147

Abstract

We describe the rationale for fractionated radio-surgery, and summarize the 4Rs of radiobiology: repair, reassortment, recruitment or repopulation and reoxygenation. Biological modeling using the linear-quadratic formalism is also explained with special reference to spinal cord tolerance dose. Our radiosurgery technique is documented in terms of fiducials, simulation, treatment planning, track-ing, treatment and dose-fractionation selection. The next chapter details some of our clinical results and reports on clinical measures of response, such as pain relief and quality of life.

Introduction

The CyberKnife® is a robotic linear accelerator that is guided with sub-millimeter accuracy in real-time by overhead X-ray imaging. Together with inverse

treatment planning algorithms, this permits high radiation doses to be administered to lesions of the spine and para-spinal structures without exceeding dose tolerances of critical structures. While many potential applications are currently under investiga-tion, the treatment of benign and malignant tumors of the spine and spinal cord remain the primary indications for spinal radiosurgery. At Georgetown University Hospital, we have successfully used the CyberKnife for treating pain and preserving quality of life in patients with primary lesions of the spine and spinal cord.

Epidemiology

Malignancies of the spine may be primary or meta-static, but metastatic tumors are far more common and, for the most part, are extradural. Table sum-marizes the incidence of primary bone tumors in

CHA P T E R

15CyberKnife Radiosurgery for Spinal Tumors with Emphasis on Tumor Biology & Treatment Technique

Fraser C. Henderson

Gregory J. Gagnon

Donald A. McRae

4 8 PA RT I I I : Central Nervous System Applications

selected populations from the most recent IARC publication on Cancer Incidence in Five Continents.1 The data is for codes C40–C41, 2 which are defined as ‘malignant neoplasms of bone and articular carti-lage’. C41.2, which is for the vertebral column (spinal column, spine & vertebra), is not recorded sepa-rately. This incidence data provides an estimate of the order of magnitude of the incidence of these tumors. Overall estimates for the USA for 2004 3 for new pri-mary disease cases and deaths, for the sites ‘bones & joints’, are for males ,230 & 720 and for females ,20 & 580, respectively.

However, an estimate of the incidence of metastatic spinal tumors is much higher: approximately 00,000 per year. Of these, approximately 20% are epidural in location, and should be considered for surgical resection. Certain primaries are osteotropic, with a high affinity for bone and spine metastases, includ-ing breast, prostate, renal and thyroid. Intradural metastases are exceptional, involving less than % of patients with metastatic disease.

Vertebral body primary tumors include chordoma, chondrosarcoma and osteogenic sarcoma. Some benign primary tumors, such as aneurysmal bone cyst, osteoblastoma and giant cell tumor, may also exhibit malignant characteristics. Intradural primary tumors include meningioma, schwannoma, and neu-rofibroma or their malignant counterparts. In order of incidence, the intramedullary tumors include: ependymoma (most common in adults), astrocyto-mas (most common in children), hemangioblastoma (Von Hippel-Landau disease) and, rarely, glioblas-toma, ganglioma or oligodendroglioma.

Pathology

Compromise of the spine results in significant func-tional impairment and poor quality of life. Pain is the most common symptom of a spinal tumor and results from compression of the spinal cord or nerve roots, gross or ‘micro-instability’, loss of alignment or excessive kyphosis or scoliosis, or internal pressure of the tumor on the periosteum. Also, the weakening of bone in the spine can cause pain without any sem-blance of instability.

Surgery for treatment of spinal malignancy car-ries significant risks to those patients who suffer from the important impairments noted above, and conventional external beam irradiation can result in loss of bone structure and significant reduction in hematopoeitic potential. These risks can be less-

Table . Incidence of primary bone cancers in males and females per 00,000 male population and per 00,000 female population for selected populations.

Age-standardized incidence rates (ASR) are quoted and not crude (uncorrected for age structure in the population), so that a direct comparison can be made among the populations. The ‘Number’ of cases is the total number of cancer registrations, usually for the five-year period 993-997, upon which the ASR rates (which are average annual rates) are based. WhiteNH : non-Hispanic white.

Population Males FemalesNumber ASR Number ASR

China, Shanghai 327 1.4 297 1.3

USA, New York State, White 481 1.3 414 1.0

USA, New Jersey, White 196 1.2 159 0.9

Canada 826 1.1 693 0.8

USA, Los Angeles, WhiteNH 107 1.1 100 1.0

Denmark 141 1.0 111 0.8

The Netherlands 383 1.0 352 0.9

UK, England 1090 0.8 857 0.6

CH A PT ER 15 : CyberKnife Radiosurgery for Spinal Tumors with Emphasis on Tumor Biology & Treatment Technique 49

ened with stereotactic fractionating of the dose and multi-directional and non-coplanar treatment plans. Within this context, we believe that the CyberKnife is an ideal therapeutic tool for treating neoplasms of the spine.

Several aspects of spinal metastases are notable: () Bone pain is commonly associated with metasta-ses and is the most common pain syndrome requiring treatment in cancer patients. (2) Patients with bone metastases typically have more severe symptoms than patients with visceral metastases. (3) Survival is typi-cally longer in patients with bone metastases than those with visceral metastases. Patients with bone metasta-ses become symptomatic earlier and have symptoms for a longer period of time. (4) Complications relat-ing to metastatic involvement of the spine occur in one-third of patients. (5) Complications produce high morbidity. (6) Treatment options for the spine are limited because of the functional requirements of the spine and the presence of the significant internal or adjoining critical structures.

Rationale for Radiosurgery

Radiation therapy is the mainstay in the treatment of metastatic disease of the spine. Preliminary experience with the CyberKnife suggests that primary intradural extramedullary and even intramedullary tumors of the spinal cord are also amenable to radiosurgery.

Radiosurgery of the spine should be considered in the light of the following benefits: () It preserves overall hematopoietic capacity. (2) It allows for a more rapid treatment, thus providing a ‘therapeutic window’ in which the patient can pursue other treatment modalities, such as chemotherapy. (3) Radiosurgical treatment does not proscribe chemotherapy. Patients can receive many forms of chemotherapy simultane-ously with radiosurgical treatment. (4) We believe that patients can more safely undergo open surgery

after stereotactic radiosurgery than after conven-tional external beam irradiation, because of the high conformality of the irradiation. (5) Stereotactic radio-surgery allows treatment with very high levels of irradiation, while minimizing exposure to surround-ing healthy tissues.

However, though stereotactic irradiation is effec-tive in controlling tumors, potential side effects (e.g., radiation myelitis) will limit the achievable doses and lessen the efficacy of treatment in previously irradi-ated areas.

Rationale for Fractionating Radiosurgery

Pre-clinical and in vitro studies have clearly demon-strated the effectiveness of single-fraction irradiation in cell-killing 4. Results from the radiosurgery literature related to the Gamma Knife ,5, 6 or linear accelerator-based radiosurgery, 7, 8 have also confirmed the clinical efficacy of single-fraction treatment.

A large amount of clinical experience attests to the efficacy and relatively low morbidity of sin-gle-dose treatments when delivered within the brain; this can be considered an established ther-apy. However, at least to some extent, the rationale for single fractionation is driven by the necessity of placing a rigid frame on the patient. Fractionating radiosurgery with a rigid frame is burdensome to both patient and physician. However, the CyberKnife is a robotic, image-guided radiosurgical system that is not constrained by the presence of an external frame, and multiple treatment fractions pose no significant difficulties.

We are interested in hypofractionation, or the delivery of radiation with a small number of large dose fractions, typically 2–5, and not with prolonged courses of radiation therapy typically employed in the practice of radiation oncology. It is our contention that hypofractionated treatments can capture some

5 0 PA RT I I I : Central Nervous System Applications

or most of the benefits of ablative single-dose frac-tions conventionally employed for radiosurgery, with the radiobiological benefits of modest fractionation.

We have chosen to fractionate most treatment plans to minimize late effects of critical tissues and to maximize tumor control probability. Our treat-ment strategy is based on six principles, four of which are motivated by radiobiological considerations and two of which are motivated by dose-delivery considerations.

Repair

It is a commonly held belief that normal cells will more faithfully undergo repair of sublethal and potentially lethal radiation injury than tumor cells. This has been demonstrated by split-dose experi-ments 9 and regrowth delay experiments, 10 although there remains some controversy regarding the impact of radiation repair differences in tumor and normal tissue response.

By fractionating, this inherent, although not uni-versal, repair difference can be exploited by two possible mechanisms: () The lower radiation doses associated with fractionation are less likely to over-whelm the repair capacity of normal cells but are more likely to do so in tumor cells, creating a dif-ferential cell-killing. Fractionation can exploit the difference in the tumor and normal tissue thresholds that separate sublethal and lethal radiation damage. (2) If repair between fractions is incomplete, a course of fractionation could result in an accumulation of radiation damage in the incompletely repairing tumor clones, eventually causing enough damage to lead to their destruction.

Reassortment

Staging irradiation may promote cell reassortment within the cell cycle. Ionizing radiation causes cells

to pause before undergoing mitosis, as a result of molecular checkpoints interfering ultimately with spindle formation. Cells that have been irradiated and that have a functioning checkpoint mechanism will pause in G2/M. Presumably, this checkpoint exists to allow cells time to repair chromosomal damage prior to mitosis. A second checkpoint exists in G1, presum-ably to allow radiation repair prior to the energetically costly and potentially mutation-prone S-phase of the cell cycle. In vitro studies of synchronized cells have shown a 50-fold difference in radiation sensitivity of tumor cells held up in the late G2 phase, when com-pared to cells in the late S phase.11

Cells in G1 arrest are also more sensitive to sub-sequent doses of radiation, although not as sensitive as G2/M cells. Cell cycle reassortment is not a sig-nificant factor when large single doses of irradiation are used, but can become significant when fraction-ation is employed because cells tend to accumulate in these sensitive phases of the cell cycle, 12 where they can be more effectively eradicated with subsequent radiation doses.

Recruitment

Cells that are not in the cell cycle (those in G0) will not be manipulated by redistribution in this man-ner, although fractionation can allow recruitment of cells into the cell cycle. That recruitment into the cell cycle as a consequence of radiation has been known for some time, 13 although the importance of this fac-tor in determining radiation curability is unclear. Quiescent cells are also considered to have a capac-ity for potentially lethal damage repair, which is less evident in cycling cells. Although there may be a det-rimental effect to recruitment into the cell cycle, with possible repopulation of tumor cells, recruitment also allows manipulation of radiation sensitivity through the cell cycle.

CH A PT ER 15 : CyberKnife Radiosurgery for Spinal Tumors with Emphasis on Tumor Biology & Treatment Technique 5

Reoxygenation

Fractionating treatment may enhance cell-kill through tissue reoxygenation. Abundant evidence exists showing that hypoxic cells are significantly more resistant to irradiation than are euoxic cells.14 Faulty angiogenesis in neoplasms results in a variable component of tissue hypoxia, and therefore resistance to irradiation. Experimentally, single fractions of 5 Gy have been shown to increase oxygen enhancement through increased tissue perfusion over the course of several days.15 This tissue reoxygenation results in a dramatic increase in sensitivity to radiation 16 with subsequent fractions.

Minimizing Random Errors

A theoretical advantage of treating patients using multiple fractions is that of averaging random errors. Errors of accuracy or precision are an unavoidable aspect of any measurement or treatment system. They can be minimized but never completely eliminated. Errors can be considered either systematic or ran-dom, where systematic errors represent a correctable inaccuracy in the system and random errors repre-sent the normal, non-systematic errors that follow a Gaussian distribution.

Despite the highly accurate nature of targeting with the CyberKnife and the correction of systematic errors, small random errors are unavoidable. The potential targeting error of the CyberKnife system has previ-ously been reported as approximately .3 mm.17 Our unpublished data with ‘end-to-end’ phantom studies shows our system to be accurate to within mm. This includes errors in CT image acquisition, target delin-eation, fiducial localization and robotic precision.

When delivering single-fraction radiosurgery, an error in treatment is more likely to be in one direction, with a deviation according to a Gaussian probability distribution on all three axes. Since the component

of this error is truly random, there is little probability that a subsequent treatment will have a displacement in the same direction in space, and of the same mag-nitude. Fractionating will therefore tend to ‘average out’ errors in space over multiple treatments, thereby lessening the error to any particular voxel either within the target or outside. Of course, unlike other radiosurgery systems, this ‘averaging out’ occurs to an extent even in single-fraction CyberKnife treatments, because of the continued imaging and alignment cor-rections performed during treatment.

Treatment Length

Fractionating permits shorter treatment times. Single long treatments may require two hours or more of irradiation time. This imposes difficulties on the patient in terms of pain and also difficulties for the radiation oncologist, who has to contend with fre-quent movements by the patient and the necessity for frequent robot corrections.

Biological Modeling

Irradiation of the spine, even radiosurgery, must be carefully considered in terms of spinal cord tolerance, as scatter-dose to the cord is inevitable. Significant inter-patient variability is evident in studies of normal tissue tolerance. This limits the utility of any predictive model. Nevertheless, some models have been devel-oped that can serve as a basis for selection of dose and volume-related tolerances of the spinal cord. These can be roughly divided into () power-law models and (2) linear-quadratic models. At Georgetown University Hospital we use the linear-quadratic method for most determinations of dose and spinal cord tolerance.

Linear-Quadratic Model

Data has accumulated that chromosomal aberra-tions, cell-killing, mutations and tumor induction

5 2 PA RT I I I : Central Nervous System Applications

follow a response to dose with both linear and qua-dratic terms. Biophysical studies of radiation damage on microscopic scales have led to the discovery of complex patterns of energy deposition in DNA. With commonly used photon energies the preponderance of damage is sparse, although there is a component of dense clustering of ionization near the track ends of secondary electrons. The dense clustering can be described by an alpha component and the sparsely ionizing component by the beta component, (although this is only one of several possible physical interpreta-tions of the linear quadratic model.)18

The linear-quadratic formalism therefore has a biophysical underpinning and fits the clinical data reasonably well. Briefly, radiation effect, E, is linearly and quadratically dependent on dose:

E(D) = αD + βD2

where α is the single-hit damage parameter, β is the multi-hit damage parameter specific to a tumor or normal tissue and D is the total dose. Some values of α and β have been determined, but it is simpler to determine the α/β ratio and these values are avail-able for normal tissue and tumor. Typically, the α/β of tumor is in the range 6–0 Gy-1 and for normal tissue α/β is in the range 2–4 Gy-1.

It is important to note that the linear-quadratic formalism also has shortcomings. There are uncer-tainties about its validity at low (< 2 Gy) fractions,9 there are uncertainties about its validity at high (> 6 Gy) fractions 19 and the determination of the α/β value is fraught with statistical uncertainties.

Biologically Effective Dose

As a rough guide for comparing spinal cord doses among patients, the linear-quadratic formula has been used to convert the physical dose to a biologi-cally effective dose (BED) at 2 Gy: using α/β = 2. for

the spinal cord. The BED formalism holds that the radiation effect, E, is related to the dose in a linear and quadratic fashion, as stated earlier:

E = αD + βD2

In fractionated treatment, the effect E, becomes:

E = n(αd + βd2)

where n is the fraction number and d is the dose per fraction. Dividing by the α term leads to an expres-sion for the BED :

E = BED=nd(+ d )α α/β

In general, the α and β terms are not known, but the ratio α/β is often known for the tumor or the nor-mal tissue in question. The BED is not easily related to effect, but it has the important qualities that BEDs from different treatment regimens to the same region are additive and that regimens with equivalent BEDs are considered to have equivalent effects.

Spinal Cord Tolerance

Equating the BED from one treatment regimen to the BED of another treatment regimen with known out-comes allows one, with some assurance, to develop dose-fraction regimens outside those currently prac-ticed in radiation oncology. Tumor repopulation is ignored in this formulation and full interfraction repair of sublethal damage is assumed. Using stan-dard fractionation regimens (i.e., .8–2.0 Gy), spinal cord tolerance would be considered by most radiation oncologists to be 45–50 Gy.

The spinal cord tolerance should also be consid-ered in terms of spinal cord anatomy and blood flow. Blood supply to the spinal cord is transmitted through major medullary feeders entering along the ventral spinal roots, and smaller radicular arterial branches

CH A PT ER 15 : CyberKnife Radiosurgery for Spinal Tumors with Emphasis on Tumor Biology & Treatment Technique 53

entering through the dorsal roots. The cervical cord is fed by the anterior spinal artery at C1, and three major medullary feeders entering the cord at C3, C5 and C8. The thoracic cord, on the other hand, is sup-plied more tenuously by a single artery: the artery of Adamkiewicz, the location of which is variable and therefore difficult to avoid.

Presumably as a consequence of blood supply and relative proportion of white to grey matter, the cervi-cal cord has a tolerance of 50 Gy, and the thoracic cord, with its tenuous blood supply, has a lower tolerance, of the order of 40–45 Gy. Another consideration in assigning risk of radiation myelitis relates to the neu-roanatomy of the cord at each level. Radiation injury to the dorsal half of the cord, including the cortico-spinal tracts and the dorsal columns, is in our opinion of more consequence than injury to the anterior part of the cord, which contains primarily grey matter and spinothalamic tracts.

Radiosurgery Technique

Fiducials

Fiducials were implanted in the spine for image-guid-ance and targeting by the CyberKnife’s dynamic tracking system, Figure . In the T, L and S spine one alternative was to use knurled markers (Med-Tec, Orange City, Iowa), which were placed percutaneously into spinal bone by an interventional radiologist in a relatively simple outpatient procedure. Alternatively, stainless steel surgical screws (Accuray, Inc.) were placed during surgery by the neurosurgeon (e.g., for C3–C7 spine).

Full 6-dimensional tracking (3-translational and 3-rotational directions) requires the non-colinear placement of at least three fiducials. Each fiducial must be independently visible in the 45-degree lat-eral oblique views used for imaging. Supporting

Figure . Examples of fiducials as seen in tracking images (top). Depite the titanium hardware, they are still visible (bottom).

5 4 PA RT I I I : Central Nervous System Applications

hardware should not overlay the fiducials in the 45-degree projection.

The fiducials were usually placed within 6 cm of the lesion, but occasionally up to 0 cm when medical circumstances required. Generally, simulation was formed 48 hours after percutaneous fiducial place-ment, and at least –2 weeks after surgery. This was to allow resolution of tissue swelling and comfort-able, reproducible patient positioning. For lesions in C1–C2, even with some extension into C3, a thermo-plastic head mask and cranial tracking were used in place of fiducials.

Simulation

Patients were placed supine in a vacuum bag immo-bilizer with head and knee support. In the cervical spine, intervertebral movement was minimized by use of a disposable neck-brace. A CT scan was obtained using 300 slices (the maximum currently allowable in the planning system) with mm thickness and spac-ing, centered on the fiducial array, as observed in the

scout films. The mm slice thickness allowed for the maximum resolution of the fiducial locations and the 300 slices for the maximum surface area for beam entry for planning and treatment. When desired, MRI scans were acquired using either a MPRAGE or VIBE sequence, and fused with the CT scans.

Treatment Planning

The neurosurgeon performed contouring of the tumor, spinal cord (not spinal canal) and other critical struc-tures. The radiation oncologist prescribed the dose and number of fractions, (i.e., the dose-fractionation schedule) and tolerances for the normal tissues. For planning, manual dose constraint points, lines and simulated critical structure contours were utilized to improve the dose distribution and dose-volume histo-grams within the treatment region. Inverse treatment planning was enhanced by altering collimator size(s), minimum and maximum target doses, maximum critical tissue constraints and the maximum number of linear accelerator monitor units per beam.

Tum

or v

olum

e (c

c)

1

10

100

1000

Individual patients

Figure 2. Tumor volume distribution.

CH A PT ER 15 : CyberKnife Radiosurgery for Spinal Tumors with Emphasis on Tumor Biology & Treatment Technique 55

Figure 3. Examples of two tumors treated using CyberKnife SRS: Thoracic spine (T5): the tumor lies within

3 mm of the cord, wrapping around 3/4 quadrants, 29 mm length, previous irradiation 17 x 1.8 Gy = 30.6 Gy (left). Cervical spine (C2-C4): the tumor lies within 1 mm of the spinal cord, wrapping around 2/4 quadrants of the cord, 59 mm length, previous irradiation 23 x 1.8 Gy = 41.4 Gy (right).

Figure 4. Isodose distributions for the tumors in Figure 3. 80% isodose line gave 83% coverage. Tumor volume 38.7 cc, 12.5 mm collimator, 242 beams. New Conformality Index (NCI) = 1.91. The light blue isodose line is 30% and the orange line 80%. NCI = TV * PIV/TIV 2 where TV is the target volume, PIV is the prescription volume and TIV is the volume of target covered by the prescription isodose volume (left). 80% isodose line gave 86% coverage. 10 mm collimator, 325 beams, NCI = 1.74, the white isodose line is 40% and the orange line is 80%, (right).

5 6 PA RT I I I : Central Nervous System Applications

The range of tumor volumes we encountered in our first year of CyberKnife use was great and exceeded three orders of magnitude, Figure 2. Examples of two tumors treated by SRS are shown in Figure 3 with their respective isodose distributions seen in Figure 4.

Tracking

The dynamic tracking system compares real-time orthogonal X-ray views of the fiducial array with digitally reconstructed radiographs (DRRs) that are derived from the treatment planning CT. The differ-ence between the fiducial array positions was reported in 3-translational and 3-rotational coordinates.

Initial patient set-up was accomplished with com-bined in-room manual patient positioning and the use of an automated couch system. Once it is known that the reported differences are within a specified range, the robot corrects for any remaining and subsequent translational and rotational differences reported to it by the dynamic tracking system. During set-up and treat-ment, anatomical information was visually compared between the real-time images and the DRRs to con-firm the positioning and targeting. Images for tracking could be obtained before every beam or, if a patient was judged quiescent, at less frequent intervals.

When there were insufficient fiducials available, such as when some fiducials were covered by other metallic hardware, anatomical features were relied on for visual rotational adjustments. Only translational correction information was available.

Treatment

Patients were treated daily, one fraction per day and offered mild sedation (Ativan) during the treatment. Intravenous sedation and full anesthesia have been successfully used for patients who could not attain or remain in position because of pain or other reasons. Special anesthesia procedures were adopted, and induction was usually completed within 20 minutes.

Figure 5. Patient with an intradural meningioma. Sagittal view of a T2-weighted MRI shows severe cord compression at T11 (top). The treatment plan shows the spinal cord contoured in green and compressed anteriorly against the vertebrae. The patient received 5 x 5 Gy to the 80% isodose line (bottom).

CH A PT ER 15 : CyberKnife Radiosurgery for Spinal Tumors with Emphasis on Tumor Biology & Treatment Technique 57

Dose Fractionation Selection

A total of –5 fractions were delivered with doses of 4–8 Gy per fraction, Table 2, and 2–6 Gy were deliv-ered for single-fraction treatments. Table provides examples of some of the dose prescription guidelines used to date at Georgetown University Hospital. These doses were prescribed to the periphery of the lesion. Treatment plans and isodoses were selected and prescribed individually for each patient, with no minimum isodose or tumor coverage imposed.

Case Histories Illustrative of Effective Pain Relief

Case 1: Intradural Meningioma

This patient was an elderly woman, wheelchair-bound because of pain (00/00) and paraparesis. MRI dem-onstrated a meningioma severely compressing the spine at the level of T11, Figure 5. The patient was a high cardiac risk and therefore not suitable for sur-gery. The treatment plan required isodose contours around the tumor with a very rapid fall-off. Within one month following irradiation, this patient’s pain decreased from 00/00 to 0/00. Although there was no visible decrease in size of the tumor, this woman was able to walk independently.

Case 2: Presacral Leiomyosarcoma

This male patient was not a candidate for open surgery, Figure 6. He had previously undergone external beam radiation therapy to his tolerance level but his pain level remained at 00/00. He was given a further 6 Gy in three stages to the 75% isodose line, using the CyberKnife. His pain level decreased to 0/00 within one month of SRS treatment. The tumor volume, initially 350 cc, was not visible at three months follow-up.

Table 2. Examples of dose fractionation schedules.

Dose per fraction

(Gy)Fraction number

Examples where a given dose fractionation schedule is used

8 3

Untreated spine (metastatic from breast, thyroid, colon, renal, bladder, melanoma, non-small cell lung, small cell lung).

7 5Unresected chordoma, chondrosarcoma, osteogenic sarcoma.

7 4Resected chordoma, chondrosarcoma, osteogenic sarcoma.

7 3

Retreatment of spinal lesions after external beam radiation therapy(metastatic renal, non-small cell lung, small cell lung, breast, giant cell, melanoma, colon, cervix, bladder).

5 5

Microscopic disease of resistant histology (e.g., renal, prostate, melanoma, adenocarcinoma, adenoid cystic).Benign spinal lesions (neuroma, schwannoma, meningioma, hemangioma, ependymoma).Gross disease of less resistant histology (e.g., leukemia, lymphoma).

5 8 PA RT I I I : Central Nervous System Applications

Discussion

CyberKnife Limitations

Placement of fiducials is not difficult, but requires localization with fluoroscopy and a sterile field. An experienced surgeon takes approximately five minutes to place each fiducial. General anesthesia is necessary for placing screws in the cervical spine. We prefer a standard anterior (Cloward) exposure. Others prefer to use the skull for stereotactic localization in the cer-vical spine.20

Xsight™, a fiducial-less spine tracking system, uses bone anatomical contours and image deformation software to track the semi-rigid anatomy of the spine. This system obviates the need for placing fiducials, and has been employed at Georgetown University Hospital since early 2005.

Unplanned down time during our two-year period of use was minimal: three days were lost in the course of the first year for general maintenance and for repair of the X-ray imaging devices. At first, several patients with complex spinal tumors required substantial time for treatment. However, treatment times have now been reduced by half with the introduction of Express treatment software (Accuray, Inc.), which speeds treatment delivery, and the Axum remote-controlled treatment couch (Accuray, Inc.), which allows rapid patient positioning.

Several patient characteristics militate against use of the CyberKnife. Excessive obesity causes difficul-ties in registration of fiducials in the lower cervical, thoracic and lumbar regions. Psychosis can poten-tially cause set-up delays, missed treatments and delays during treatment. Patients with extreme pain or an inability to lie supine may require sedation and monitoring by an anesthesiologist. Severe pulmonary disorders, especially those associated with frequent coughing, can result in excessive movement during

Figure 6. Patient with a presacral leiomyosarcoma (top). The leiomyosarcoma measured 350 cc. After CyberKnife SRS no tumor was evident, (bottom).

CH A PT ER 15 : CyberKnife Radiosurgery for Spinal Tumors with Emphasis on Tumor Biology & Treatment Technique 59

treatments and frequent delays. In our first year of operation, we excluded two patients from CyberKnife treatment because of obesity, and one because of a pulmonary disorder.

Patients with sacral tumors at first presented difficulty in positioning on the treatment table. Recognizing that some patients breached the theo-retical safe zone (defined as a patient too close to the robot and therefore risking a collision), we posi-tioned these patients feet first (toward the robot) on the treatment table. This entailed performing treat-ment planning with the patient positioned feet first, which has the potential for left-right confusion on the imaging study. We currently perform all treatments of the sacral and lumbar spine in this ‘reverse’ posi-tion, and strongly encourage all other users to adopt this strategy.

Adverse Effects

Complications associated with radiosurgery in our patients were self-limited and mild in almost all cases. There was one patient who developed breakdown at a surgical site, and required surgery for debridement and re-closure of the wound. Otherwise, complications potentially attributable to radiosurgery included only increased nocturia (one patient), mild esophagitis or dysphagia (three patients), paresthesias (one patient), fatigue (one patient), transient diarrhea (one patient) and hoarseness (one patient). There was no evidence of myelitis or neurologic damage in any patient as a result of radiosurgery.

Conclusions

Spinal robotic radiosurgery is efficient, well tolerated, safe and effective in terms of pain palliation and quality of life. Limited long-term follow-up data restricts conclusions on long-term benefits or impact on survival.

References. Parkin DM, Whelan SL, Ferlay J et al, eds. Cancer

Incidence in Five Continents Volume VIII. IARC Scientific Publications No. 5. Lyon: International Agency for research on Cancer, 2003.

2. Percy C, (Surveillance Program, Division of Cancer Prevention & Control, National Cancer Institute). ICD-9 to ICD-0 Neoplasms. NIH Publication No. 95–400. Bethesda: National Cancer Institute, 995.

3. American Cancer Society. Cancer Facts & Figures 2004. Atlanta: ACS, 2004.

4. Brenner DJ, Martel MK, Hall EJ. Fractionated regimens for stereotactic radiotherapy of recurrent tumors in the brain. Int J Radiat Oncol Biol Phys 99;2:89–824.

5. Feigl GC, Bonelli CM, Berghold A et al. Effects of Gamma Knife radiosurgery of pituitary adenomas on pituitary function. J Neurosurg 2002;97 suppl 5:45–42.

6. Stafford SL, Pollock BE, Leavitt JA et al. A study of the irradiation tolerance of the optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol Phys 2003;55:77–8.

7. Friedman WA, Foote KD. Linear accelerator radiosur-gery in the management of brain tumours: review. Ann Med 2000;32:64–80.

8. Naoi Y, Cho N, Miyauchi T et al. Usefulness and problems of stereotactic radiosurgery using a linear accelerator. Radiat Med 996;4:25–29.

9. Phillips TL. Split-dose recovery in euoxic and hypoxic normal and tumor cells. Radiology 972;05:27–34.

0. Denekamp J, Stewart FA. Evidence for repair capacity in mouse tumors relative to skin. Int J Radiat Oncol Biol Phys 979;5:2003–200.

. Sinclair WK. Cyclic X-ray responses in mammalian cells in vitro. Radiat Res 968;33:620–643.

2. Taylor E. Radiosensitivity and cell age. In: Hall E, ed. Radiobiology for the Radiologist. Philadelphia: 5th edn. Lippincott, Williams & Wilkins, 2000, 5–66.

6 0 PA RT I I I : Central Nervous System Applications

3. Denekamp J, Ball MM, Fowler JF. Recovery and repopulation in mouse skin as a function of time after X-irradiation. Radiat Res 969;37:36–370.

4. Cuisnier O, Serduc R, Lavieille JP et al. Chronic hypoxia protects against gamma irradiation induced apoptosis by inducing bcl-2 up-regulation and inhibiting mito-chondrial translocation and conformational change of bax protein. Int J Oncol 2003;23:033–04.

5. Howes AE. An estimation of changes in the proportions and absolute numbers of hypoxic cells after irradiation of transplanted C3H mouse mammary tumours. Br J Radiol 969;42:44–447.

6. Palcic B, Skarsgard LD. Reduced oxygen enhancement ratio at low doses of ionizing radiation. Radiat Res 984;00:328–339.

7. Chang SD, Main W, Martin DP et al. An analysis of the accuracy of the CyberKnife: a robotic frame-less stereotactic radiosurgery system. Neurosurgery 2003;52:40–47.

8. Goodhead DT. The initial physical damage produced by ionizing radiation. Int J Radiat Biol 989;56:623–634.

9. Withers HR, Taylor JM. Volume effect in spinal cord. Br J Radiol 988;6:973–975.

20. Ma L, Xia P, Verhey LJ, Boyer AL. A dosimetric com-parison of fan-beam intensity modulated radiotherapy with Gamma Knife stereotactic radiosurgery for treat-ing intermediate intracranial lesions. Int J Radiat Oncol Biol Phys 999;45:325–330.