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Hypofractionated Stereotactic Body Radiotherapy in Spinal Metastasis — With or Without Epidural Extension
Clinical Oncology 27 (2015) 345e352 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Hypofractionated Stereotactic Body Radiotherapy in Spinal Metastasis d With or Without Epidural Extension A.K. Anand *, G. Venkadamanickam *, A.U. Punnakal *, B.S. Walia y, A. Kumar z, A.K. Bansal x, H.M. Singh x * Department
of Radiation Oncology, Max Super Speciality Hospital, New Delhi, India Department of Neurosurgery, Max Super Speciality Hospital, New Delhi, India z Department of Radiodiagnosis, Max Super Speciality Hospital, New Delhi, India x Division of Medical Physics, Max Super Speciality Hospital, New Delhi, India y
Received 8 September 2014; received in revised form 11 December 2014; accepted 30 January 2015
Abstract Aims: To evaluate clinical outcome and the effect of malignant epidural compression (MEC) in the treatment of spine metastasis with stereotactic body radiotherapy (SBRT). Materials and methods: Seventy-six lesions in 52 patients with spinal metastasis received SBRT during the period July 2010 to December 2012. MEC was detected in 20 patients (38.4%) and was separately contoured. The median dose prescribed to involved vertebra (planning target volume) was 24 Gy (range 24e27 Gy) in a median of three fractions (range 1e3). Uninvolved elements were prescribed 21 Gy in three fractions. In 59 lesions (77.6%), the entire vertebra was treated and in 17 lesions (22.4%) only the anterior elements were treated. All patients were treated with volumetric modulated arc therapy with image guidance on a Novalis Tx linear accelerator with the ExacTrac system. Dosimetric and clinical outcomes were compared in patients with or without MEC. Results: At a median follow-up of 8.48 months (range 3e40 months), 1 year local control and overall survival was 94 and 68%, respectively. In patients with or without epidural extension, the median dose to the gross tumour volume (GTV; 95%) was 23.48 Gy (range 13.70e25.75) and 22.99 Gy (range 13.55e26.84), the median spinal cord Dmax was 17.36 Gy (range 8.47e21.63) and 15.71 Gy (range 8.39e23.33). The median GTV epidural (D95%) was 21.16 Gy (range 15.43e23.92). Complete pain relief was seen in 90% of patients with MEC and 93.75% without MEC (P ¼ NS) and neurological improvement was seen in 60% of patients in both groups of patients. Conclusion: It is feasible to deliver a high dose of radiation (w90% of the prescription dose) to the epidural component with volumetric modulated arc therapy SBRT and image guidance. It yielded high rates of pain control and local control in patients with spine metastases with or without MEC. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Epidural compression; SBRT; spinal metastases
Introduction About 60e70% patients with metastatic cancer will have spine metastasis in their life time [1]. Conventionally, radiotherapy in spine metastasis is mainly used for palliation of pain. The pain control rate with conventional radiotherapy was 66% at 3 months with a single fraction of 8
Author for correspondence: A.K. Anand, Department of Radiation Oncology, Max Cancer Centre, Max Super Speciality Hospital, 2 Press Enclave Road, Saket, New Delhi 110017, India. Tel: þ91-11-26515050x2050, þ91-1126515050x2047; Fax: þ91-11-26510050. E-mail address: [email protected] (A.K. Anand).
Gy or 10 fractions of 3 Gy each in the Radiation Therapy Oncology Group (RTOG) 97-14 study [2]. The complete response rate, however, was much lower at 16%. With the advent of newer agents of chemotherapy, targeted drugs and biological agents, survival in patients with distant metastasis is steadily improving. Therefore, these patients would benefit from improved local control to prevent a relapse of symptoms and avoid disease progression that can result in spinal cord compression [3]. Stereotactic body radiotherapy (SBRT) delivers precise, highly conformal and image-guided external beam radiotherapy to the affected vertebra(e). With the accurate delivery techniques of SBRT, it is possible to deliver an ablative
http://dx.doi.org/10.1016/j.clon.2015.01.035 0936-6555/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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radiation dose to the affected vertebra with a sharp fall in dose to most of the surrounding critical structures, like the spinal cord. SBRT in spine metastasis has yielded high rates of pain relief and local tumour control of the order of 80e90% [3,4]. SBRT is also efficacious in the re-treatment of spinal metastasis after recurrence with conventional radiotherapy [5]. Metastatic epidural compression (MEC) may be present in a significant proportion of patients with spinal metastasis and can have a direct mass effect on the spinal cord, leading to neurological deterioration [6]. SBRT for vertebral metastasis has been adopted by an increasing number of centres. However, there is a paucity of data on SBRT in patients with MEC. It could be due to the limitation of radiation tolerance of the spinal cord adjacent to the epidural component of the tumour. However, a few studies have reported an encouraging response rate of 60e80% with SBRT for patients of vertebral metastasis with MEC [6,7]. The aim of this study was to evaluate the dosimetric and clinical outcome of patients undergoing SBRT for spine metastasis with or without MEC.
Materials and Methods Patients We reviewed the medical records of patients who received SBRT at our centre for spinal metastasis from July 2010 to December 2012. The study was approved by the Institutional Review Board. The eligibility criteria included patients with age >18 years and a histopathological diagnosis of primary malignancy with spinal metastasis, preferably oligometastasis. Patients with involvement of one to two vertebrae at one level and up to four vertebrae at two different levels and pain/neurological deficit related to involved vertebra were included. A neurosurgical opinion was taken for patients with neurological deficit. Patients with rapid neurological deterioration and retropulsed fragment of vertebra were taken for surgery first. Computed Tomography Simulation and Image Guidance Patients were immobilised on an All in One (OrfitÒ Industries, Belgium) high precision base plate with head and knee supports. A thermoplastic mask (four or six points) was cast over the patient according to the region being treated. Vertical and lateral lasers were marked on the skin to ensure quick and accurate positioning during treatment. Exactrac infrared markers were placed on the cast to utilise the Exactrac positioning system (Brainlab, Feldkirchen, Germany) for automatic isocentre localisation before treatment. Daily verification of the patient position in six dimensions (6D) was carried out with the help of the Exactrac system and verified by cone beam computed tomography (CBCT). Acceptable six dimension limits were 1 mm translational and 1 rotational.
A planning computed tomography (CT) scan of the region of interest was taken with a 2 mm slice thickness. A treatment planning magnetic resonance imaging (MRI) scan was taken of the involved vertebra and adjacent vertebral region with a flat table couch and appropriate alignment. T1-, T2-weighted, contrast and STIR (Short Term Inversion Recovery) images with a 2 mm slice thickness were obtained in the supine position. All available diagnostic images, including positron emission tomography (PET)-CT and planning MRI, were fused with planning CT scans in Eclipse software (Varian, Palo Alto, CA, USA) for target delineation. Target Volume and Dose Prescription The gross tumour volume (GTV) consisted of tumor in the involved vertebral body and adjacent pedicle with paraspinal extension if any. MEC was separately contoured as the GTV (epidural) with CT-MRI fusion with the help of a radiologist. Its extension in the cranio-caudial direction had to be limited to the single vertebral level or two contiguous vertebrae. MEC was graded according to the classification proposed by Ryu et al. [6]. Grade 0: only bone involvement; grade I: thecal sac impinged; grade II: thecal sac compressed; grade III: spinal cord impinged; grade IV: cord displaced, cerebrospinal fluid visible between cord and tumour; grade V: cord compressed, cerebrospinal fluid not visible between cord and tumour. GTV2 consisted of the remaining uninvolved parts of the vertebra, which included the lamina, transverse process and spinous process. The end plates of adjacent vertebrae were included in the GTV on either sides of the involved vertebra. This target volume with no expansion became the planning target volume. All relevant organs at risk (OAR) specific to that anatomical region, such as lungs, kidneys, vessels, oesophagus and heart, were contoured. The spinal cord and thecal sac were contoured 6 mm above and below the GTV on T2-weighted MRI. The planning target volume was prescribed 24e27 Gy, whereas GTV2 was prescribed 21 Gy in three fractions. The aim was to deliver at least 90% of the GTV dose to the GTV epidural within the constraints of the thecal sac and spinal cord. For single fraction treatment, the dose prescribed was 14e18Gy. The dose was determined by the treating physician taking into account tumour histology, target volume and the location of OARs. Dose constraints to OARs were given according to the TG 101 report [8]. For single fraction treatment, the dose to 0.35 cm3 of the spinal cord was <10 Gy and the maximum point dose (0.03 cm3) was <14 Gy. For three fraction treatment the dose to 0.35 cm3 of the spinal cord was <18 Gy and the maximum point dose was limited to <21.9 Gy. The same dose constraints were prescribed to both the thecal sac and the spinal cord. Contouring of the thecal sac was carried out to provide an additional safety margin of about 1 mm beyond the spinal cord. Volumetric modulated arc radiotherapy treatment plans were generated using Eclipse (Varian) treatment planning software. The treatment plan was optimal when 80e90% of the target volume was covered by the prescribed dose. All patients were planned with two arcs and treatment was delivered
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on a Novalis Tx (Varian) linear accelerator with HD (High Definition) multileaf collimators (MLC) (2.5 mm) and a six dimension robotic couch. During the delivery of SBRT, the positions of the vertebra, spinal cord and other critical structures were verified using the Exactrac system and CBCT daily. Necessary corrections were applied before the delivery of treatment. Snap verification images were also acquired with Exactrac to detect any intrafraction motion. Pre-medication with dexamethasone 8e16 mg and anti-emetics were given to all patients. All patients continued further chemotherapy, hormonal therapy and biotherapy as indicated and followed up 2 weeks after SBRT and then 2 monthly thereafter. MRI or PET-CT scans were carried out at 2e4 month intervals for the assessment of systemic disease and local control. Local control was evaluated with respect to symptoms related to treated site(s) and radiological evaluation with MRI or PETCT. Local control was defined as local pain control and either regression or a non-progressive radiological response. Pain was assessed using the visual analogue scale (VAS score) before SBRT and at each subsequent visit. It was graded as ‘complete’ pain relief if pain disappeared completely and ‘partial’ relief if there was >50% pain relief on the VAS score. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0. Statistical Analysis Local control and overall survival were measured from the day of starting SBRT and were calculated using the KaplaneMeier method. If more than one vertebral level per patient had been treated at different times, local control was evaluated for each site separately. All statistical computations were carried out using Statistical Package of the Social Sciences version 16.0 for windows (Chicago, IL, USA).
Results Seventy-six lesions in 52 patients were treated with SBRT. The most common primary sites of cancer were breast (30.8%) and lung (19.2%). The patients’ clinical characteristics are shown in Table 1. The median follow-up was 8.48 months (range 3e40.02) and the median overall survival of the entire cohort was 19.2 months. Actuarial overall survival at 1 year was 68% and at 2 years was 45.4% (Figure 1a). MEC was seen in 20 patients (38.4%) and its grading is shown in Table 2. All patients in this study presented with pain of score 2e8 on VAS. Fifteen patients (28.8%) had neurological deficit at presentation. Neurological deficit was present in 50% of patients with epidural extension and 15.6% of patients with no epidural extension (Table 2). In the latter group, neurological deficit was a result of exiting nerve root compression due to pre- and para-vertebral extension (two patients), a retropulsed bone segment (one patient) and previously treated non-index spinal lesions (two patients). Five patients with paraplegia who were medically unfit or had multiple sites of metastases or refused surgery received
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Table 1 Patient characteristics Age
Gender Male Female Neurological status No deficit Paraparesis Paraplegia Epidural extension Yes No Primary Breast Lung Prostate Soft tissue sarcoma Renal cell carcinoma Head and neck Multiple myeloma Thyroid Others GIT (Gastrointestinal tract) Sites of metastases Bone only Visceral þ bone Oligometastases (<5 sites) Vertebra Cervical Dorsal Lumbar Stereotactic body radiotherapy 24e27 Gy/3 fractions 14e18 Gy/1 fraction
Mean 58 years (range 34e79) n
Percentage
30 22
57.7 42.3
37 10 5
71.1 19.2 9.6
20 32
38.5 61.5
16 10 7 2 3 1 4 2 3 4
30.8 19.2 13.5 3.8 5.8 1.9 7.7 3.8 5.8 7.7
30 22 15
57.7 42.3 28.8
14 44 18 dose (76 lesions) 71 5
18.4 57.9 23.7 93.4 6.6
SBRT for severe local pain as it was a short treatment and involved only three visits to the hospital. In almost all patients pain was the principle indication for SBRT. Eight patients (15.4%) underwent surgery due to spine instability and/or rapid neurological deterioration. In 59 lesions (77.6%), the entire vertebra was treated and in 17 lesions only the anterior elements were treated. In 38 patients, a single vertebra was treated and in 14 patients two vertebral levels were treated. Four patients had received previous radiotherapy to a median dose of 25.5 Gy (range 18e30 Gy) in six to 10 fractions. Patients presenting with neurological deficit were evaluated by a team of neurosurgeons and radiation oncologists. Medical decompressive measures were immediately started and SBRT was delivered either on the same day or within 24 h. Seventy-one lesions (93.4%) were treated with three fractions of SBRT and five lesions (6.6%) received a single fraction of SBRT. The median dose prescribed was 24 Gy (range 24e27 Gy) in a median of three fractions (range 1e3). Prescribed doses in single fraction SBRT were 18 Gy (two lesions), 14 Gy (two lesions) and 16 Gy (one lesion). Detailed dosimetric data are shown in Tables 3 and 4. A
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Fig 1. Kaplan e Meier estimate of (a) overall survival and (b) local control.
comparison of dosimetric parameters of patients with and without epidural extension is shown in Table 2. For all patients the prescription isodose was 100%. The median spinal cord Dmax was higher for patients with MEC in order to achieve the maximum possible dose to the epidural component. Local control at 1 year was 94% and at 2 years was 82.6% (Figure 1b). Local control with or without MEC is shown in Figure 2. Forty-eight (92.3%) patients experienced complete pain relief within 3e5 days after SBRT and three had partial pain relief. One patient (1.9%) with renal cell carcinoma had no pain relief. Fifteen patients presented with neurological deterioration and nine of 15 patients (60%) showed improvement in their neurological status after SBRT (Table 2). Two of four patients with paraplegia due to MEC showed a remarkable improvement in neurological status. One breast cancer patient with thecal sac compression and
early onset paraplegia showed marked improvement in motor power to grade 4/5 with SBRT and subsequently underwent spine stabilisation surgery. A second patient had complete paraplegia of 2 months’ duration from cord compression due to metastatic prostate cancer. He refused surgery and was treated with SBRT. He showed remarkable recovery in paraplegia and can now walk without support 2 years later (Figure 3). Three other patients did not show any improvement. In the two groups of patients with or without MEC, pain control and improvement in neurological status with SBRT were similar with no statistically significant difference (Table 2). Three patients, two with MEC and one without MEC had grade 1e2 motor power, which improved in two patients with SBRT. Seven patients, four with MEC and three without MEC, with motor power grade 3 showed good neurological recovery in four patients, whereas motor
Table 2 Clinical profile and response to SBRT in patients with or without metastatic epidural compression. Epidural compression (n ¼ 20) *Grade of epidural compression
Pain Relief Complete Partial No relief Neurological Status Motor power before SBRT Motor power after SBRT
Local control (1 yr) Overall survival (1 yr) *
Grade Grade Grade Grade
I e 4 (16%) II e 10 (4%) III e 7 (28%) IV e 4 (16%)
18 (90%) 1 (5%) 1 (5%) Neurological deficit ¼ 10 (50%) Paraplegia e 4 Paraparesis e 6 Improved e 6 Static e 3 Deterioration e 1 94% 68%
25 lesions in 20 patients with epidural extension.
Without epidural compression (n ¼ 32)
30 (93.75%) 2 (6.25%) e Neurological deficit ¼ 5 (15.6%) Paraplegia e 1 Paraparesis e 4 Improved e 3 Static e 2 Deterioration e 0 82.6% (p ¼ 0.35) 45.4% (p ¼ 0.41)
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Table 3 Dose to GTV, thecal sac and spinal cord in patients with or without epidural extension.
GTV volume (cc) GTV 2 volume (cc) GTV D95% (Gy) GTV Epidural D95% (Gy) GTV V100 (%) GTV2 D95% (Gy) GTV2 V100 (%) Spinal cord Dmax (Gy) Spinal cord 0.35cc (Gy) Thecal sac Dmax (Gy) Thecal sac 0.35cc (Gy)
Epidural extension (n ¼ 20)
Without epidural extension (n ¼ 32)
p value
52.55 20.22 23.48 21.16 88.84 20.22 87.22 17.36 15.59 21.38 19.44
51.90 24.60 22.99 e 89.19 20.51 91.91 15.71 14.10 20.57 18.84
(8.10e187.30) (7.90-97.00) (18.62e26.84)
<0.94 <0.07 <0.11
(15.01e96.57) (16.68e24.09) (36.70e99.20) (11.14e23.33) (9.70e22.55) (14.81e24.39) (13.79e23.33)
<0.30 <0.94 <0.30 <0.16 <0.46 <0.19 <0.23
(2.40e138.50) (4.89e49.80) (18.85e25.75) (15.43e23.92) (73.36e98.01) (15.89e23.99) (40.65e97.56) (10.81e21.63) (9.07e21.05) (15.64e23.45) (13.88e22.96)
Table 4 Doses to other critical structures around target volume. Volume (cc) Right kidney 128.30 (6.30e372.20) Left kidney 122.20 (4.40e174.40) Dysphagia related structures 34.50 (22.50e122.10) Esophagus 17.30 (2.90e62.70) Trachea 22.00 (1.60e53.90)
Minimum (Gy)
Maximum (Gy)
DMean (Gy)
D5O% (Gy)
0.62 0.63 0.51 0.91 0.79
17.19 16.10 23.27 21.45 17.89
4.83 4.16 4.65 7.19 5.75
1.88 1.67 2.79 3.97 4.88
(0.04e1.53) (0.07e1.37) (0.02e3.60) (0.02e25.73) (0.12e6.50)
power remained the same with no further deterioration in three patients (Table 2). Overall, 10 of 15 patients were ambulatory after treatment with SBRT. There was no difference in local control (Figure 2) and overall survival in the two groups of patients (Table 2). Radiological evaluation with MRI and PET-CT scans was available for 36 treated lesions. A radiological complete response was seen in 13 lesions (36.1%), a stable/partial response in 18 lesions (50.0%) (overall response rate 86.1%)
Fig 2. Local control in patients with or without metastatic epidural compression.
(1.08e22.37) (1.38e22.54) (10.99e27.09) (0.91e28.81) (3.03e28.81)
(0.22e4.71) (0.29e7.04) (1.22e12.83) (0.38e25.74) (1.28e25.69)
(0.15e9.48) (0.21e7.18) (0.91e11.76) (0.19e11.77) (0.98e10.80)
and progression in five lesions (13.09%). All patients tolerated SBRT well. Acute side-effects were generally mild, except in two patients who experienced pain ‘flare’ for 3e5 days despite premedication with steroids. No long-term complications, including neurotoxicity, have been observed so far.
Discussion The spine is the third most common site of metastatic disease following the lung and liver and the most common bony site [9]. About 90% of symptomatic spinal metastases present with pain and over 40% of patients have a neurological deficit, including cord compression [9]. MEC is one of the major factors causing neurological deficit in patients with spinal metastases. In this study, 50% of patients with MEC had a neurological deficit as compared with 15.6% of patients without MEC. MEC is seen as a result of direct extension from vertebral metastases by extension through intervertebral foramina, by haematogenous dissemination or rarely by lymphatic infiltration. Involvement of the epidural space may result in compression of the spinal cord or cauda equina or in radiculopathy because of compression of nerve roots [10]. Twenty of 52 patients (38.4%) had MEC in this study. MRI of the spine helps in delineating both the bony involvement and neural compression from epidural tumour. Subtle epidural extension may be missed on CT and MRI is considered superior in patients with suspected epidural extension of the tumour [1]. The combination of
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Fig 3. A patient of carcinoma prostate with spine metastasis. A-MRI axial scan showing D9 metastasis with MEC. B-MRI e sagittal scan. CSagittal scan showing isodose distribution through D8 and D9 vertebrae. D-GTV (black), GTV (epidural) (arrow), in planning CT scan. E-SBRT dose distribution with VMAT (2 Arcs), 24Gy Isodose encompassing GTV, 21Gy GTV (epidural) and posterior elements (GTV 2). F-follow up MRI scan through D9 vertebra shows significant radiosurgical decompression achieved at 24 months.
T1-weighted spin-echo and STIR sequences has been shown to be the most useful. Lesions tend to be T1 hypotense, T2 hyperintense and avidly enhancing. Contrast enhancement in MRI is helpful in delineating the extent of the tumour and outlining the regions of spinal cord compression [11]. Epidural lesions are more clearly seen in cervical and thoracic spine where there is paucity of epidural fat [12]. It can cause minimal canal compromise to thecal indentation and spinal cord displacement (Table 2). Conventionally patients with spine metastasis have been treated with palliative radiation in one to 12 fractions. It yielded pain control in 60e70% and neurological improvement in around 50% of patients [2]. However, the median duration of response with 8 Gy (single fraction) or fractionated radiation of 20e35 Gy in 10e12 fractions is around 6 months [2]. Advances in systematic therapy have led to improved survival rates of many cancers and, therefore, better local control in the spine would provide a better quality of life. In patients with MEC, different approaches of fractionated radiation have yielded local control ranging from 60 to 77% and improvement in motor functions in 28e30% of patients [13]. Some of the retrospective studies have reported better local control with long-course radiotherapy
than with short-course radiotherapy [14]. It emphasises the need for a higher dose of radiation for improved local control of the epidural component. However, the radiation dose is often compromised due to the limited radiation tolerance of the spinal cord, resulting in a suboptimal dose to the epidural component. Patients with spinal metastases with MEC have also been managed with surgery followed by radiation. It can improve the neurological status and the ability to walk significantly as compared with radiation alone [15]. However, most patients with spine metastasis have a limited life span due to multiple metastases and poor general condition and therefore surgery is only possible in a few selected patients [6]. In this study, 42.3% of patients with spine metastases also had visceral metastases (Table 1). Surgery is usually reserved for patients with rapid neurological deterioration, unstable spine or sub-luxation of the affected vertebra [16]. Caution must be exercised with SBRT in patients with motor power less than grade 3e4. In case of neurological deterioration, surgical intervention can be re-explored. SBRT in single or hypofractionated regimens has been shown to be safe and effective in the treatment of spinal metastases. It yielded local control as high as 80e90% and neurological improvement in 85% of patients, which is
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much superior to that reported with conventional radiation [4,6]. However, there is lack of clarity regarding the efficacy of SBRT in patients with MEC due to spinal metastasis. Some authors have excluded patients from the SBRT protocol if the patient had ‘symptomatic’ malignant spinal cord compression [3]. On the other hand, a response rate of 82% has been reported in patients with epidural cord compression documented on radiographic reduction of epidural or paraspinal extension of the tumour [6]. Others have treated patients with rapid neurological deterioration or spine instability with surgery followed by SBRT [4]. With increasing use of SBRT, more and more patients with MEC will be offered SBRT. In the present series, 20 of 52 patients (38.4%) had MEC from vertebral metastasis and 50% of them had neurological deficit. Due to the close proximity of the epidural component to the spinal cord, it is often difficult to achieve the desired dose to the affected vertebra within the spinal cord tolerance. Furthermore, two primary sites of failure in patients treated with spine SBRT have been observed, either at the osseous margin posterior to the vertebral body or in the epidural space, which is often under-dosed in order to meet the spinal cord planning constraints [17]. The fusion of planning CT with MRI with contrast is crucial to delineate the GTV and the adjoining epidural extension. CT-MRI fusion was carried out for all patients with suspected epidural extension and neurological deficit in this study. About 50% of the recurrences after SBRT spine have been reported to occur at the epidural space [18]. Other sites included pedicle and posterior structures that were not routinely covered in the high dose region. One of the reasons could be missing the unsuspected epidural extension on CT. Another reason could be the under-dosing of the epidural component due to its close proximity to the spinal cord. In this study, the epidural component (GTV epidural) received a median dose of 21.16 Gy as compared with 23.44 Gy to GTV vertebra (w90%) within the constraints of the spinal cord (Table 3). In the present study, the SBRT dose delivered was 8 Gy three fractions instead of a single fraction to achieve a higher biological dose to the vertebra and the epidural component. Conversion of the SBRT dose using the linear quadratic model yielded a median biologically equivalent dose (BED) (a/b ¼ 10) for the GTV of 40.6 Gy10 (range 30.1e50.8 Gy) in patients without MEC. The BED equivalent single fraction dose was 15.8 Gy10 (range 13.0e18.1 Gy10). Similarly for patients with MEC, the median BED was 41.8 Gy10 (30.7e47.9 Gy) and the single fraction equivalent dose was 16.0 Gy10 (range 13.2e17.4 Gy10). The median three fraction spinal cord Dmax (a/b ¼ 3) was 15.71 Gy3 in patients without MEC and 17.36 Gy3 in patients with MEC (Table 3). The corresponding single fraction Dmax equivalents were 10.7 Gy3 and 11.0 Gy3, respectively. The median spinal cord Dmax was higher for patients with MEC in order to achieve the maximum possible dose to the epidural component. The three fraction schedule of SBRT provided higher spinal cord constraint (to 0.35 cm3) of 18 Gy in three fractions (2 Gy equivalent 32 Gy3) in comparison with 10 Gy in one fraction
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(2 Gy equivalent 25.9 Gy3) [8]. It further helped in achieving a higher dose to the GTV and GTV epidural. Recently, thecal sac constraints of Dmax 17.4e18.8 Gy in three fractions have been proposed that would limit myelitis rates to below 2e3% [19]. We did not see any patient with radiation myelitis in this study, although the follow-up was short to assess this complication. Complete pain relief was seen in 90% of patients with MEC and in 93.75% of patients without MEC, which was comparable in the two groups. Similarly, neurological improvement was seen in 60% of patients in both groups; in the rest of the patients except one, neurological status remained the same with no further deterioration. Ten of 15 patients who presented with varying degrees of neurological deficit were ambulatory after SBRT. Ryu et al. [6] reported an epidural tumour response rate of 80%, with a complete response of 27%, a partial response (>50% tumour volume reduction) of 30%, a minimal response (25e50% tumour volume reduction) of 23% and no response/tumour progression in 6%. In the present study, corresponding figures of complete response, partial response and progressive tumour were 36.1, 50 and 13.09%, respectively, as assessed on CT-PET and/or MRI, which are in agreement with the study by Ryu et al. [6]. Improved techniques of detection of epidural tumour with MRI, better radiation techniques like volumetric modulated arc therapy delivered with high definition MLC (2.5 mm leaf width in our set-up) and sophisticated image guidance systems (like the Exactrac 6D X-ray system) have helped to deliver the highest possible dose to the vertebra and adjacent epidural component while sparing the spinal cord. These factors seemed to have contributed to high rates of local control in patients with MEC in this study. The epidural component received a median of 90% of the dose received by the vertebra (GTV), which yielded good local control. Thus, SBRT can deliver a high dose of radiation to the affected vertebra(e) and the epidural extension with high local control, pain relief and neurological recovery. The presence of MEC did not confer an adverse influence on the outcome of SBRT and, therefore, surgery can be avoided in a significant number of patients. However, patients with rapid neurological deterioration, spine instability and motor power grade 3 should undergo surgery first for a better neurological outcome. More studies and a longer follow-up would help in further defining patient selection for SBRT in spine metastases with MEC.
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[13] Rades D, Lange M, Veninga T, et al. Preliminary results of spinal cord compression recurrence evaluation (score-1) study comparing short-course versus long course radiotherapy for local control of malignant epidural spinal cord compression. Int J Radiat Oncol Biol Phys 2009;73(1):228e234. [14] Rades D, Fehlauer F, Schulte R, et al. Prognostic factors for local control and survival after radiotherapy of metastatic spinal cord compression. J Clin Oncol 2006;24:3388e3393. [15] Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 2005;366:643e648. [16] Krishnaney AA, Steinmetz MP, Benzel EC. Biomechanics of metastatic spine cancer. Neurosurg Clin North Am 2004;15:375e380. [17] Chang EL, Shiu AS, Mendel E, et al. Phase I/II study of stereotactic body radiotherapy for spinal metastasis and its pattern of failure. J Neurosurg Spine 2007;7:151e160. [18] Nguyen QN, Shiu AS, Rhines LD, et al. Management of spinal metastases from renal cell carcinoma using stereotactic body radiotherapy. Int J Radiat Oncol Biol Phys 2010;76(4):1185e1192. [19] Sahgal A, Weinberg V, Ma L, et al. Probabilities of radiation myelopathy specific to stereotactic body radiation therapy to guide safe practice. Int J Radiat Oncol Biol Phys 2013;85(2):341e347.
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Original Article
Hypofractionated Stereotactic Body Radiotherapy in Spinal Metastasis d With or Without Epidural Extension A.K. Anand *, G. Venkadamanickam *, A.U. Punnakal *, B.S. Walia y, A. Kumar z, A.K. Bansal x, H.M. Singh x * Department
of Radiation Oncology, Max Super Speciality Hospital, New Delhi, India Department of Neurosurgery, Max Super Speciality Hospital, New Delhi, India z Department of Radiodiagnosis, Max Super Speciality Hospital, New Delhi, India x Division of Medical Physics, Max Super Speciality Hospital, New Delhi, India y
Received 8 September 2014; received in revised form 11 December 2014; accepted 30 January 2015
Abstract Aims: To evaluate clinical outcome and the effect of malignant epidural compression (MEC) in the treatment of spine metastasis with stereotactic body radiotherapy (SBRT). Materials and methods: Seventy-six lesions in 52 patients with spinal metastasis received SBRT during the period July 2010 to December 2012. MEC was detected in 20 patients (38.4%) and was separately contoured. The median dose prescribed to involved vertebra (planning target volume) was 24 Gy (range 24e27 Gy) in a median of three fractions (range 1e3). Uninvolved elements were prescribed 21 Gy in three fractions. In 59 lesions (77.6%), the entire vertebra was treated and in 17 lesions (22.4%) only the anterior elements were treated. All patients were treated with volumetric modulated arc therapy with image guidance on a Novalis Tx linear accelerator with the ExacTrac system. Dosimetric and clinical outcomes were compared in patients with or without MEC. Results: At a median follow-up of 8.48 months (range 3e40 months), 1 year local control and overall survival was 94 and 68%, respectively. In patients with or without epidural extension, the median dose to the gross tumour volume (GTV; 95%) was 23.48 Gy (range 13.70e25.75) and 22.99 Gy (range 13.55e26.84), the median spinal cord Dmax was 17.36 Gy (range 8.47e21.63) and 15.71 Gy (range 8.39e23.33). The median GTV epidural (D95%) was 21.16 Gy (range 15.43e23.92). Complete pain relief was seen in 90% of patients with MEC and 93.75% without MEC (P ¼ NS) and neurological improvement was seen in 60% of patients in both groups of patients. Conclusion: It is feasible to deliver a high dose of radiation (w90% of the prescription dose) to the epidural component with volumetric modulated arc therapy SBRT and image guidance. It yielded high rates of pain control and local control in patients with spine metastases with or without MEC. Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Key words: Epidural compression; SBRT; spinal metastases
Introduction About 60e70% patients with metastatic cancer will have spine metastasis in their life time [1]. Conventionally, radiotherapy in spine metastasis is mainly used for palliation of pain. The pain control rate with conventional radiotherapy was 66% at 3 months with a single fraction of 8
Author for correspondence: A.K. Anand, Department of Radiation Oncology, Max Cancer Centre, Max Super Speciality Hospital, 2 Press Enclave Road, Saket, New Delhi 110017, India. Tel: þ91-11-26515050x2050, þ91-1126515050x2047; Fax: þ91-11-26510050. E-mail address: [email protected] (A.K. Anand).
Gy or 10 fractions of 3 Gy each in the Radiation Therapy Oncology Group (RTOG) 97-14 study [2]. The complete response rate, however, was much lower at 16%. With the advent of newer agents of chemotherapy, targeted drugs and biological agents, survival in patients with distant metastasis is steadily improving. Therefore, these patients would benefit from improved local control to prevent a relapse of symptoms and avoid disease progression that can result in spinal cord compression [3]. Stereotactic body radiotherapy (SBRT) delivers precise, highly conformal and image-guided external beam radiotherapy to the affected vertebra(e). With the accurate delivery techniques of SBRT, it is possible to deliver an ablative
http://dx.doi.org/10.1016/j.clon.2015.01.035 0936-6555/Ó 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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radiation dose to the affected vertebra with a sharp fall in dose to most of the surrounding critical structures, like the spinal cord. SBRT in spine metastasis has yielded high rates of pain relief and local tumour control of the order of 80e90% [3,4]. SBRT is also efficacious in the re-treatment of spinal metastasis after recurrence with conventional radiotherapy [5]. Metastatic epidural compression (MEC) may be present in a significant proportion of patients with spinal metastasis and can have a direct mass effect on the spinal cord, leading to neurological deterioration [6]. SBRT for vertebral metastasis has been adopted by an increasing number of centres. However, there is a paucity of data on SBRT in patients with MEC. It could be due to the limitation of radiation tolerance of the spinal cord adjacent to the epidural component of the tumour. However, a few studies have reported an encouraging response rate of 60e80% with SBRT for patients of vertebral metastasis with MEC [6,7]. The aim of this study was to evaluate the dosimetric and clinical outcome of patients undergoing SBRT for spine metastasis with or without MEC.
Materials and Methods Patients We reviewed the medical records of patients who received SBRT at our centre for spinal metastasis from July 2010 to December 2012. The study was approved by the Institutional Review Board. The eligibility criteria included patients with age >18 years and a histopathological diagnosis of primary malignancy with spinal metastasis, preferably oligometastasis. Patients with involvement of one to two vertebrae at one level and up to four vertebrae at two different levels and pain/neurological deficit related to involved vertebra were included. A neurosurgical opinion was taken for patients with neurological deficit. Patients with rapid neurological deterioration and retropulsed fragment of vertebra were taken for surgery first. Computed Tomography Simulation and Image Guidance Patients were immobilised on an All in One (OrfitÒ Industries, Belgium) high precision base plate with head and knee supports. A thermoplastic mask (four or six points) was cast over the patient according to the region being treated. Vertical and lateral lasers were marked on the skin to ensure quick and accurate positioning during treatment. Exactrac infrared markers were placed on the cast to utilise the Exactrac positioning system (Brainlab, Feldkirchen, Germany) for automatic isocentre localisation before treatment. Daily verification of the patient position in six dimensions (6D) was carried out with the help of the Exactrac system and verified by cone beam computed tomography (CBCT). Acceptable six dimension limits were 1 mm translational and 1 rotational.
A planning computed tomography (CT) scan of the region of interest was taken with a 2 mm slice thickness. A treatment planning magnetic resonance imaging (MRI) scan was taken of the involved vertebra and adjacent vertebral region with a flat table couch and appropriate alignment. T1-, T2-weighted, contrast and STIR (Short Term Inversion Recovery) images with a 2 mm slice thickness were obtained in the supine position. All available diagnostic images, including positron emission tomography (PET)-CT and planning MRI, were fused with planning CT scans in Eclipse software (Varian, Palo Alto, CA, USA) for target delineation. Target Volume and Dose Prescription The gross tumour volume (GTV) consisted of tumor in the involved vertebral body and adjacent pedicle with paraspinal extension if any. MEC was separately contoured as the GTV (epidural) with CT-MRI fusion with the help of a radiologist. Its extension in the cranio-caudial direction had to be limited to the single vertebral level or two contiguous vertebrae. MEC was graded according to the classification proposed by Ryu et al. [6]. Grade 0: only bone involvement; grade I: thecal sac impinged; grade II: thecal sac compressed; grade III: spinal cord impinged; grade IV: cord displaced, cerebrospinal fluid visible between cord and tumour; grade V: cord compressed, cerebrospinal fluid not visible between cord and tumour. GTV2 consisted of the remaining uninvolved parts of the vertebra, which included the lamina, transverse process and spinous process. The end plates of adjacent vertebrae were included in the GTV on either sides of the involved vertebra. This target volume with no expansion became the planning target volume. All relevant organs at risk (OAR) specific to that anatomical region, such as lungs, kidneys, vessels, oesophagus and heart, were contoured. The spinal cord and thecal sac were contoured 6 mm above and below the GTV on T2-weighted MRI. The planning target volume was prescribed 24e27 Gy, whereas GTV2 was prescribed 21 Gy in three fractions. The aim was to deliver at least 90% of the GTV dose to the GTV epidural within the constraints of the thecal sac and spinal cord. For single fraction treatment, the dose prescribed was 14e18Gy. The dose was determined by the treating physician taking into account tumour histology, target volume and the location of OARs. Dose constraints to OARs were given according to the TG 101 report [8]. For single fraction treatment, the dose to 0.35 cm3 of the spinal cord was <10 Gy and the maximum point dose (0.03 cm3) was <14 Gy. For three fraction treatment the dose to 0.35 cm3 of the spinal cord was <18 Gy and the maximum point dose was limited to <21.9 Gy. The same dose constraints were prescribed to both the thecal sac and the spinal cord. Contouring of the thecal sac was carried out to provide an additional safety margin of about 1 mm beyond the spinal cord. Volumetric modulated arc radiotherapy treatment plans were generated using Eclipse (Varian) treatment planning software. The treatment plan was optimal when 80e90% of the target volume was covered by the prescribed dose. All patients were planned with two arcs and treatment was delivered
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on a Novalis Tx (Varian) linear accelerator with HD (High Definition) multileaf collimators (MLC) (2.5 mm) and a six dimension robotic couch. During the delivery of SBRT, the positions of the vertebra, spinal cord and other critical structures were verified using the Exactrac system and CBCT daily. Necessary corrections were applied before the delivery of treatment. Snap verification images were also acquired with Exactrac to detect any intrafraction motion. Pre-medication with dexamethasone 8e16 mg and anti-emetics were given to all patients. All patients continued further chemotherapy, hormonal therapy and biotherapy as indicated and followed up 2 weeks after SBRT and then 2 monthly thereafter. MRI or PET-CT scans were carried out at 2e4 month intervals for the assessment of systemic disease and local control. Local control was evaluated with respect to symptoms related to treated site(s) and radiological evaluation with MRI or PETCT. Local control was defined as local pain control and either regression or a non-progressive radiological response. Pain was assessed using the visual analogue scale (VAS score) before SBRT and at each subsequent visit. It was graded as ‘complete’ pain relief if pain disappeared completely and ‘partial’ relief if there was >50% pain relief on the VAS score. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v3.0. Statistical Analysis Local control and overall survival were measured from the day of starting SBRT and were calculated using the KaplaneMeier method. If more than one vertebral level per patient had been treated at different times, local control was evaluated for each site separately. All statistical computations were carried out using Statistical Package of the Social Sciences version 16.0 for windows (Chicago, IL, USA).
Results Seventy-six lesions in 52 patients were treated with SBRT. The most common primary sites of cancer were breast (30.8%) and lung (19.2%). The patients’ clinical characteristics are shown in Table 1. The median follow-up was 8.48 months (range 3e40.02) and the median overall survival of the entire cohort was 19.2 months. Actuarial overall survival at 1 year was 68% and at 2 years was 45.4% (Figure 1a). MEC was seen in 20 patients (38.4%) and its grading is shown in Table 2. All patients in this study presented with pain of score 2e8 on VAS. Fifteen patients (28.8%) had neurological deficit at presentation. Neurological deficit was present in 50% of patients with epidural extension and 15.6% of patients with no epidural extension (Table 2). In the latter group, neurological deficit was a result of exiting nerve root compression due to pre- and para-vertebral extension (two patients), a retropulsed bone segment (one patient) and previously treated non-index spinal lesions (two patients). Five patients with paraplegia who were medically unfit or had multiple sites of metastases or refused surgery received
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Table 1 Patient characteristics Age
Gender Male Female Neurological status No deficit Paraparesis Paraplegia Epidural extension Yes No Primary Breast Lung Prostate Soft tissue sarcoma Renal cell carcinoma Head and neck Multiple myeloma Thyroid Others GIT (Gastrointestinal tract) Sites of metastases Bone only Visceral þ bone Oligometastases (<5 sites) Vertebra Cervical Dorsal Lumbar Stereotactic body radiotherapy 24e27 Gy/3 fractions 14e18 Gy/1 fraction
Mean 58 years (range 34e79) n
Percentage
30 22
57.7 42.3
37 10 5
71.1 19.2 9.6
20 32
38.5 61.5
16 10 7 2 3 1 4 2 3 4
30.8 19.2 13.5 3.8 5.8 1.9 7.7 3.8 5.8 7.7
30 22 15
57.7 42.3 28.8
14 44 18 dose (76 lesions) 71 5
18.4 57.9 23.7 93.4 6.6
SBRT for severe local pain as it was a short treatment and involved only three visits to the hospital. In almost all patients pain was the principle indication for SBRT. Eight patients (15.4%) underwent surgery due to spine instability and/or rapid neurological deterioration. In 59 lesions (77.6%), the entire vertebra was treated and in 17 lesions only the anterior elements were treated. In 38 patients, a single vertebra was treated and in 14 patients two vertebral levels were treated. Four patients had received previous radiotherapy to a median dose of 25.5 Gy (range 18e30 Gy) in six to 10 fractions. Patients presenting with neurological deficit were evaluated by a team of neurosurgeons and radiation oncologists. Medical decompressive measures were immediately started and SBRT was delivered either on the same day or within 24 h. Seventy-one lesions (93.4%) were treated with three fractions of SBRT and five lesions (6.6%) received a single fraction of SBRT. The median dose prescribed was 24 Gy (range 24e27 Gy) in a median of three fractions (range 1e3). Prescribed doses in single fraction SBRT were 18 Gy (two lesions), 14 Gy (two lesions) and 16 Gy (one lesion). Detailed dosimetric data are shown in Tables 3 and 4. A
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Fig 1. Kaplan e Meier estimate of (a) overall survival and (b) local control.
comparison of dosimetric parameters of patients with and without epidural extension is shown in Table 2. For all patients the prescription isodose was 100%. The median spinal cord Dmax was higher for patients with MEC in order to achieve the maximum possible dose to the epidural component. Local control at 1 year was 94% and at 2 years was 82.6% (Figure 1b). Local control with or without MEC is shown in Figure 2. Forty-eight (92.3%) patients experienced complete pain relief within 3e5 days after SBRT and three had partial pain relief. One patient (1.9%) with renal cell carcinoma had no pain relief. Fifteen patients presented with neurological deterioration and nine of 15 patients (60%) showed improvement in their neurological status after SBRT (Table 2). Two of four patients with paraplegia due to MEC showed a remarkable improvement in neurological status. One breast cancer patient with thecal sac compression and
early onset paraplegia showed marked improvement in motor power to grade 4/5 with SBRT and subsequently underwent spine stabilisation surgery. A second patient had complete paraplegia of 2 months’ duration from cord compression due to metastatic prostate cancer. He refused surgery and was treated with SBRT. He showed remarkable recovery in paraplegia and can now walk without support 2 years later (Figure 3). Three other patients did not show any improvement. In the two groups of patients with or without MEC, pain control and improvement in neurological status with SBRT were similar with no statistically significant difference (Table 2). Three patients, two with MEC and one without MEC had grade 1e2 motor power, which improved in two patients with SBRT. Seven patients, four with MEC and three without MEC, with motor power grade 3 showed good neurological recovery in four patients, whereas motor
Table 2 Clinical profile and response to SBRT in patients with or without metastatic epidural compression. Epidural compression (n ¼ 20) *Grade of epidural compression
Pain Relief Complete Partial No relief Neurological Status Motor power before SBRT Motor power after SBRT
Local control (1 yr) Overall survival (1 yr) *
Grade Grade Grade Grade
I e 4 (16%) II e 10 (4%) III e 7 (28%) IV e 4 (16%)
18 (90%) 1 (5%) 1 (5%) Neurological deficit ¼ 10 (50%) Paraplegia e 4 Paraparesis e 6 Improved e 6 Static e 3 Deterioration e 1 94% 68%
25 lesions in 20 patients with epidural extension.
Without epidural compression (n ¼ 32)
30 (93.75%) 2 (6.25%) e Neurological deficit ¼ 5 (15.6%) Paraplegia e 1 Paraparesis e 4 Improved e 3 Static e 2 Deterioration e 0 82.6% (p ¼ 0.35) 45.4% (p ¼ 0.41)
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Table 3 Dose to GTV, thecal sac and spinal cord in patients with or without epidural extension.
GTV volume (cc) GTV 2 volume (cc) GTV D95% (Gy) GTV Epidural D95% (Gy) GTV V100 (%) GTV2 D95% (Gy) GTV2 V100 (%) Spinal cord Dmax (Gy) Spinal cord 0.35cc (Gy) Thecal sac Dmax (Gy) Thecal sac 0.35cc (Gy)
Epidural extension (n ¼ 20)
Without epidural extension (n ¼ 32)
p value
52.55 20.22 23.48 21.16 88.84 20.22 87.22 17.36 15.59 21.38 19.44
51.90 24.60 22.99 e 89.19 20.51 91.91 15.71 14.10 20.57 18.84
(8.10e187.30) (7.90-97.00) (18.62e26.84)
<0.94 <0.07 <0.11
(15.01e96.57) (16.68e24.09) (36.70e99.20) (11.14e23.33) (9.70e22.55) (14.81e24.39) (13.79e23.33)
<0.30 <0.94 <0.30 <0.16 <0.46 <0.19 <0.23
(2.40e138.50) (4.89e49.80) (18.85e25.75) (15.43e23.92) (73.36e98.01) (15.89e23.99) (40.65e97.56) (10.81e21.63) (9.07e21.05) (15.64e23.45) (13.88e22.96)
Table 4 Doses to other critical structures around target volume. Volume (cc) Right kidney 128.30 (6.30e372.20) Left kidney 122.20 (4.40e174.40) Dysphagia related structures 34.50 (22.50e122.10) Esophagus 17.30 (2.90e62.70) Trachea 22.00 (1.60e53.90)
Minimum (Gy)
Maximum (Gy)
DMean (Gy)
D5O% (Gy)
0.62 0.63 0.51 0.91 0.79
17.19 16.10 23.27 21.45 17.89
4.83 4.16 4.65 7.19 5.75
1.88 1.67 2.79 3.97 4.88
(0.04e1.53) (0.07e1.37) (0.02e3.60) (0.02e25.73) (0.12e6.50)
power remained the same with no further deterioration in three patients (Table 2). Overall, 10 of 15 patients were ambulatory after treatment with SBRT. There was no difference in local control (Figure 2) and overall survival in the two groups of patients (Table 2). Radiological evaluation with MRI and PET-CT scans was available for 36 treated lesions. A radiological complete response was seen in 13 lesions (36.1%), a stable/partial response in 18 lesions (50.0%) (overall response rate 86.1%)
Fig 2. Local control in patients with or without metastatic epidural compression.
(1.08e22.37) (1.38e22.54) (10.99e27.09) (0.91e28.81) (3.03e28.81)
(0.22e4.71) (0.29e7.04) (1.22e12.83) (0.38e25.74) (1.28e25.69)
(0.15e9.48) (0.21e7.18) (0.91e11.76) (0.19e11.77) (0.98e10.80)
and progression in five lesions (13.09%). All patients tolerated SBRT well. Acute side-effects were generally mild, except in two patients who experienced pain ‘flare’ for 3e5 days despite premedication with steroids. No long-term complications, including neurotoxicity, have been observed so far.
Discussion The spine is the third most common site of metastatic disease following the lung and liver and the most common bony site [9]. About 90% of symptomatic spinal metastases present with pain and over 40% of patients have a neurological deficit, including cord compression [9]. MEC is one of the major factors causing neurological deficit in patients with spinal metastases. In this study, 50% of patients with MEC had a neurological deficit as compared with 15.6% of patients without MEC. MEC is seen as a result of direct extension from vertebral metastases by extension through intervertebral foramina, by haematogenous dissemination or rarely by lymphatic infiltration. Involvement of the epidural space may result in compression of the spinal cord or cauda equina or in radiculopathy because of compression of nerve roots [10]. Twenty of 52 patients (38.4%) had MEC in this study. MRI of the spine helps in delineating both the bony involvement and neural compression from epidural tumour. Subtle epidural extension may be missed on CT and MRI is considered superior in patients with suspected epidural extension of the tumour [1]. The combination of
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Fig 3. A patient of carcinoma prostate with spine metastasis. A-MRI axial scan showing D9 metastasis with MEC. B-MRI e sagittal scan. CSagittal scan showing isodose distribution through D8 and D9 vertebrae. D-GTV (black), GTV (epidural) (arrow), in planning CT scan. E-SBRT dose distribution with VMAT (2 Arcs), 24Gy Isodose encompassing GTV, 21Gy GTV (epidural) and posterior elements (GTV 2). F-follow up MRI scan through D9 vertebra shows significant radiosurgical decompression achieved at 24 months.
T1-weighted spin-echo and STIR sequences has been shown to be the most useful. Lesions tend to be T1 hypotense, T2 hyperintense and avidly enhancing. Contrast enhancement in MRI is helpful in delineating the extent of the tumour and outlining the regions of spinal cord compression [11]. Epidural lesions are more clearly seen in cervical and thoracic spine where there is paucity of epidural fat [12]. It can cause minimal canal compromise to thecal indentation and spinal cord displacement (Table 2). Conventionally patients with spine metastasis have been treated with palliative radiation in one to 12 fractions. It yielded pain control in 60e70% and neurological improvement in around 50% of patients [2]. However, the median duration of response with 8 Gy (single fraction) or fractionated radiation of 20e35 Gy in 10e12 fractions is around 6 months [2]. Advances in systematic therapy have led to improved survival rates of many cancers and, therefore, better local control in the spine would provide a better quality of life. In patients with MEC, different approaches of fractionated radiation have yielded local control ranging from 60 to 77% and improvement in motor functions in 28e30% of patients [13]. Some of the retrospective studies have reported better local control with long-course radiotherapy
than with short-course radiotherapy [14]. It emphasises the need for a higher dose of radiation for improved local control of the epidural component. However, the radiation dose is often compromised due to the limited radiation tolerance of the spinal cord, resulting in a suboptimal dose to the epidural component. Patients with spinal metastases with MEC have also been managed with surgery followed by radiation. It can improve the neurological status and the ability to walk significantly as compared with radiation alone [15]. However, most patients with spine metastasis have a limited life span due to multiple metastases and poor general condition and therefore surgery is only possible in a few selected patients [6]. In this study, 42.3% of patients with spine metastases also had visceral metastases (Table 1). Surgery is usually reserved for patients with rapid neurological deterioration, unstable spine or sub-luxation of the affected vertebra [16]. Caution must be exercised with SBRT in patients with motor power less than grade 3e4. In case of neurological deterioration, surgical intervention can be re-explored. SBRT in single or hypofractionated regimens has been shown to be safe and effective in the treatment of spinal metastases. It yielded local control as high as 80e90% and neurological improvement in 85% of patients, which is
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much superior to that reported with conventional radiation [4,6]. However, there is lack of clarity regarding the efficacy of SBRT in patients with MEC due to spinal metastasis. Some authors have excluded patients from the SBRT protocol if the patient had ‘symptomatic’ malignant spinal cord compression [3]. On the other hand, a response rate of 82% has been reported in patients with epidural cord compression documented on radiographic reduction of epidural or paraspinal extension of the tumour [6]. Others have treated patients with rapid neurological deterioration or spine instability with surgery followed by SBRT [4]. With increasing use of SBRT, more and more patients with MEC will be offered SBRT. In the present series, 20 of 52 patients (38.4%) had MEC from vertebral metastasis and 50% of them had neurological deficit. Due to the close proximity of the epidural component to the spinal cord, it is often difficult to achieve the desired dose to the affected vertebra within the spinal cord tolerance. Furthermore, two primary sites of failure in patients treated with spine SBRT have been observed, either at the osseous margin posterior to the vertebral body or in the epidural space, which is often under-dosed in order to meet the spinal cord planning constraints [17]. The fusion of planning CT with MRI with contrast is crucial to delineate the GTV and the adjoining epidural extension. CT-MRI fusion was carried out for all patients with suspected epidural extension and neurological deficit in this study. About 50% of the recurrences after SBRT spine have been reported to occur at the epidural space [18]. Other sites included pedicle and posterior structures that were not routinely covered in the high dose region. One of the reasons could be missing the unsuspected epidural extension on CT. Another reason could be the under-dosing of the epidural component due to its close proximity to the spinal cord. In this study, the epidural component (GTV epidural) received a median dose of 21.16 Gy as compared with 23.44 Gy to GTV vertebra (w90%) within the constraints of the spinal cord (Table 3). In the present study, the SBRT dose delivered was 8 Gy three fractions instead of a single fraction to achieve a higher biological dose to the vertebra and the epidural component. Conversion of the SBRT dose using the linear quadratic model yielded a median biologically equivalent dose (BED) (a/b ¼ 10) for the GTV of 40.6 Gy10 (range 30.1e50.8 Gy) in patients without MEC. The BED equivalent single fraction dose was 15.8 Gy10 (range 13.0e18.1 Gy10). Similarly for patients with MEC, the median BED was 41.8 Gy10 (30.7e47.9 Gy) and the single fraction equivalent dose was 16.0 Gy10 (range 13.2e17.4 Gy10). The median three fraction spinal cord Dmax (a/b ¼ 3) was 15.71 Gy3 in patients without MEC and 17.36 Gy3 in patients with MEC (Table 3). The corresponding single fraction Dmax equivalents were 10.7 Gy3 and 11.0 Gy3, respectively. The median spinal cord Dmax was higher for patients with MEC in order to achieve the maximum possible dose to the epidural component. The three fraction schedule of SBRT provided higher spinal cord constraint (to 0.35 cm3) of 18 Gy in three fractions (2 Gy equivalent 32 Gy3) in comparison with 10 Gy in one fraction
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(2 Gy equivalent 25.9 Gy3) [8]. It further helped in achieving a higher dose to the GTV and GTV epidural. Recently, thecal sac constraints of Dmax 17.4e18.8 Gy in three fractions have been proposed that would limit myelitis rates to below 2e3% [19]. We did not see any patient with radiation myelitis in this study, although the follow-up was short to assess this complication. Complete pain relief was seen in 90% of patients with MEC and in 93.75% of patients without MEC, which was comparable in the two groups. Similarly, neurological improvement was seen in 60% of patients in both groups; in the rest of the patients except one, neurological status remained the same with no further deterioration. Ten of 15 patients who presented with varying degrees of neurological deficit were ambulatory after SBRT. Ryu et al. [6] reported an epidural tumour response rate of 80%, with a complete response of 27%, a partial response (>50% tumour volume reduction) of 30%, a minimal response (25e50% tumour volume reduction) of 23% and no response/tumour progression in 6%. In the present study, corresponding figures of complete response, partial response and progressive tumour were 36.1, 50 and 13.09%, respectively, as assessed on CT-PET and/or MRI, which are in agreement with the study by Ryu et al. [6]. Improved techniques of detection of epidural tumour with MRI, better radiation techniques like volumetric modulated arc therapy delivered with high definition MLC (2.5 mm leaf width in our set-up) and sophisticated image guidance systems (like the Exactrac 6D X-ray system) have helped to deliver the highest possible dose to the vertebra and adjacent epidural component while sparing the spinal cord. These factors seemed to have contributed to high rates of local control in patients with MEC in this study. The epidural component received a median of 90% of the dose received by the vertebra (GTV), which yielded good local control. Thus, SBRT can deliver a high dose of radiation to the affected vertebra(e) and the epidural extension with high local control, pain relief and neurological recovery. The presence of MEC did not confer an adverse influence on the outcome of SBRT and, therefore, surgery can be avoided in a significant number of patients. However, patients with rapid neurological deterioration, spine instability and motor power grade 3 should undergo surgery first for a better neurological outcome. More studies and a longer follow-up would help in further defining patient selection for SBRT in spine metastases with MEC.
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