|
 
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| SYMPOSIUM - METASTATIC SPINAL TUMORS |
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| Year : 2022 | Volume
: 5
| Issue : 2 | Page : 185-192 |
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Radiotherapy for spinal metastasis: A narrative review
Rajesh Balakrishnan1, Patricia Sebastian1, Gautam R Zaveri2
1 Department of Radiation Oncology, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Spine Surgery, Jaslok Hospital & Research Centre, Mumbai, Maharashtra, India
| Date of Submission | 12-Aug-2021 |
| Date of Decision | 07-Sep-2021 |
| Date of Acceptance | 30-Mar-2022 |
| Date of Web Publication | 08-Jun-2022 |
Correspondence Address:
Rajesh Balakrishnan
Department of Radiation Oncology, Christian Medical College, Vellore, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | 3 |
DOI: 10.4103/isj.isj_79_21
Despite the rapid evolution of systemic therapies and significant advances in surgical techniques, radiation therapy by itself or as an adjuvant to surgery remains the modality of choice for local control of spinal metastasis. Radiation can be used with an ablative intent for lasting local control of spinal metastasis or with a palliative intent to ameliorate pain, prevent pathological fractures, and relieve epidural spinal cord compression. This article aims to review the various modalities of radiotherapy. The lack of precision with conventional external beam radiotherapy (cEBRT) poses a significant radiation hazard to vital structures adjacent to the spine. This necessitates lowering of the radiation dosage, which may not be adequate to treat certain resistant tumors. Currently, the use of cEBRT is recommended for radiosensitive histologies only. Stereotactic body radiotherapy (SBRT) allows tumoricidal doses of radiation to be safely delivered to the tumor tissue. SBRT has been shown to provide durable local control, even for spine metastasis from tumors with radioresistant histologies. SBRT can also be offered as a reirradiation technique for tumor progression following a course of cEBRT. Currently, SBRT alone is recommended for radioresistant spinal metastasis limited to 1–2 spinal segments, with limited paraspinal spread and mild-to-moderate spinal cord compression in a stable spine. Charged particle therapy is useful for resistant histologies and further reduces the dose to normal structures within the vicinity of the tumor. Keywords: Conventional external beam radiotherapy, local tumor control, spinal metastases, stereotactic body radiotherapy
How to cite this article:
Balakrishnan R, Sebastian P, Zaveri GR. Radiotherapy for spinal metastasis: A narrative review. Indian Spine J 2022;5:185-92 |
| Introduction | |  |
Radiotherapy (RT) is the most effective treatment modality for local control of spinal metastasis. Ablative RT aims to destroy tumor tissue in order to provide lasting local control of metastatic disease limited to 1–2 levels within the spine. This in turn contributes to prolongation of overall survival. Palliative RT aims to shrink tumor tissue in order to alleviate pain, prevent pathological fractures, and relieve epidural spinal cord compression.[1] Conventional external beam radiotherapy (cEBRT) has been widely and successfully used in the management of radiosensitive spinal metastasis for decades. The advent of stereotactic body radiotherapy (SBRT) has extended the indications of primary RT in the setting of spinal metastasis. Spinal metastasis that were hitherto considered radioresistant can now be effectively treated with SBRT.[2]
This article aims to provide spine surgeons an overview of currently used techniques of RT, and an insight to the role of RT within the treatment strategy.
In this narrative review, we have discussed the evolution of various RT treatment delivery techniques for spinal metastasis. Current concepts and recent trends in RT along with surgery for spinal metastasis are also included.
| Effects of Radiotherapy on Bony Metastases | | |
Conventional RT treats cancer with ionizing photon beams (X-rays or gamma rays), resulting in damage to cellular DNA. When radiation passes through a living cell, it can damage the reproductive material in the cell directly and indirectly. Direct damage includes base deletions and single- and double-strand breaks in the DNA chain.[3] Indirect damage occurs when radiation interacts with water molecules in the cell, releasing toxic-free radicals. Repair of the damage is possible both in normal cells and cancer cells, although it is thought that cancer cells have less capacity to repair damaged DNA and, hence, a therapeutic ratio can be exploited.
Hoskin et al.[4] have proposed that radiation-induced killing of tumor cells results in reduced production of osteoclast activating factors or the radiation may directly damage osteoclasts within the tumor volume. This inhibits bone resorption and promotes the laying down of new bone, thereby reducing the risk of developing a pathological fracture. Vakaet and Boterberg[5] have proposed that reduction of inflammatory cells and chemical pain mediators may be an additional mechanism for pain relief in patients with bony metastases receiving RT.
| Types of Radiotherapy | | |
Radiation therapy can be broadly classified as follows:
- A. External beam radiotherapy (EBRT)
- - Conventional two-dimensional (2D) external beam radiotherapy (cEBRT)
- - 3D conformal radiotherapy (3DCRT)
- - Intensity-modulated radiotherapy (IMRT)
- - Image-guided radiotherapy (IGRT)
- - Stereotactic body radiotherapy (SBRT)
- - Charged particle RT (protons, carbon ions)
- B. Internal RT (brachytherapy)
- - Permanent implants
- - Temporary internal RT delivered through needles and catheters.
EBRT is the most commonly used method of delivering RT. It involves the generation of high-energy X-rays outside the body by a machine called as a linear accelerator. The beams are then precisely delivered to the target tumor tissue using computer software to adjust the size, shape, depth, direction, and intensity of the beam.
Conventional two-dimensional radiotherapy
2D conventional RT (cEBRT) uses orthogonal X-rays of the patient to define the boundaries of the radiation target. A limited number of simple square or rectangular beams are used. A single posterior beam is used for the lower thoracic and lumbosacral regions, a combination of anterior and posterior beams is used in the upper thoracic spine, whereas a pair of parallel opposed lateral beams are used in the cervical spine. Due to the low conformity of these treatments, adjacent tissues/organs including the spinal cord often fall into the high dose region resulting in treatment side effects. Also, the amount of radiation delivered to the targeted tumor is usually not adequate resulting in less effective treatment
The precise radiation dose and the dosage schedule are determined based on the performance status of the patient, presence or absence of visceral metastases, volume to be treated, nature of primary tumor, and probable life expectancy. Typical dosage schedules include 30 Gy in 10 fractions, 20 Gy in 5 fractions, 16 Gy in 2 fractions, one week apart, and 8 Gy in single fraction. Although there is no difference in pain relief among the various fractionation schedules, fractionated schedules have been reported to produce a longer-lasting neurological response compared to a single fraction.[6] Two major prospective trials (SCORE-1 and SCORE -2) compared various RT schedules used for metastatic spinal cord compression and studied the functional outcome in terms of overall response, improvement of motor function, and post-RT ambulatory status [Table 1]. They found no statistical significance among the various regimens.[7],[8] The advantage of using a single fraction is that reirradiation is possible if needed. Repeating single fraction of treatment can be done as early as one month after previous radiation. The pain relief is better if the gap between the two is more than six months.[9] | Table 1: Selected conventional RT series for spinal metastases with dose fractionation and outcomes
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2D conventional RT is offered to patients with poor performance status, shorter life expectancy (<3 months) with multilevel spinal involvement to palliate symptoms of pain or cord compression.[10] It has been shown to offer immediate pain relief with a short duration of local control. In a prospective study conducted by Maranzano et al.,[11] 82% of patients treated with RT alone for spinal cord compression experienced pain relief, 76% had neurological improvement and improvement in sphincter dysfunction was observed in 44%. Because of the simplicity of planning treatment with 2D conventional RT, same-day treatment can be administered.
Three-dimensional conformal radiotherapy
Detailed 3D pictures of the target area that includes the entire tumor mass, the spinal canal, the width of the involved vertebrae, and a vertebra above and below the diseased vertebrae are created using computed tomography (CT) and magnetic resonance imaging (MRI) scans. 3DCRT uses a multileaf collimator (MLC) that creates nearly limitless beam shapes. Several of these “conformal” beams would then be delivered from different angles to treat the tumor volume. The intensity is the same throughout each beam. The entire target area plus a margin beyond it, should ideally be covered by the 95% isodose of the planned RT dose.
3DCRT allows more accurate planning and delivery of radiation so that higher (tumoricidal) doses of radiation can be delivered to the tumor while limiting spread to adjacent healthy tissue and vital organs such as the spinal cord. This lowers the risk of side effects. The conformal techniques require time for simulation, volume delineation, planning and quality assurance prior to starting the treatment.
Intensity modulated radiotherapy
IMRT is a type of conformal RT where not only the shape but also the intensity of each beam is varied.[12] Therefore, it is superior to 3DCRT. Typically, combinations of multiple intensity-modulated fields coming from different beam directions produce a customized radiation dose that maximizes tumor dose while also minimizing the dose to adjacent normal tissues, reducing side effects. Due to its complexity, IMRT does require slightly longer daily treatment times and additional planning and safety checks before the patient can start the treatment when compared to conventional RT.
Stereotactic body radiotherapy
Using the IMRT platform together with advanced techniques of patient immobilization, SBRT delivers high doses of tightly focused radiation to a small tumor area in one or more fractions with an ablative intent. With stereotaxy, it is possible to deliver a higher biologically equivalent dose to the entire target area while sparing the spinal cord. SBRT is the one of the most common modalities of radiation therapy used for spine metastasis.
Indications and contraindications
The International Spine Radiosurgery consortium recommends SBRT for those who have oligometastases to the spine and for those with radioresistant histology.[13] There is concern in offering SBRT to patients who have epidural extension, cord compression with neurologic deficit, paraspinal extension and when multiple consecutive vertebrae are involved [Figure 1]. This concern is because it would increase the dose to the spinal cord and the other normal structures. The RTOG (Radiation Therapy Oncology Group) 0631 study did not include patients who had paraspinal lesions >5 cm, lesions within 3 mm of spinal cord and involvement of >2 consecutive vertebrae.[14] The CCTG (Canadian Cancer Trials Group) SC 24 trial permitted inclusion of patients with involvement of up to three consecutive vertebrae. They did not have any restriction for distance to cord or paraspinal extension. However, they used presence of neurological deficit as an exclusion criteria.[15] | Figure 1: Decision-making algorithm. RTOG 0631––inclusion criteria for SBRT includes the target >3 mm from spinal cord, not more than two consecutive vertebrae involved, paraspinal mass < 5 cm
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Evidence
The major evidence in favor of SBRT over conventional RT comes from the randomized controlled trials (RCTs) tabulated in [Table 2] and [Table 3]. The NRG /RTOG 0631 compared single fraction of SBRT with a single fraction of EBRT and found that the pain relief at 3 months was comparable in both arms (40.3% vs. 57.9%, P = 0.99).[14] However, the RCT done by CCTG–SC 24 showed the superiority of the SBRT over the conventional fractionation arm (35% vs. 14%).[15] | Table 2: Selected SBRT series (upfront SBRT, postop SBRT) for spinal metastases with dose fractionation and outcomes
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 | Table 3: Randomized trials comparing SBRT and conventional external beam RT (cEBRT) for spinal metastases with dose fractionation and outcomes
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Procedure
SBRT involves near rigid immobilization of cervical/ upper thoracic spine using thermoplastic masks and of the lower thoracic and lumbar spine using vacuum bags. A planning CT scan with slice thickness of 1–1.5 mm is acquired. MRI (T1, T2W, and DWI) sequences are required for accurate delineation of the tumor. The clinical target volume usually includes the entire vertebral body, pedicle, transverse process, lamina or spinous process. Volumetric modulated arc therapy plans are made with dose constraints based on set guidelines.[16] SBRT should not be utilized when the coverage goals cannot be met without violating the dose constraints. Prior to treatment delivery, set up accuracy is verified using a cone beam CT which is present in the linear accelerator. Some centers perform a second cone beam CT in between the two arcs (intra-fraction). A third CBCT is done post treatment to document the treated location. The radiation distribution of conventional RT and SBRT is shown in [Figure 2]. | Figure 2: Planned treatment volume coverage in a patient with L4 vertebral body metastases who has been treated with SBRT (A). For the same patient a conventional direct posterior field plan has been simulated (B)
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Outcome
The commonly used dosage regimens for SBRT are 16–24 Gy in a single fraction and 24–30 Gy in 2–3 fractions.[14],[15] Various studies have shown that treatment with SBRT has resulted in improved pain relief, more durable local tumor control (80%–98% at 2 years) and longer overall survival which suggests its superior efficacy when compared with conventional palliative RT.[17],[18],[19],[20],[21],[22] The outcomes of patients who have been treated with SBRT in terms of pain control, local control and overall survival have been tabulated in [Table 2] and [Table 3].[17],[19],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32] We have compared the pros and cons of the various treatment modalities available for delivery of radiation in spinal metastases and shown how SBRT evolved to be superior to the others in [Table 4]. | Table 4: Comparison of various radiotherapy techniques used for treatment of spinal metastases with external beam radiotherapy
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Toxicity associated with stereotactic body radiotherapy
The most common complications that have been observed following SBRT for spinal metastasis include pain flares, esophageal toxicity, vertebral compression fractures (VCFs), nerve injury and myelopathy.[33] Most complications are related to a high radiation dose (>20 Gy) when delivered as a single fraction.[34]
A transient increase in pain during or shortly after RT (pain flare) is the commonest toxicity reported post SBRT. A pain flare is reported in 15%–68% of patients receiving SBRT. Concomitant administration of dexamethasone reduces the incidence of pain flares following SBRT to less than 15%.[35]
Another common adverse effect is esophageal toxicity, especially seen with ablative doses (>20 Gy) of SBRT. Cox et al.[36] reported acute or late esophageal toxicity in 27% of 182 patients with thoracic spine metastases who received single fraction SBRT to a dose of 24 Gy. Grade 3 or higher toxicities were reported in 6.8% of patients.
The incidence of VCFs in patients receiving SBRT ranges from 5% to 40%[37] and is likely to be due to radiation necrosis of the underlying bone. VCFs are more common (39% vs. 10%) with high dose (≥24 Gy) single fraction dosage regimens when compared to fractionated regimens.[38]
Radiation myelopathy is perhaps the most dreaded complication of SBRT. It has been reported in 0.5% patients.[39] The incidence of radiation myelopathy increases when the maximum cord dose increases beyond 13.85 Gy.[40]
Charged particle therapy
Most cancer radiation therapy uses ionizing photons beams (X-rays or gamma rays). Charged particle RT uses beams of protons or other charged particles such as helium, carbon, or other ions instead of photons. Charged particles deposit most of their energy in the last final millimeters of their trajectory when their speed slows. This results in a sharp localized peak of dose within the tumor. By adjusting the energy and intensity of the charged particle, one can deliver prespecified doses anywhere in the patient`s body with high precision. In addition, charged particles interact with tissues in different ways than photons so that the same amount of radiation can cause greater cellular damage. Their dose profile limits/ avoids damage to adjacent normal structures. A dosimetric study done at Heidelberg University, comparing SBRT, Proton beam therapy and Carbon ion RT for spinal metastases, found that the PTV coverage was similar among all modalities. However, the maximum spine dose could be reduced to 8.1 Gy with protons and to 4.3 Gy with carbon ions, but photons delivered 11.9 Gy when treating cervical spinal locations.[41] Carbon ion therapy has proven to be effective in treating resistant histologies.
However, charged particle therapy with protons is debatable for use in spinal metastasis due to the need for matching line feathering and the higher sensitivity of protons to high z metal artefacts (that are often present in the vicinity of target). Moreover, proton therapy takes a longer time for treatment delivery. This can lead to intrafraction variation in patients who experience pain and cannot lie down for longer periods of time. There are no randomized data or prospective data addressing the outcomes in previously unirradiated spinal metastases. However it is an option to consider when reirradiation is being considered.[42] The scarcity of centers offering charged particle therapy and the cost involved must also be kept in mind when these are offered.
Brachytherapy
Brachytherapy is a form of RT in which a sealed radiation source is placed adjacent or within the area requiring treatment. It allows for delivery of high doses of radiation to the region of concern with very less doses to the surrounding organs at risk such as spinal cord. In the context of spinal metastases, it is used mostly in patients who have failed multiple modalities including radiation therapy and is not a candidate for open surgery or as an adjunct in combination with other therapies. It is also commonly used for pain relief. Brachytherapy can be in the form of seeds (iodine 125 or iridium 192) or plaques (phosphorus 32) or with radionuclides (samarium 153 or yttrium 90). CT guided insertion of catheters also have been evolving in order to deliver brachytherapy where seeds or radionuclides are not available, and the patient not fit for open surgery.[43]
Local control varies from 51% to 87%. Studies have shown significant pain control by improvement in visual analog scale scores. Brachytherapy is with infrequent complications (bleeding/ fracture/wound infections/cement leakage). Survival information is difficult to summarize due to the lack of differentiation between primary and metastatic tumors in many of the published literature.[44] Survival at 6 months ranged from 66% to 100%. Advantages are that higher doses of radiation can be delivered with almost negligible dose to surrounding organs at risk. Radiation can be repeated by brachytherapy (another salvage treatment option) when the tumor is refractory to other modalities. The cost of brachytherapy is lesser compared to SBRT or other precise external beam techniques. Disadvantages are that brachytherapy is an invasive procedure; it may not encompass all the disease; it needs expertise and availability.
| Conclusions | | |
RT is the most effective modality for local control of spinal metastasis. RT alone has been shown to provide durable local control of spinal metastasis, alleviate pain and treat epidural spinal cord compression. However, spinal stabilization is recommended for patients with significant instability.
By enabling effective local tumor control of even radioresistant spinal metastasis, SBRT has challenged conventional treatment paradigms. With the advent of SBRT, the need for surgical intervention is limited to patients with spinal instability or those with high grade epidural spinal cord compression and a major neurologic deficit. Currently, SBRT is recommended for oligometastatic disease from radioresistant tumors in patients with a life expectancy of more than six months. SBRT can also be offered as a reirradiation technique for tumor progression following a course of cEBRT.
The use of cEBRT is limited to radiosensitive spinal metastasis and in patients who do not fit the criteria for SBRT. Charged particle therapy is useful for resistant histologies and further reduces the dose to normal structures within vicinity of the tumor.
Ethical policy and institutional review board statement
Not applicable.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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