Stereotactic Radiosurgery for Tumors of the Spine

16 Stereotactic Radiosurgery for Tumors of the Spine

Maha Saada Jawad and Daniel K. Fahim

Abstract

Stereotactic radiosurgery for tumors of the spine has emerged as a safe and effective method for the primary treatment of localized spinal tumors or as salvage treatment in patients who have undergone prior irradiation to the spine. Treatment can be delivered using linear accelerator–based radiation treatment, incorporating the use of image-guided radiotherapy. Treatment planning using intensity-modulated radiation therapy or volumetric modulated arc therapy allows for delivery of highly conformal ablative tumor doses, while minimizing dose to surrounding organs at risk. Delayed treatment–related toxicity can include vertebral compression fractures or radiation-induced myelopathy. Appropriate patient and tumor selection, as well as careful attention to dose-volume data, is essential in minimizing the risks of these toxicities. Several studies have yielded favorable results with respect to tumor control and pain relief following stereotactic spinal radiosurgery, making it a favorable option for well-selected spinal tumors.

Keywords: radiosurgery, stereotactic radiosurgery, spine tumors, radiation, treatment planning

16.1 Introduction

Stereotactic radiosurgery (SRS) of the spine has emerged as a safe and effective method of primary treatment for localized spinal tumors, as well as a salvage option in patients who have received prior irradiation. The spinal SRS technique was developed by merging concepts and technology from intracranial SRS, frameless stereotaxis, and modern radiotherapy techniques. Intracranial SRS was first used by a neurosurgeon, Lars Leksell, in 1951,¹ who introduced the concept of delivering a single high dose of radiation to a stereotactically defined target. Improvements in machine accuracy, multiplanar imaging, and computer speed have led to exponential growth in the use and effectiveness of intracranial SRS since that time, most commonly Gamma Knife radiosurgery (although other systems are also available).²^,³^,⁴^,⁵

Many years of careful study of intracranial SRS were required to obtain even a rudimentary understanding of dose tolerance of critical organs such as the optic apparatus, trigeminal and facial nerves, brainstem, and motor cortex.⁶^,⁷ Clear understanding of dose-volume toxicity also required the study of large numbers of treated patients.⁸^,⁹ The dose–response relationships of benign and malignant tumors, as well as other benign conditions such as arteriovenous malformations and trigeminal neuralgia, also required extensive study, with the optimal total dose and dose fractionation still subjects for debate. However, certain basic information is now widely accepted, such as the tumor response and complication rates for single-dose treatment of acoustic neuromas and the high sensitivity to dose of sensory cranial nerves.¹⁰^,¹¹^,¹²^,¹³

Taking the lessons learned from intracranial SRS, the application of extracranial SRS first required the advancement of other methodologies. Frameless stereotaxis was originally developed for real-time intraoperative guidance.¹⁴^,¹⁵ More recently, this technique has been introduced into the radiation suite to allow real-time tracking for extracranial stereotactic targets.¹⁶ Simultaneously, advancements in the delivery of radiation therapy including three-dimensional treatment planning, mini-multileaf collimators, intensity-modulated radiation therapy (IMRT), and volumetric modulated arc therapy (VMAT) enabled dose escalation with precise targeting and conformality.²^,³^,⁴^,⁵ Additionally, the increasing use of image-guided radiotherapy (IGRT) has allowed further improvements in treatment delivery and accuracy. Taken together, these techniques have ushered in the modern age of spinal SRS.

16.2 Potential for Spine Stereotactic Radiosurgery

Tumors involving the spinal column are common, the majority of which represent spinal metastases. Approximately 40% of patients with malignancy will develop spinal metastases, with over 18,000 new cases diagnosed in North America each year.¹⁷^,¹⁸ Patients may present with pain, neurological compromise, or vertebral fractures. While some tumors are amenable to surgical resection, many patients with cancer are poor surgical candidates, requiring some other less invasive form of therapy. For palliation, steroids, medical management of pain, and conventional external beam radiation therapy (EBRT) are frequently used. Although conventional EBRT does offer effective pain relief and maintenance of neurological function, options are limited in patients who fail treatment. Many patients experience recurrent symptoms within 6 to 9 months following EBRT.

Initial studies of extracranial SRS demonstrated the accuracy and reproducibility of the various systems.¹⁶^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵^,²⁶^,²⁷ More recently, larger case series and retrospective studies have emerged, demonstrating effective pain and tumor control following SRS.²⁸^,²⁹^,³⁰^,³¹^,³²^,³³^,³⁴^,³⁵^,³⁶

16.3 Challenges of Spine Stereotactic Radiosurgery

The advancement of SRS as a treatment for tumors of the spine requires a thorough understanding of possible dose-related toxicity. Radiobiologic models have limitations for deciding what the maximal fraction dose and total dose should be, except at the extremes.³⁷^,³⁸^,³⁹^,⁴⁰^,⁴¹ Extending our knowledge about the safety and efficacy of intracranial SRS to the spine is difficult. It is not yet known whether the dose tolerance of the spinal cord is similar to those of the brainstem, cortex, or optic apparatus, which exhibit a wide range of sensitivity to single and cumulative doses. The spinal cord is smaller and more compact than even the brainstem, and peripheral nerves have no real counterpart in the cranial nerves. In addition, the effects of chemotherapy, surgery, medical conditions such as diabetes, and previous radiation treatments also have to be considered to fully understand dose-related toxicity of spine SRS.⁸^,³⁹ In addition, toxic effects of spine SRS on solid organs including the heart, lung, kidneys, esophagus, bowel, and liver need to be considered. Optimal dosage regimens, margins, and early and late toxicity associated with this new technology continue to be studied. Finally, although theoretical accuracy has been demonstrated in all of the commercially available systems, the accuracy and reproducibility of treatment delivery in patients has yet to be determined.

16.4 Stereotactic Radiosurgery Technique

Spine SRS is typically delivered using linear accelerator–based IMRT or VMAT in a radiosurgical treatment suite equipped with image-guidance, mini-multileaf collimation, and integrated treatment planning software with automated image fusion.

16.4.1 Patient Immobilization and Imaging

During treatment simulation, the patient is positioned with their arms above their head or high on the chest, depending on the treatment location. Extracranial immobilization is performed using an Elekta BodyFIX (Elekta; Crawley, UK). The BodyFIX system is composed of a BlueBAG with a total body cover sheet, using a vacuum pump to create accurate and precise patient positioning and immobilization( Fig. 16.1). The system is designed to reduce both voluntary and involuntary motion during treatment. Once the patient is immobilized, CT simulation is performed in the planned treatment position utilizing a CT scanner (Phillips Brilliance Big Bore, Phillips Medical Systems; Andover, MA).

The area of interest and at least two vertebral bodies above and below the tumor level are scanned with 2- to 3-mm-thick contiguous slices. The field of view is set wide enough to encompass the area of interest as well. CT images are then transferred using the local area network and standard DICOM software to the SRS treatment planning system (Pinnacle, Phillips; Fitchburg, WI). In some patients, spinal MRI planning is also done with the patient immobilized in the BodyFIX apparatus. Imaging sequences include gadolinium-enhanced, T1-weighted, contiguous 3-mm images covering the same area covered with the CT images and also 2-mm images focused on the involved vertebral bodies. Additional sequences required for specific cases are also used. MRI images are transferred directly to the planning station in the same manner as the CT images. These images are then fused with the CT images to aid in target delineation. In patients who do not undergo MRI with immobilization but have a pretreatment diagnostic spinal MRI performed close to the CT simulation date, the diagnostic images are fused with the treatment planning CT images to aid in target delineation.

16.4.2 Treatment Planning

Once the CT images are imported and fused with either diagnostic or planning MRI images, the radiation oncologist and neurosurgeon work together to delineate volumes for the target and organs at risk, and a treatment plan can be developed using the treatment planning system.

Target Volumes

The target lesion is outlined on both the CT and MRI images by the radiation oncologist and neurosurgeon, with the assistance of a neuroradiologist as needed( Fig. 16.2). The lesion can be defined by enhancing tumor mass or by bony changes directly attributable to tumor invasion. This is defined as the gross tumor volume, or GTV (extent of gross tumor). The clinical target volume (CTV) is then defined as the GTV plus a margin to account for subclinical disease. This volume represents an anatomical-clinical concept; it must be treated adequately in order to achieve the aim of the radiation therapy. The CTV is typically equal to the GTV in cases of spine SRS. The third volume to be defined is the planning target volume (PTV), which is a geometrical concept. The PTV accounts for uncertainties in planning or treatment delivery, which could include organ motion or setup errors. The PTV is defined as a 2-mm expansion of the GTV in three dimensions, excluding the volume represented by a 2-mm expansion of the spinal cord.

Fig. 16.1 Extracranial immobilization is performed using an Elekta BodyFIX (Elekta; Crawley, UK). The BodyFIX system is composed of a BlueBAG with a total body cover sheet, using a vacuum pump to create accurate and precise patient positioning and immobilization. (Reproduced with permission from Elekta: http://ecatalog.elekta.com/oncology/bodyfix(r)/products/0/22325/22341/20231/bodyfix(R).aspx.)

Fig. 16.2 The target lesion is outlined on CT and MRI images by a radiation oncologist and neurosurgeon, with the assistance of a neuroradiologist as needed.

Critical Organ Definition

Critical organs considered to be at risk for toxicity during treatment are defined as the organs at risk (OARs). These represent normal tissues whose radiation sensitivity may significantly influence treatment planning and/or prescribed dose. OARs are delineated anatomically using both CT and MRI images. The organs defined will depend on the level of the spine receiving treatment. These may typically include esophagus, lung, liver, heart, kidneys, bowel, and aorta. Some institutions also define the endplates as a critical structure due to the potential risk of increased fracture with high-dose radiation; however, this is currently being studied and not considered standard practice at this point. In all cases, a spinal cord volume must be defined. The spinal cord is considered the most critical structure. The cord is defined anatomically at least two vertebral bodies above and below the area of tumor involvement, and is defined by the thecal sac, usually visualized best on MRI. In addition to the spinal cord volume, the spinal cord + 2 mm is also defined, which is used in determining the PTV as previously described.

Dosimetric Planning

The dose of radiation is prescribed to achieve coverage of a given isodose line. The concept of the isodose line reflects the volumetric and planar variation in absorbed radiation dose in tissue. These distributions are depicted by the isodose lines, which are expressed as a percentage of the dose at a reference point. For spinal SRS, the prescription isodose is chosen such that ≥ 80% of the PTV receives the prescription dose, ensuring coverage of the GTV. Careful attention is given to the dose constraints of the OARs. When tolerance to the OARs is exceeded, coverage to the target may have to be compromised. The most important dose constraint is that of the spinal cord, which is typically limited to a maximum dose of 10 Gy to 0.1 mL of the spinal cord volume, and 13 Gy to 0.1 mL of spinal cord + 2 mm. In patients who have had prior irradiation to the SRS site, adjustments in the dose constraints may be required to account for prior dose received by the OARs.

Treatment optimization using IMRT or VMAT is completed. Four choices of treatment are presented by the software for review. One option, PTV-only, disregards all OAR to deliver the optimal dose to the lesion. Another option, OAR-high, gives maximal protection to OAR even at the cost of dose delivery to the lesion. The remaining treatment options, OAR-normal and OAR-low, give variable weights to OAR and lesion dose. Once the optimal treatment optimization has been selected, the final plan is approved by both the radiation oncologist and the neurosurgeon.

Dose Selection

A wide variety of total dose and fractionation schemes have been reported.²⁷^,²⁸^,³⁰^,³¹

At our institution, a dose of 16 to 18 Gy in a single fraction is typically chosen, if it can be achieved while respecting OAR constraints. The total dose prescribed and dose per fraction (in the case of multiple fractions) are selected on the basis of tumor location, tumor size and volume, proximity to critical structures, and previous radiation treatment within the given treatment field. In most cases, single-fraction treatment is the method of choice. However, in larger volume targets and previously irradiated areas, multifraction regimens are selected to offer further sparing of the critical structures. Patients may receive anywhere from one to five total treatments.

16.4.3 Treatment Delivery

At the time of treatment delivery, patients are positioned and immobilized in the BodyFIX apparatus on the treatment table. Once the patient is immobilized, image guidance is used to evaluate patient positioning and organ motion prior to treatment. This is performed with cone-beam CT (CBCT)—an X-ray volumetric imaging system which is mounted on the linear accelerator used at the time of treatment delivery with the patient in the treatment position. A three-dimensional CBCT (3D-CBCT) is taken to assess alignment and position in the x-, y-, and z-axes to a tolerance of 2 mm. If the position is found to be ≥ 2 mm off, adjustments are made. A 3D-CBCT is then repeated to ensure that the proper position has been achieved. If necessary, a third 3D-CBCT is performed. The treatment position is then verified with an orthogonal pair of X-ray images. Both the 3D-CBCT and orthogonal pair images must be reviewed and approved by the treating radiation oncologist prior to treatment delivery.

The setup time including positioning, alignment, and quality checks for each treatment varies, ranging from 30 to 60 minutes. Radiation treatment is then delivered via a linear accelerator, most commonly using an energy of 6 MV, but as high as 15 MV if needed. The total beam-on treatment time varies depending on the complexity of the treatment plan and number of beams used, but can range from 10 to 20 minutes.

Quality checks are performed daily, monthly, and annually on the linear accelerator as indicated. Complete IMRT or VMAT dose quality assurance is completed for each treatment plan prior to delivery of treatment. This can take several hours and is usually performed in the day prior to the first planned treatment.

16.5 Complications

16.5.1 Treatment-Related Toxicity

Treatment-related toxicity is assessed immediately following treatment to monitor acute SRS complications. Following treatment, patients are then seen in follow-up with radiation oncologist, neurosurgeon, or both, at 8 and 12 weeks posttreatment, and then at approximately 3-month intervals (with additional follow-up as needed). At each follow-up, an assessment of pain control, neurological status, radiation-related toxicity, and local control is performed. Local control is typically evaluated with the use of MRI and/or CT images.

Specific radiation-related toxicities will highly depend on the anatomic location of the treatment being delivered. In the acute setting, some of the possible side effects include pain, dysphagia, mucositis, esophagitis, nausea, diarrhea, or fatigue. In our experience, however, these side effects are rare and the majority of patients tolerate spinal SRS without incident. In the subacute setting, pneumonitis and myositis are possible. The most significant and feared complications of spinal SRS in the delayed setting are those of radiation-induced myelopathy (RIM) and vertebral compression fractures (VCF).

16.5.2 Radiation-Induced Myelopathy

RIM is rare, but represents one of the most serious late radiation toxicities following spinal cord irradiation and can lead to paralysis or death. RIM is likely a multifactorial process, involving both damage to the white matter and damage to the local vasculature. Acute RIM can lead to sensory or motor deficits, which are usually reversible. In delayed RIM, damage can potentially be permanent, leading to profound weakness, paresthesia, spasticity, pain, or bowel/bladder incontinence. Given the devastating consequences, understanding the need to respect spinal cord radiation tolerance is of paramount value in spinal SRS.

Delayed RIM was examined by Gibbs et al,⁴² in a series of 1,075 patients with spinal cord tumors treated with CyberKnife radiosurgery at Stanford and the University of Pittsburgh. Of the 1,075 patients, 6 developed RIM in a mean time of 6.3 months and their data were retrospectively reviewed. Radiation doses ranged from 12.5 to 25 Gy in one to five fractions with 90% PTV coverage and a spinal cord dose constraint of 8 to 10 Gy maximum. Clinical symptoms were correlated with MRI findings, and specific biologic radiation dose equivalents were calculated. Logistic regression failed to demonstrate any predictors of spinal cord injury.⁴² Other series have demonstrated similarly low rates of RIM following stereotactic body radiation therapy. A multi-institutional collaboration between the University of Toronto, the University of California, San Francisco, and the MD Anderson Cancer Center⁴³ evaluated the probability of RIM specific to spinal SRS. The relationship between dose at a given volume and the occurrence of RIM was determined using a logistic regression model, utilizing specific dose-volume data from treatment plans of 9 patients with RIM compared to 66 patients without. The greatest significance for basing dose thresholds was found for the maximum point value, or Pmax. Based on logistic estimates, the probability of RIM was < 5% when limiting thecal sac Pmax to 12.4 Gy in one fraction, 17 Gy in twofractions, 20.3 Gy in three fractions, 23 Gy in four fractions, and 25.3 Gy in five fractions.⁴³ As the majority of centers follow more conservative dose constraints in comparison, the likelihood of RIM is low with current treatment planning methods.

16.5.3 Vertebral Compression Fractures

A more frequent late effect of spinal SRS is compression fracture of the vertebral body. Crude rates of VCF following spinal SRS range from 11 to 39% in previously reported series. These rates are much higher in comparison to conventional radiation, where VCF is seen in < 5% of cases. The management and prevention of VCF is a major challenge because the tumor itself typically lies within the bone needing irradiation. Several series have explored predictors of VCF following SRS.

The first major report of the risk of VCF following SRS is from Memorial Sloan-Kettering Cancer Center in 2009.⁴⁴ This series included 62 patients with 71 sites treated using spinal SRS. Tumors received a median of 24 Gy in a single fraction. At a median follow-up of 19 months, the VCF rate following SRS was 39%, with a median time to fracture of 25 months. Predictors for VCF included larger volume of vertebral body involvement (> 40%), lytic tumors, and lesions in T10–sacrum. Interestingly, the rate of VCF was not associated with the radiation dose.⁴⁴ Other centers have since reported their experience. In 2012, the MD Anderson Cancer Center⁴⁵ reported the VCF outcomes of 93 patients who underwent spinal SRS to 123 vertebral bodies to doses of 18 to 30 Gy in one to three fractions. At 16 months of follow-up, new or progressive VCF was seen in 20%. Age over 55, preexisting fracture, baseline pain, and lytic lesions were predictors for VCF.⁴⁵ Multi-institutional data were reported in 2013 by Sahgal et al⁴⁶ for 252 patients with 410 spinal segments treated with spinal SRS. The rate of VCF in this series was lower, reporting a 14% rate at a median follow-up of 12 months. The 1- and 2-year cumulative incidence of VCF was 12.4 and 13.5%, respectively. Baseline fractures, lytic lesions, and spinal deformity were predictive of VCF. Unlike the prior studies, this series also found that radiation dose per fraction was a significant predictor, with the greatest risk seen at a dose of ≥ 24 Gy per fraction (vs. 20–23 Gy and ≤ 19 Gy).⁴⁶ Unpublished data from our institution as part of a multi-institutional collaboration with seven total institutions evaluated 704 spinal tumors treated with spinal SRS to a median dose of 21 Gy (6–65 Gy). At a median follow-up of 10 months (1–33 months), the incidence of a new or progressive VCF was approximately 8%. Patients with a solitary metastasis at the time of SRS were more likely to develop a VCF, as well as those tumors with larger treatment volumes, higher prescription doses, and preexisting VCF at the site of treatment. With all of these factors in mind, more consideration could be made for percutaneous cement augmentation procedures in appropriately selected patients prior to spinal SRS, to help minimize the risk of VCF development.

16.6 Outcomes

Multiple studies have evaluated the effectiveness of radiation therapy in the management of pain relief from bony metastases using either multifraction or single-fraction radiotherapy.⁴⁷^,⁴⁸^,⁴⁹ Several of these studies demonstrated no significant difference in overall or complete pain relief between the multifractionated or single-fractioned regimens, providing the rationale for further study of single-fraction treatment for bony metastases. In these series, however, single-fraction treatments were delivered using conventional radiotherapy methods using a dose of 8 Gy. Current practice today utilizes much higher single-fraction doses, owing to the fact that treatment planning is much more conformal, allowing dose escalation in a safe manner. With more centers performing spinal SRS, increasing data are becoming available regarding the safety and efficacy with regard to pain relief and local control.

To date, the largest single-institution series of spinal SRS in the literature comes from the University of Pittsburgh Medical Center.³² In this prospective, nonrandomized, longitudinal cohort study, 500 patients with spinal metastases were treated with single-fraction SRS using the CyberKnife Image-Guided Radiosurgery system. The study allowed patients with prior radiation therapy (n=344, 30 Gy in 10 fractions or 35 Gy in 14 fractions), in which further conventional radiotherapy was not possible. Patients with overt spinal instability or neurological deficit from bony compression of neural structures were excluded. A mean dose of 20 Gy (12.5–20 Gy) was delivered, prescribed to the 80% isodose line. At a median follow-up of 21 months, long-term radiographic tumor control was demonstrated in 90% of patients who had received SRS as primary treatment, and in 88% of patients who had received prior irradiation. Long-term pain control was demonstrated in 86% of patients overall following SRS. None of the patients developed radiation-induced spinal cord damage.

Other smaller series have demonstrated similar outcomes. Yamada et al³⁶ evaluated 93 patients with 103 spinal metastases without high-grade epidural compression treated with IMRT-based SRS at Memorial Sloan-Kettering Cancer Center. Patients were excluded for mechanical instability, epidural spinal cord compression, or previous radiotherapy to the SRS site. Patients received single-fraction SRS to a median dose of 24 Gy (18–24 Gy) prescribed to the 100% isodose line. The overall actuarial local control rate was 90% at a median follow-up of 15 months, noting a 9-month median time to local failure. Radiation dose was a predictor for local control, with 95 versus 80% local control in 24 Gy versus 18 to 23 Gy, respectively. Durable symptom palliation was achieved in all locally controlled patients, with no radiculopathy or myelopathy noted. Ahmed et al³⁵ reported the experience of the Mayo Clinic, which prospectively assessed 85 malignant spinal lesions in 66 patients, 25% of which received prior radiotherapy to the site. With similar exclusion criteria as prior studies, eligible patients received a median of 24 Gy in one to three total fractions, with the most common dose regimen being 24 Gy in three fractions. Actuarial local control at 1 year was 89% overall, and 83 and 91% in patients with and without prior radiotherapy. Limited toxicity was noted, even in patients who had reirradiation.

Besides local control, pain relief is regarded as one of the most important outcomes following spinal SRS. The Radiation Therapy Oncology Group (RTOG)⁵⁰ reported favorable results from the phase II portion of RTOG 0631, a study designed to assess the feasibility and safety of spine SRS for localized spine metastases. The study is currently accruing to the phase III component, which is planned to compare pain relief and quality of life between single-fraction SRS to 16 to 18 Gy versus single-fraction conventional external beam radiation to 8 Gy. As the utilization of spinal SRS continues, results of this important trial will be critical in understanding the durability of pain relief for patients undergoing this type of treatment.

16.6.1 Clinical Cases Case 1

A 59-year-old woman presented with an abnormal screening mammogram, demonstrating a mass in the right breast, which was biopsy-proven invasive lobular carcinoma. Further workup was completed including staging with a CT of the chest, abdomen, and pelvis. CT revealed bony abnormalities within the left scapula and T11 vertebral body suggesting metastases, confirmed with MRI and bone scan. She underwent a biopsy of the T11 vertebra demonstrating metastatic disease. She was asymptomatic, specifically without back pain or neurological deficits. Given her excellent performance status in the setting of oligometastatic disease, she was treated with SRS to both the left scapular lesion and T11, to a dose of 15 Gy delivered in a single fraction. Images from her IMRT treatment plan can be seen in Fig. 16.3. SRS treatment was followed by systemic chemotherapy, right breast partial mastectomy, and adjuvant radiation therapy to the right breast and axillary lymph nodes. She had no treatment-related complications. Now 3 years out from treatment completion, she remains free of disease, with local control at the sites of SRS.