient with idiopathic TN. This patient received 65 Gy prescribed to the 85% isodose in a single stage. The length of the nerve segment treated was approximately 8 mm. The 50% isodose was kept outside the brainstem and the gasserian ganglion.

426 Romanelli et al. conventional radiosurgery was difficult or impossible because of the need to immobilize the head in a frame. Giller et al. showed that image-guided systems (in this case, the CyberKnife) may be used in these patients. They reported on the outcomes of 38 procedures in 21 children harboring unresectable tumors, including pilocytic astrocytomas, anaplastic astrocytomas, ependymomas, medulloblastomas, teratoid/rhabdoid tumors, and craniopharyngiomas. The mean target volume was 10.7 cc, and a mean marginal dose of 18.8 Gy was delivered. Twenty-seven (71%) of the treatments were performed in a single stage. Local control was achieved in the patients with pilocytic and anaplastic astrocytoma, three of the patients with medulloblastoma, and the three with craniopharyngioma (31). Image-guided SRS was also studied in five infants (30); in four of them control of tumor progression was achieved, and in no case were toxic effects observed. Spine Prior to image-guided SRS the only attempts to perform SRS on the spine required the surgical application of a stereotactic frame specifically designed to immobilize the spine and permit tumor localization (32). Tumor progression was controlled in this study. In the first report of spinal radiosurgery with the CyberKnife, Ryu and co-workers demonstrated safety and short-term efficacy for a variety of tumoral and vascular lesions. Fiducials implanted on the spine were used to track the spinal lesion. A more extensive series of reports from Gerstzen et al. has confirmed the safety and efficacy of CyberKnife treatment of the spine (5, 33, 34). In their procedure cervical spine lesions were located and tracked using cranial bony landmarks and lesions lower on the spine were tracked using fiducial bone markers. In their largest series, 125 spinal lesions were treated with a singlefraction radiosurgery. Most of these lesions were metastatic (108 cases), and 59% of them had been treated previously with conventional irradiation. Tumor volumes ranged from 0.3 to 232 cc (mean, 27.8 cc). The mean tumor dose was 14 Gy (range 12-20 Gy) prescribed to the 80% isodose. No acute radiation toxicity or new neurological deficits occurred during the median 18-month follow-up. Axial and radicular pain improved in 74 of 79 patients who were symptomatic before treatment. The authors suggest that CyberKnife radiosurgery may become an important treatment option for a variety of spinal lesions as a primary treatment or as an adjunct to other treatment options. The same group recently reported on CyberKnife treatment of metastatic tumors of the spine following repair of pathological compression fractures using kyphoplasty (35). The combination of these two minimally invasive procedures, which is likely to be a welcome approach to patients dealing with the long-term effects of primary cancer treatment, was safe and effective on shortterm (7-20 months) follow-up. Other Extracranial Lesions By eliminating the need for the stereotactic frame, imageguided SRS introduced the capability to treat any lesion that could be localized and tracked by the image-guided SRS system. The CyberKnife was approved in 2001 by the FDA to treat lesions anywhere in the body, including those that move with respiration. We briefly reviewed above the technical means by which the CyberKnife accomplishes SRS in such lesions. Here were review the outcome literature in this emerging field. Lung: CyberKnife treatment of pulmonary lesions was studied in 23 patients with biopsy-proven lung tumors in a Phase I trial by Whyte and coworkers (11). Fifteen patients had primary lung tumors and eight had metastatic tumors. Tumor size ranged from 1 to 5 cm. After CT-guided percutaneous placement of 2-4 small metal fiducials into the tumor, the patients received 15 Gy in a single fraction. The treatment was well tolerated despite some complications related to the implantation of fiducials. Radiographic progression was found only in two patients in a follow-up period ranging from 1 to 26 months (mean, 7 months). Hopefully this important experience will be updated soon. In particular, evidence is accumulating that shows that doses much higher than those used by Whyte et al. can result in excellent tumor control with few side effects if the radiation is delivered accurately (36-39). CyberKnife users are exploring higher dose, hypofractionation regimens for lung tumors. Pancreas: Romanelli et al. reported preliminary results of CyberKnife radiosurgery for pancreatic tumors (9). Twelve patients with pancreatic adenocarcinomas were treated with 15, 20, or 25 Gy to the primary tumor in a single fraction. Preliminary analysis did not reveal any significant acute toxicity. Although this study was not designed to evaluate efficacy, the majority of patients with an elevated CA 19-9 (a marker for pancreatic cancer) prior to treatment had a decrease in CA 19-9 following treatment. In addition, all patients with pain prior to treatment experienced an improvement. In Phase I and II trials conducted by Koong and associates (40, 41), patients with advanced adenocarcinoma were treated with CyberKnife SRS. In the Phase I study 15 patients received 15, 20, or 25 Gy. Local control of tumor progression was achieved with a dose of 25 Gy, without serious gastrointestinal toxicity. In the Phase II study of 16 patients, a 25 Gy boost of CyberKnife SRS followed treatment with 5-fluorouracil (5-FU) and intensity-modulated radiotherapy (IMRT). Grade 3 toxicity was experienced by two patients. Although local progression was controlled in 15/16 patients, the combined therapy did not affect overall survival (patients died from distant progression), and toxicity was greater than with SRS alone. The authors reported that their current practice is

Image-guided Radiosurgery 427 to replace IMRT with chemotherapy using gemcitabine and image-guided SRS for local tumor control. Other Targets: In a recent report of outcomes in 44 patients of image-guided SRS for a variety of benign lesions in several extracranial sites, Bhatnagar et al. (42) treated with a median dose of 16 Gy to the 80% isodose line. Their series included treatment of three orbital lesions, eight neck lesions, and one in the foramen magnum. They achieved excellent tumor control rates (96%) and symptom relief (78%) while sparing sensitive structures such as the spinal cord. Research is underway to determine the efficacy of imageguided SRS for treatment of lesions at other sites, including the prostate and the kidney. A recent study showed that CyberKnife treatment plans resulted in superior dosevolume histograms compared to IMRT, both for coverage of the prostate lesion and for sparing of surrounding tissue (43). In addition, using a porcine model it was determined that the CyberKnife produced highly circumscribed fibrotic lesions at predetermined renal locations. This finding suggests that image-guided SRS may be useful for the treatment of renal cell carcinoma, which is difficult for traditional radiotherapy due to radiosensitivity of surrounding tissues (44). Because the technology to perform extracranial radiosurgery is of such recent vintage, published clinical studies are still few in number. However, if one accepts the logic of extrapolating from past experience with brain radiosurgery, the concept of minimally invasive ablation for lesions in the chest, pelvis, and abdomen would seem likely to be of great potential value. In fact, radiosurgical destruction of select non-neoplastic targets may one day play a role in treating disorders ranging from intractable facet syndrome to atrial fibrillation. Of course, caution in the extension of radiation technology to new applications must always be exercised; whether these concepts will prove to be idle fantasy or a new surgical realm will need to be hammered out in clinical studies over the next decade. Conclusions Although image-guided SRS is still in its infancy, and the number of outcome studies in peer-reviewed journals is modest, it would, nevertheless, appear to have a promising future. While radiosurgery in the past was essentially restricted to the treatment of lesions within the skull, now this technology can be used to treat lesions anywhere in the body. 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