TagedFiur TagedEn TagedFiur TagedEn

TagedH1Stereotactic Body Radiation Therapy for

Spinal Metastases: Benefits and LimitationsTagedEn
TagedPMatthias Guckenberger, MD,* Max Dahele, MBChB, PhD,y Wee Loon Ong, MBBS,z,x and
Arjun Sahgal, MDzTagedEn

Progress in biological cancer characterization, targeted systemic therapies and multimo-

dality treatment strategies have shifted the goals of radiotherapy for spinal metastases
from short-term palliation to long-term symptom control and prevention of compilations.
This article gives an overview of the spine stereotactic body radiotherapy (SBRT) method-
ology and clinical results of SBRT in cancer patients with painful vertebral metastases,
metastatic spinal cord compression, oligometastatic disease and in a reirradiation situa-
tion. Outcomes after dose-intensified SBRT are compared with results of conventional
radiotherapy and patient selection criteria will be discussed. Though rates of severe toxic-
ity after spinal SBRT are low, strategies to minimize the risk of vertebral compression frac-
ture, radiation induced myelopathy, plexopathy and myositis are summarized, to optimize
the use of SBRT in multidisciplinary management of vertebral metastases.
Semin Radiat Oncol 33:159−171 Ó 2023 The Authors. Published by Elsevier Inc. This is an
open access article under the CC BY license (http://creativecommons.org/licenses/by/
4.0/)

TagedH1Conventional Radiotherapy and metastases, which form the majority of all sites of bone
metastases.2 Spinal metastases often present with pain, com-
Rationale for SBRTTagedEn pression of the spinal cord or cauda equina and associated
neurological deficits, spinal instability, pathological fractures
T ogether with lung and liver metastases, bone metastases
are a frequent sites of tumor spread, with » 18.8 per
100,000 cancer patients diagnosed with de novo bone
and bone marrow failure that can all deleteriously affect
patient QoL and present a significant economic burden.3
metastases per year.1 The most common primary tumor TagedPTreatment of spinal metastases requires multidisciplinary
types resulting in bone metastases among patients over 25 collaboration, and radiation therapy being a key component
are lung cancer followed by prostate and breast cancers. of the management strategy. Conventional radiation therapy
Overall survival (OS) has been reported not to be different is an evidence-based treatment modality for localized pain
between metastatic cancer patients with and without bone caused by spine metastases. Based on multiple randomized
metastases,1 with median survivals of about 6 months. How- trials and subsequent meta-analyses, conventional radiother-
ever, the pattern of metastasis to the skeletal system is associ- apy achieves overall pain response rates of »60% and com-
ated with potentially serious consequences on patient plete pain response rates ranging from 10%-25%.4,5
quality-of-life (QoL), especially for patients with spinal Importantly, the evaluation of pain outcome is influenced by
the method used for pain response evaluation, the scoring
*
TagedEn Department of Radiation Oncology, University Hospital Zurich, University system and whether pain medications are incorporated into
of Zurich, Zurich, Switzerland the assessment.TagedEn
TagedEnyDepartment of Radiation Oncology and Amsterdam Cancer Center, TagedPConventional palliative external beam radiotherapy has
Amsterdam UMC, location Vrije Universiteit, Amsterdam, the traditionally been delivered with low radiation doses. A sin-
Netherlands
z
TagedEn Department of Radiation Oncology, Sunnybrook Health Sciences Centre,
gle fraction of 8Gy, 20Gy in 5 fractions, and 30Gy in 10 frac-
Odette Cancer Centre, University of Toronto, Toronto, Canada tions are commonly prescribed regimens that have been
x
TagedEn Department of Radiation Oncology, Alfred Health, Central Clinical School, evaluated in randomized trials. No dose response relation-
Monash University, Melbourne, Australia ship has been confirmed within these regimens, though
TagedEnAddress reprint requests to: Matthias Guckenberger, MD, Department of retreatment rates are higher for less dose intense single frac-
Radiation Oncology, University Hospital Zurich (USZ), University of
Zurich (UZH), R€amistrasse 100, CH - 8091, Zurich, Switzerland.
tion (8Gy) RT[cite]. Approximately 20% of patients will
E-mail: [email protected] require retreatment after a single fraction of 8Gy.

https://doi.org/10.1016/j.semradonc.2022.11.006 159
1053-4296/© 2023 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
TagedEn160 M. Guckenberger et al.

Furthermore, increased remineralization after multiple-frac- spinal cord and all other adjacent critical organs-at-risk
tion radiotherapy as compared to single-fraction radiother- (OAR). The close spatial relationship between the target vol-
apy has been observed, 6 in addition to a lower rate of ume and the spinal cord makes vertebral SBRT one of the
vertebral compression fracture (VCF), that may promote bet- most complex applications of radiotherapy,16 with a thin
ter longer-term spinal stability. For these reasons conven- line between optimal local tumor control and avoidance of
tional radiotherapy is most appropriate for patients being radiation-induced myelopathy − a rare but serious complica-
treated palliatively, with a limited life expectancy of less than tion in radiation oncology. Best practice of spinal SBRT has
3 to 6 months. Typically, the conventional radiation treat- been described by several expert groups.17-20 After accurate
ment volume includes those spinal segments causing pain, staging and careful medical and medication history, supple-
and up to 1 segment above and below as a safety margin, mented by clinical examination including neurological func-
using conventional 2D simulation or 3D-conformal planning tion, the following vertebral metastasis specific assessments
and simple delivery techniques.TagedEn are ideally performed as part of the decision-making process
TagedPFor metastatic spinal cord compression (MSCC) and of SBRT vs conventional radiotherapy: pain is documented
cauda equina syndrome, rapid and multidisciplinary man- quantitatively using validated instruments such as the visual
agement is essential. Evaluation with a full spine MRI, initia- analogue scale (VAS) or brief pain inventory (BPI),21 spinal
tion of systemic steroids, and consideration of surgical instability is assessed using the Spinal Instability Neoplastic
decompression and/or radiotherapy are the hallmarks of the Score (SINS) 22 and epidural spinal cord compression using
treatment strategy.7-9 No difference in efficacy with respect the score developed by Bilsky et al. 23. Multimodality imag-
to motor function, bladder function or OS has been reported ing using high-resolution CT and MRI (T1 thin slice axial
between single-fraction and multiple-fraction conventional sequences without contrast, which can be performed with
radiotherapy.7 However recurrences after RT for MSCC are contrast in presence of paraspinal or epidural disease, and
noted to be higher for less dose intense regimens among T2 thin slice axial non-contrast sequences) are the corner-
patients living long enough to experience risk of recurrence, stones for organ-at-risk and target definition,17 preceded by
generally greater than 4 to 6 months.10TagedEn careful image registration.24 Target volume definition follows
TagedPThe landscape of metastatic cancer care has changed sub- international consensus recommendations 18,20 and the plan-
stantially within the last decade, and this has had significant ning organs-at-risk (PRV) concept is applied for the spinal
consequences for radiotherapy of spinal metastases. In sev- cord. Intensity-modulated treatment (IMRT) planning allows
eral patient cohorts, OS has been substantially improved by generation of highly conformal dose distributions with steep
advances in systemic therapy, for example in metastatic mel- dose gradients between the target volume and the spinal
anoma treated with immune checkpoint inhibition (6.5 years cord; volumetric modulated arc therapy (VMAT) and flatten-
OS of 49%),11 ALK-translocated non-small cell lung cancer ing-filter-free (FFF) technologies are of value to minimize
(NSCLC) treated with ALK inhibitors (5 years OS of 63%) 12 radiotherapy delivery times.25 Image-guided treatment deliv-
and non-driver mutated NSCLC treated with immune check- ery, 26 as well as active 27,28 (imaging) or passive 29 (immobi-
point inhibition +/- chemotherapy (5 years OS of 23%).13 lization) management of inter- and intra-fractional
These advances in systemic therapy and improved OS rates uncertainties, are mandatory components of SBRT delivery.
have changed the goals of “palliative” radiotherapy from Robotic SBRT is an alternative to C-arm linac based SBRT,
short-term palliation to durable symptom management and and no differences in outcomes have been reported between
prevention in the context of cancer as a chronic disease. these 2 technologies.30 Both clinical and imaging-based 31
Dose intensified radiotherapy in the form of stereotactic follow-up are performed for efficacy assessment and to diag-
body radiotherapy (SBRT) might achieve durable local con- nose SBRT-induced toxicity assessment, especially vertebral
trol of metastases and, therefore, achieve longer duration of compression fracture (Fig. 1). Spinal MR is the gold standard
pain response and long-term prevention of spinal instability to follow patients as the most common pattern of local fail-
and fracture. Additionally, more effective tumor cell killing ure is epidural progression. Alternative methods of imaging-
by SBRT might improve overall pain response rates and com- based follow-up include (spinal) CT, and for patients where
plete pain response rates to more effectively palliate patients blood markers are reliably (eg PSA in prostate cancer
even with a limited life expectancy. In patients with MSCC, patients) follow-up can be personalized at the discretion of
SBRT might enhance the response leading to relief of spinal the treating radiation oncologist with clinical assessments.
cord compression and consequently durable as well higher The process of spine SBRT is summarized in Table 1.TagedEn
rates of preservation of neurological function. Finally, SBRT
in the context of oligometastatic disease aims for a definitive
treatment of spinal metastases to achieve long-term local TagedH1Outcome of SBRT for Painful Spinal
metastases control, freedom from disease and even cure.14,15TagedEn
MetastasesTagedEn
TagedPFour randomized trials comparing conventional radiother-
TagedH1SBRT MethodologyTagedEn apy to SBRT for painful vertebral metastases have been
reported, 3 of which have been fully published. Sahgal et al.
TagedPSBRT for spinal metastases aims to deliver dose-escalated performed a multicenter randomized phase 2/3 trial compar-
radiation therapy to the tumor while adequately sparing the ing SBRT (24Gy in 2 fractions) with conventional
TagedEnStereotactic Body Radiation Therapy for Spinal Metastases 161
TagedEn TagedFiur

Figure 1 (A, B): Pre-treatment MRI and CT imaging of a 74 years old patient with metastatic prostate cancer; (C, D):
VMAT-based SBRT planning using a simultaneous integrated boost concept with 30Gy in 10 fractions (low-dose target
volume) and 48.5Gy in 10 fractions (high-dose target volume); (E, F): MRI and CT imaging follow-up showing local
control w/o vertebral compression fracture;TagedEn

radiotherapy (20Gy in 5 fractions).32 Patients with a painful standardized BPI and International Consensus Pain Response
site of spinal metastases, no more than 3 consecutive verte- Endpoint (ICPRE) criteria specific to the radiation target vol-
bral segments, a SINS score of less than 12, and no neurolog- ume. Patients were followed up to 6 months from treatment,
ically symptomatic spinal cord or cauda equina compression and the median follow-up for the 229 patients was 6.7
were enrolled. Complete pain response at 3 months was the months. The trial achieved its primary endpoint with the
primary endpoint and assessment was based on the complete pain response rate at 3 months favoring SBRT at

TagedEnTable 1 Workflow Process for Spine SBRT

Pre-treatment assessments
Clinical examination including neurological function assessment
Quantitative pain assessment using validated instruments such as the visual analogue scale (VAS) or brief pain inventory (BPI)
Spinal instability assessment using the Spinal Instability Neoplastic Score (SINS)
Epidural spinal cord compression assessment using the score developed by Bilsky et al.
SBRT planning
High-resolution CT imaging
High-resolution MR imaging: T1 without contrast; T1 with contrast in presence of paraspinal or epidural disease; T2 non-
contrast
Careful rigid image-registration
Target volume definition following international consensus recommendations
IMRT treatment planning
VMAT and flattening-filter-free (FFF) technologies to minimize SBRT delivery times
Daily pre-treatment image-guided patient set-up
Passive or active intra-fraction motion control
Follow-up
Clinical follow-up using pre-treatment assessments
Imaging follow-up using high-resolution CT and / or MR imaging
TagedEn162 M. Guckenberger et al.

Pain Reduction 35% vs 14% following conventional radiation. This signifi-

40.3% vs 57.9% 3.00 vs 3.83

69.6% vs 47.8% 22.4 vs 20.3

2.9 vs 2.5
cant difference was maintained in multivariable-adjusted
analyses (odds ratio 3.5), and was durable at the 6-month
secondary endpoint. The University Hospital of Heidelberg
performed a randomized explorative trial comparing high
dose single-fraction SBRT (24Gy) to 3D conformal palliative
radiotherapy (30Gy in 10 fractions).33 The primary endpoint

Study used the trials within a cohort concept (TwiCs), allowed various fractionations, included non-spine bone metasatses and is limited due to large number of drop-outs.
was pain relief determined by a >2 point improvement based
Overall Pain

53% vs 39%

40% vs 32%
Response

on the visual analog scale at 3 months and ICPRE applied.

Although at 3 months the complete pain response rate was
44% following SBRT vs 17% with conventional radiation,
the difference was of borderline significance, only (P=0.057).
43.5% vs 17.4%

At 6 months the complete pain response rate was 53% fol-

Complete Pain

Complete pain response @ 3 mo 35% vs 14% *

lowing SBRT vs 10% with conventional radiation, and was

Response

significant (P=0.003). It is important to note that the trial

was underpowered with only 55 patients. In both trials,
SBRT was not associated with worsened QoL.34 The Utrecht
University medical center performed a phase II randomized
trial within a prospective cohort (TwiCs) comparing various
SBRT fractionations (18Gy in 1 fraction, 30Gy in 3 fractions,
Pain response @ 3 mo (min 3

Pain response @ 3 mo (min 2

Pain response @ 3 mo (min 2

or 35Gy in 5 fractions) to various conventional radiotherapy

regimens (8Gy in 1 fraction, 20Gy in 5 fractions, or 30Gy in
10 fractions).35 The trial was not specific to spinal metasta-
TagedEnTable 2 Randomized Trials Comparing Conventional Radiotherapy and SBRT for Painful Spine metastases

ses, the dosing non-standardized, the design was based on a

TwiCs design as opposed to standard randomized controlled
trial methods as performed by Sahgal et al. and Sprave et al,
Endpoint

points)

points)

points)

and the trial was underpowered with a high rate of dropout.

Therefore, we cannot draw definitive conclusions from this
negative study, which did not observed improved pain
response after SBRT. The randomized phase 3 RTOG 0631
trial, which compared single fraction SBRT (16Gy or 18Gy
1 £ 18 Gy, 3 £ 10 Gy or 5 £ 7 Gy
16Gy / 18Gy in 1Fx vs 8Gy in 1Fx

vs 1 £ 8 Gy, 5 £ 4 Gy or 10 £ 3

in 1 fraction) to conventional radiotherapy (8Gy in 1 frac-

24Gy in 1Fx Vs 30Gy in 10Fx

tion) to sites of painful spinal metastases, reported no

24Gy in 2Fx vs 20Gy in 5Fx

improvement in pain response (defined as a minimum 3

point drop in the VAS pain score) at 3 months.36 The trial
has only been reported as an abstract in 2019 and, as such,
no firm conclusions can be drawn until the final report is
# pts Randomization

published. A summary of all 4 randomized trials is given in

Table 2.TagedEn
TagedPSeveral single arm prospective phase II trials have
Gy

reported pain response after spinal SBRT. Gerszten et al.

Reported as abstract and not as full manuscript, yet.

reported a pain response rate of 96% after single fraction

SBRT with median 19Gy for painful breast cancer spine
229
339

110
55

metastases (n=50 patients).37 Ito et al. reported an overall

and complete pain response rate of 83% and 71%, respec-
University Medical Center Utrecht 35,#

tively, after SBRT with 24Gy in 2 fractions.38 Guckenberger

LBA 2 CCTG SC.24/TROG 17.0632

et. al performed a multicenter phase II trial with pain

response at 3 months as the primary endpoint.39 After treat-
ment with fractionated SBRT (48.5Gy in 10 fractions or
University of Heidelberg33

35Gy in 5 fractions), overall and complete pain response

* Statistically significant.
NRG / ROTG 063136 +

rates were 82% and 31%, respectively. With a median fol-

low-up of 60 months for living patients, the net pain relief
(sum of time with pain response divided by overall follow-
up time) was 74% indicating durable pain response after
SBRT.TagedEn
TagedPTherefore, despite heterogeneity in clinical trial design
Study

and details of SBRT practice and outcome, the available data

+
#

indicate that SBRT is associated with higher rates of overall

TagedEnStereotactic Body Radiation Therapy for Spinal Metastases 163
TagedEn TagedFiur

Figure 2 Patient with a L2 RCC metastases involving the vertebral body, left sided posterior elements and significant
paraspinal extension. The patient was treated with 28 Gy in 2 daily fractions. The baseline treatment planning axial T2
image is shown on the left with representative isodose lines from the dose distribution superimposed. On the right is
the 2 year post-SBRT MRI with T2 signal changes evident within the left paraspinal muscles and psoas muscle which is
distinctive from the left. However, some left sided paraspinal muscle signal change is observed, which is associated
with exposure to the higher dose isodose lines. The patient’s disease responded with reduction in the paraspinal dis-
ease and, therefore, myositis was diagnosed and the patient clinically suffered from chronic discomfort.TagedEn

and complete pain response when compared to conventional frequently used:52,53 2 of the 4 spinal oligometastases studies
radiotherapy. Especially patients with longer life expectancy used single fraction SBRT (n=72 SBRT treatments) with
and patients with so-called “radioresistant” histologies doses ranging between 16Gy [BED10 41.6Gy] and 24Gy
should be evaluated as candidates for SBRT. The strongest [BED10 81.6Gy] and 2 studies (n=185 SBRT treatments)
evidence is available for delivery of SBRT with 24Gy in 2 used fractionated SBRT (27Gy or 30Gy in 3 fractions [BED10
fractions. For patients with short life expectancy (<3-6 51.3 or 60Gy]; 35Gy in 5 fractions [BED10 59.5Gy]). Long-
months) and radiosensitive histologies, single fraction con- term local spinal metastasis control has been reported in a
ventional radiotherapy is an effective standard of care.TagedEn prospective phase II trial with 57 patients 39: after fraction-
ated SBRT with 5 or 10 fractions the freedom from local spi-
nal-metastasis progression was 82% after a median follow-
TagedH1Spine SBRT in Oligometastatic up of 60 months for living patients. Studies using a single
Cancer PatientsTagedEn fraction SBRT approach with 24Gy confirmed high rates of
local metastases control beyond 5 years follow-up.54,55TagedEn
TagedPSBRT is the most frequently applied treatment to sites of TagedPTherefore, we conclude that SBRT achieves high and
metastases in those randomized trials evaluating the role of durable rates of local metastasis control in oligometastatic
local tumor ablation in patients with oligometastatic dis- cancer patients, and should be considered as a standard of
ease.40-45 Importantly, patients with vertebral metastases care in this situation. SBRT has been performed most fre-
were not excluded from any of these trials. In the UK pro- quently using a multiple-fraction regimen, and the optimal
spective registry study, which enrolled 1422 oligometastatic dosing has yet to be determined, highlighting the need for
cancer patients treated with SBRT, spinal metastases were comparative randomized studies. We would recommend
the site first treated in 132 patients (9.4%);46 spinal metasta- either high dose single fraction SBRT (20-24 Gy in 1 fraction)
ses were the fourth most frequent location after lymph node or high BED multi-fraction regimens ranging from 24-28 Gy
metastases (31.3%), lung metastases (29.3%) and bone in 2, 30Gy in 3 or 35-40Gy in 5 fractions.TagedEn
metastases (12%). The large international retrospective study
by Poon et al. included 1033 patients and 1416 SBRT treat-
ments, of which 225 (15.9%) were located in the spine. A
systematic review and meta-analysis about safety and efficacy
TagedH1Spine SBRT for MSCCTagedEn
of SBRT for oligometastatic disease identified and analyzed TagedPWith MSCC being frequent in metastatic cancer patients 56,57
21 studies with 943 patients and 1290 SBRT treatments;47 4 and limited progress in early detection 58 and treatment, 59
studies with 257 SBRT treatments were focused on oligome- SBRT has been considered as a promising strategy to achieve
tastatic spinal SBRT.48-51 In these 4 prospective studies the 1 rapid and durable tumor response, relief of the spinal cord
year local progression free survival (PFS) ranged between compression and preservation of neurological function. Pri-
80.5% and 100% with median follow-up times between 9 mary SBRT for symptomatic high-grade MSCC has not been
and 24 months. These favorable local control rates were tested in prospective trials, and the retrospective evidence is
achieved with SBRT doses lower than usually applied for limited. In a series of 62 60 and 33 patients,61 epidural tumor
lung or liver oligometastases, where minimum dose of volume reduction was 65% on average following 16Gy in 1
100Gy BED10 (biological effective dose to tumor) are SBRT fraction, and improvement of neurological function
TagedEn164 M. Guckenberger et al.

was achieved in 81% of the patients. Despite these promising radiation dose.75 This is especially important in patients with
results, this strategy has not been widely adopted most likely a good prognosis. Image-guided, intensity-modulated stereo-
due to the challenges of delivering SBRT within a very short tactic RT fulfills these requirements. Depending on the clini-
timeframe after diagnosis of MSCC.62,63 Knowledge-based cal situation, such techniques can be used to deliver a classic
and machine learning approaches for spine SBRT planning SBRT schedule (high total dose with high-dose per fraction)
are currently being developed,64,65 which might help to or a more suitable alternative (eg a longer, more convention-
address this issue in the future.TagedEn ally fractionated schedules with varying total doses, lower
TagedPA hybrid approach of minimally invasive separation sur- dose/fraction and more fractions).TagedEn
gery with circumferential spinal cord decompression fol- TagedPThe available evidence for the use of spine SBRT in the re-
lowed by SBRT is an alternative strategy. The gain lies in irradiation setting was described in a 2019 review for the
surgical decompression to immediately relieve mass effect on National Health Service in England.76 This identified 1 sys-
the critical neural structure, and any associated deficits. tematic review and 9 non-comparative cohort studies, and
Therapeutically this combined approach has been associated concluded that there were severe limitations in the quality of
with excellent local control rates and data suggest that those the evidence, high levels of heterogeneity in study popula-
patients downgraded from high (Bilsky) grade epidural dis- tions and variation in methodology and the reporting of
ease to lower (or no) grade epidural disease following post- end-points.77-86TagedEn
operative SBRT66,67 have a local control benefit. Therefore, TagedPFor patients salvaged with re-irradiation spine SBRT, the
the goal is to decompress and resect the epidural disease and local control rate ranges from » 80-90% at 1-2 years. Consis-
consolidate with SBRT. Ito et al. performed a prospective tent with prior reports by Garg et al observing a 12-month
phase II trial in patients with symptomatic MSCC, who were local control rate of 76%81 and Hashmi et al observing a 12-
treated with preoperative embolization, separation surgery, month local control rate of 83%,82 Detsky et al reported an
and spine SBRT (24Gy in 2 fractions);68 surgery was per- actuarial risk of local failure of 14% and 19% at 12 and 24
formed via a posterior approach, with decompression and a months, respectively, with a median time to failure of 8.2
fixation procedure. The majority of the 33 enrolled patients months. In that series of 43 patients and 83 treated spinal seg-
had a baseline pre-operative Bilsky score of 3 (64%), which ments receiving salvage spine SBRT after prior conventional
was reduced to a score of 1 in 90% of the patients 3 months radiotherapy (1-3 courses in 60, 16 and 1 segments respec-
after treatment. The 1-year local failure rate was 13%, and 20 tively) or SBRT (6/83 segments),87 epidural progression alone
of the 33 patients were ambulatory after 12 months; among (8/15 segments) and vertebral body/posterior element pro-
the 15 patients with normal ambulatory function at registra- gression with epidural disease progression (5/15 segments)
tion, 8 (53%) had maintained their function 12 months later. were the dominant patterns of failure. The importance of epi-
Similar promising data have been reported by other stud- dural progression was also highlighted by Garg et al who
ies.69-72TagedEn found that 13/16 tumors that progressed were within 5mm of
TagedPTherefore, where available, minimally invasive separation the spinal cord (6 subsequently developed spinal cord com-
surgery followed by post-operative SBRT may be considered pression)81 and, by Ito et al, who reported a 25.8% 1-year rate
in selected cases. It requires appropriate surgical expertise of local failure in a series of 133 lesions in 123 patients, of
and experience, close collaboration between spine surgery which 53 (39.8%) were compressing the spinal cord.88TagedEn
and radiation oncology, and it is important to recognize that TagedPWhile the incidence of grade 3-4 toxicities were low,
post-operative spine SBRT has its own challenges with ranging from 2%-7.3%, there is potential for significant tox-
respect to technique and imaging - a recent guideline has icity and recently, Ito et al reported radiculopathy in 4/17
been published by the International Stereotactic Radiosur- patients (4/19 lesions) treated with 2 high-dose courses of
gery Society (ISRS) to guide safe practice.73TagedEn spine SBRT, causing near complete upper or lower limb
paralysis in 3 patients.89 Garg et al reported lumbar plexop-
athy in 2/59 patients re-treated with spine SBRT, both of
whom remained independently ambulant.81 Ito et al
TagedH1SBRT for Re-irradiationTagedEn reported radiation myelopathy in 3% (4/133) of re-irradiated
TagedPAs patients live longer with metastatic disease, and with lesions.88 This emphasizes the importance of due diligence
many being treated with upfront conventional palliative and care with respect to cumulative radiation dose and treat-
radiotherapy, there will be an increasing number of patients ment technique.90 It is also important to be aware of the
that may require re-treatment of a previously irradiated spine potential for increased risks and unexpected toxic interac-
metastases. Especially since after standard low-dose single- tions between radiation and (new) targeted therapies which
fraction palliative radiotherapy (eg 1 £ 8Gy), the re-treat- many long-term survivors with metastatic disease may be
ment rate (eg for persisting or recurrent pain at least 4 weeks taking.91 With respect to vertebral compression fractures
after prior RT) is »20%.74TagedEn (VCF) a multi-center study reported about 23 patients,
TagedPFor re-irradiation of spinal metastases, the spinal cord and where post-SBRT surgery allowed for analysis of histopatho-
cauda equina are the dose-limiting organs at risk (OAR). logical specimens.92 There was no difference in osteonecrosis
Advanced RT techniques that can limit the dose in the direc- or soft tissue necrosis in patients treated with primary SBRT
tion of such OARS are essential to minimize the risk of as compared to patients treated with salvage SBRT in a reirra-
potentially debilitating toxicity caused by a high cumulative diation situation. This finding is agreement with clinical data
TagedEnStereotactic Body Radiation Therapy for Spinal Metastases 165

by Detsky et al 87 and Hashmi et al,82 which reported sur- 51% were treated with single fraction SBRT.99 After a median
prisingly low (see below) overall (new and progressive) rates follow-up of 11.5 months, there were 57 fractures in the 410
of 4 and 4.5%, respectively, and no radiation myelopathy.TagedEn segments (13.9%) of which 47% were new vs 53% progres-
TagedPIn conclusion, the available evidence for salvage re-irradi- sion of an existing fracture. Median time to VCF was 2.5
ation with spine SBRT indicates that it is effective (local fail- months and 65% occurred within 4 months of SBRT. Jawad
ure » 15-25% at 12 months); generally safe, assuming et al analyzed 594 tumors treated from 8 institutions, most
adherence to appropriate (technical) standards; and an treated with a single fraction SBRT and 24% had a baseline
important option for patients with tumor progression after VCF.100 After a median imaging follow-up of 8.8 months
prior irradiation. Following reirradiation, epidural progres- post-spine SBRT, they observed new and progressive VCF in
sion is the dominant pattern of progression and influenced 3% and 2.7%, respectively.TagedEn
by factors such as the proximity of the target to the spinal TagedPFrom the SC24 Canadian Clinical Trial Group (CCTG)
cord and the dose-constraints applied. Radiculopathy and multicenter randomized phase 2/3 trial comparing SBRT
myelopathy have been reported and patients should be (24Gy in 2 fractions) with conventional radiotherapy (20Gy
appropriately counselled. The risk of toxicity that is deemed in 5 fractions) the risk of any grade VCF was 17% in the con-
to be acceptable, may be influenced by factors like the ventional arm and 11% in the SBRT arm, which was not sig-
patient’s wishes/attitude to risk, alternative/additional treat- nificantly different, however, follow-up concluded at the 6
ment options and the consequences of uncontrolled disease. month post-SBRT visit. Long term outcomes from a sub-
Therefore, selected patients should be considered candidates cohort of those patients in the SC24 randomized trial treated
for SBRT if a prolonged life expectancy is anticipated.39,93TagedEn at the Sunnybrook Odette Cancer Center (Toronto, Canada)
were recently published and, importantly, they report not
only on the target segment but all metastases within the
TagedH1Vertebral Compression Fracture study defined radiation treatment volume. The sample con-
After SBRTTagedEn sisted of 66 patients with 119 spinal segments treated with
24Gy in 2 SBRT fractions, and 71 patients with 169 spinal
TagedPVertebral compression fracture (VCF) has emerged as the segments treated with 20 Gy in 5 conventional fractions.93
most relevant toxicity associated with high-dose SBRT. There were 12 iatrogenic VCF, 8 of which occurred after
Although commonly seen in post-menopausal women with SBRT (8/119 segments=6.7%). Grade 3 VCF toxicity was
osteoporosis, which weakens the structural integrity and only seen in the SBRT group and 4 of the SBRT-induced
resilience of the vertebra, metastatic tumor and sufficient VCF required surgery or cement augmentation (4/66
doses of radiation can also adversely affect bone architecture patients=6.1%), compared with none in the conventional
and biomechanical properties leading in some cases to frac- radiation cohort. Sprave et al reported a relatively small ran-
ture and collapse.94 VCF are important because they can domized study of 1 £ 24Gy SBRT (n=27 patients, with base-
lead to significant pain that may require opiate analgesia, spi- line VCF in 40.7%) vs 10 £ 3Gy conventional RT (3D
nal deformity, neurological deficit, in some cases spinal conformal RT, 3DCRT, n=28 patients, with baseline VCF in
instability or spinal cord compression requiring invasive sta- 17.9%).101 There were 2 (8.7%) and 1 (4.3%) new fractures
bilization/decompression, reduction in quality of life, and in the SBRT and 3DCRT groups at 3 months post-treatment;
increased healthcare resource utilization.95TagedEn at 6 months there were new/progressive fractures in 5
TagedPTo put it into context, it is important to note that VCF patients (27.8%) the SBRT arm vs 1 new fracture (5%) in the
occurs commonly in vertebrae involved by metastatic 3DCRT arm. No patient required surgical intervention.
tumors. For example, Van den Brande et al recently reported Lastly, Mantel et al reported a new or progressive VCF in
a mean cumulative incidence of 12.6% in patients with spi- 18% and 16.4% of lesions respectively after 5 or 10 fraction
nal metastases,96 and a meta-analysis by Chow et al reported spine SBRT within a phase 2 study (61 lesions in 56 patients,
an incidence of 3.3% and 3% after single (eg 1 £ 8Gy) and pre-SBRT VCF in 27.9% of lesions).102 A total of 3/56
multi-fraction radiotherapy (eg 5 £ 4Gy and 10 £ 3Gy),97 patients (5.4%) had a painful VCF and 2/56 (3.6%) required
which may further increase with longer follow-up. Therefore, surgical stabilization. Lockney et al have also looked specifi-
VCF is not specific to SBRT, however, the risk of serious VCF cally at the vertebrae adjacent to the treated segment(s) and
requiring intervention is potentially greater following high reported a 2.9% rate of adjacent-level VCF after single-frac-
dose SBRT.93 Simultaneously, SBRT might also have a pro- tion SBRT.103 A summary of selected studies reporting VCF
tective effect by achieving long-term local metastases control.TagedEn after spine SBRT is given in Table 3.TagedEn
TagedPThe incidence of VCF after spine SBRT has been TagedPMany factors have been associated with an increased risk
described in numerous single center reports, with a rate of of VCF after SBRT, including the dose per fraction, single-
fracture progression as high as 39% (baseline endplate frac- fraction SBRT vs multi-fraction (for which there is also pre-
ture / mild VCF in 12/62 patients, 19%) being described after clinical support), pre-existing VCF, presence of lytic tumor
high-dose single-fraction SBRT.98 We have learned from and the associated extent of lytic disease, baseline pain, loca-
larger multi-institutional analyses and some prospective trial tion in thoracic spine, a higher (eg >8) pre-treatment SINS
data that there is a dose-complication relationship. For score, a Bilsky score >0, older age (eg >55 years), female sex
example, Sahgal et al reported on 410 treated spinal seg- and histology (eg lung tumor metastases higher, prostate
ments comprising 252 patients from 3 institutions, of which cancer metastases lower).74,93,98-100,102-106 Evidence for a
 TagedEn166
TagedEnTable 3 Summary of Selected Series Reporting VCF Following SBRT
Study Number Patients Median Follow-up Dose and Fractionation (BED New/Progressive VCF Time to VCF Number of Patients
(Spinal Segments (Y) With a/b=3) (Median, Mo) Requiring
Treated) Percutaneous or
Surgical Intervention
Moussazadeh 54 31 (36) 6.1 1 £ 24Gy (216Gy3) 13 treated segments 25.7 mo 5
(36%) in 12 patients
Guckenberger 39 57 (63) 5 10 £ 3/4.85Gy (127Gy3) in 56%; 12 pts (21%) new; 8 pts 2 mo 3 (1 stabilization sur-
5 £ 4/7Gy (117Gy3) in 44% (14%) progressive gery, 2
decompression)
Ning 55 52 (69) 6.7 Varied from 3 £ 8Gy (88Gy3) up 8 treated sites (14%) in 7 7.5 mo 6 (percutaneous ver-
to 1 £ 24Gy (216Gy3) pts (13%) tebroplasty or
surgery)
Ling 135 43 (54) 6.8 1 £ 12-24Gy (60Gy3-216Gy3) 9/54 sites (17%) 10.2 mo 5 (stabilization
surgery)
Zeng 93 66 (119) 0.9 2 £ 12Gy (120Gy3) 8 iatrogenic VCF (8/119 Not reported 4 (3 surgery, 1 percu-
segments=7%) taneous cement)
Abbouchie 136 84 (113) 1.1/treated lesion; Median: 3 £ 10Gy (130Gy3) 2 new (2/113=2%); 3 9.2 mo None
1.0 imaging progressive (3/
113=3%)
Lee 137 85 (173) 1.2 1 £ 16 or 18Gy (101/126Gy3) 21/173 (12%) 11.1 mo 4
Jawad 100 541 0.8; 0.7 imaging Median 1 £ 20Gy (153Gy3) 18 new (3% pts), 16 pro- 3 mo Rate of surgery specif-
gressive (3% pts) ically for VCF not
reported
Sahgal 99 252 (410) 1.0 Varied from 1 £ 8Gy (29Gy3) up 27/410 new (7%); 30/410 2.5 mo 24 (17 cement aug-
to 1 £ 26Gy (251Gy3) progressive (7%) mentation, 6 surgical
stablization, 1 percu-
taneous
instrumentation)

M. Guckenberger et al.
TagedEnStereotactic Body Radiation Therapy for Spinal Metastases 167

protective effect of bisphosphonates is lacking as a mitigating are: 12.4-14.0Gy in 1 fraction, 17.0-19.3Gy in 2 fractions,
strategy,107 and there is increasing recognition that in 20.3-23.1Gy in 3 fractions, 23.0-26.2Gy in 4 fractions and
selected patients with spinal instability, stabilization inter- 25.3-28.8Gy in 5 fractions to keep the risk under 5% for de
vention prior to, or soon after, SBRT may be a consider- novo spine SBRT.122TagedEn
ation.108-110TagedEn TagedPGuidance specific to re-irradiation spine SBRT is more
TagedPIn conclusion, while definitions and reporting vary, post- limited.88,90 In the HyTEC report, factors associated with
SBRT VCF develops in » 10-30% of patients, depends on a lower risk of radiation myelopathy in the re-irradiation set-
number of factors including the dose prescribed and number ting include (1) cumulative thecal sac (or cord PRV) maximal
of fractions, and typically occurs within 3 to 6 months of dose (in EQD2 with a/b of 2) of 70Gy, (2) SBRT thecal sac
treatment. A small minority of these patients » <5%, will maximal dose (in EQD2) of <25Gy, (3) thecal sac maximal
require invasive management.93,98-100 Patients should be dose (in EQD2) to cumulative maximal dose (in EQD2) ratio
counseled about the risks and treating centers should have of < 0.5, and (4) minimum interval between irradiation of
access to a multidisciplinary team able to manage compli- >5 months.122 The number for 1 to 5 fractions re-irradiation
cated VCF.TagedEn tolerance are conservative and although dose escalation has
been reported without complications,62,79,121 there remains
a need for further modelling.TagedEn
TagedPA better understanding of the inherent patient factors
TagedH1Radiation MyelopathyTagedEn determining radiosensitivity is critical to individualizing the
TagedPThe risk of radiation myelopathy is primarily driven by the risk tolerance, as it is clear that some patients can tolerate far
total radiation dose, dose-per-fraction, and history of previ- greater doses than even the most aggressive tolerance data
ous spinal cord irradiation.111 In the de novo spine SBRT set- suggest. Even more critical is to understand the potential
ting, the incidence of radiation myelopathy was reported to effect of concurrent/near-temporal use of radio-sensitizing
be 0.4% in a pooled analyses of more than 1,000 patients,112 targeted therapies and immunotherapies.123-126 Optimal
and the risk is slightly higher at 1.2% following spine SBRT treatment of radiation myelopathy is also poorly understood
reirradiation.77TagedEn with many resorting to corticosteroid, pentoxifylline, vitamin
TagedPIt is generally recognized that external beam radiotherapy D, hyperbaric oxygen and bevacizumab, with no clear data to
of up to 50Gy to the full-thickness of the spinal cord results in guide a treatment algorithm.TagedEn
very low risk of radiation myelopathy.113,114 However, these
data are based on conventional fractionation of 1.8-2Gy per
fraction and homogenous dose distribution to the whole spi-
nal cord circumference. There are challenges in directly trans-
TagedH1Radiation PlexopathyTagedEn
lating these data to spine SBRT for several reasons. Firstly, TagedPBrachial plexopathy and lumbosacral plexopathy are late tox-
there is uncertainty in the applicability of the linear quadratic icities following spine SBRT that are often under-recognized
(LQ) model, that forms the basis for the equation(s) com- and under-reported. Similar to radiation myelopathy, the
monly used to compare different dose-fractionation schedules, risk factors for SBRT-induced plexopathy include total dose
given the much higher dose-per-fraction exposure with to the plexus, dose-per-fraction, and history of prior irradia-
SBRT.115-117 Secondly, the inherent inhomogeneous dose dis- tion. However, in this situation, as the myelination and tra-
tributions in SBRT, with sharp dose fall-off between the target jectory of peripheral nerves are different to the intradural
and spinal cord, can result in small volumes of the spinal cord central nervous system tissue, there may be a dose-length
receiving high doses while the remainder of the spinal cord effect.127 The presumably parallel or mixed radiation
volume is exposed to much lower, markedly sub-toxic response-characteristics of peripheral nerves likely explains
doses.118 Whether the spinal cord is a serial OAR (in which why the toxicity is not as clinically apparent, especially as the
case severe damage to a point in the cord will cause down- nerve roots may not be spared from the full prescribed dose.TagedEn
stream failure in function) or mixed OAR (in which case there TagedPThere are limited published series reporting on radiation-
may be redundancy that effectively allows the damaged region induced plexopathy following spine SBRT.89,128,129 In 1 of
to be bypassed) has been debated extensively. At present the the largest series by Stubblefield et al, 447 patients were
point maximum dose must be respected, however, given the treated with 557 courses of 18-26Gy in a single spine SBRT
greater tolerance than expected, especially with high single- fraction in de novo setting, and there were 14 events of plex-
fraction SBRT, it is likely there is a dose and volume effect opathy reported in 13 patients, at a median of 10 months
(bath and shower effect).119TagedEn post-SBRT.128 In each case, the location of treatment was
TagedPSpecific to spine SBRT, there has been an evolution in the specific to the cervical or lumbosacral spine. In a mature out-
understanding of the radiation dose tolerance. From the ini- come series reported by Zeng et al, in the 79 patients who
tial papers describing the limited cases of radiation survived >3 years following spine SBRT, there were 6 cases
myelopathy,118,120,121 to the most recent comprehensive of plexopathy (1 brachial and 5 lumbosacral) observed at a
modelling analyses by the Hypofractionation Treatment median of 36 months post-SBRT.129 The estimated 3- and 5-
Effects in the Clinic (HyTEC) report,122 the spinal cord dose year cumulative incidence of plexopathy were 2.2% and
constraints have been relaxed. Essentially, the current recom- 5.1% respectively. In this series, all but 1 were cases involv-
mended maximum point dose exposure to the spinal cord ing reirradiation.TagedEn
TagedEn168 M. Guckenberger et al.

TagedPMost of the SBRT tolerance threshold analyses are based maximizing efficacy while minimizing toxicities of spine
on brachial plexus dose following lung SBRT.130,131 From SBRT, including establishing optimal spine SBRT dose regi-
the American Association of Physicist in Medicine (AAPM) mens, refining the understanding of normal tissue dose tox-
Task Group 101 report, for safe delivery of SBRT, the maxi- icity parameters, and guiding optimal management strategies
mum point dose recommendations to the brachial plexus are for VCFs and other potential morbidities of treatment.TagedEn
17.5Gy in 1 fraction, 24Gy in 3 fractions, and 30.5Gy in 5
fractions; and 16Gy in 1 fraction, 24Gy in 3 fractions, and
32Gy in 5 fractions for the sacral plexus.132 However, it is TagedH1Conflict of InterestTagedEn
important to recognize that these dose recommendations are
based on expert recommendations as opposed to toxicity- TagedPMatthias Guckenberger: None. Max Dahele: Research fund-
based evidence.132 More recent modelling work based on ing and honorarium from Varian Medical Systems. Wee
pooled data of 89 patients from the US and Sweden who had Loon Ong: None. Arjun Sahgal: Consultant with Varian
lung SBRT, of which 14 patients developed brachial plexop- (Medical Advisory Group), Elekta (Gamma Knife Icon),
athy, suggested a 10% risk of plexopathy following a maxi- BrainLAB, Merck, Abbvie, Roche; Past educational seminars
mum dose exposure of 26Gy in 3-4 fractions.133 Much has (honorarium) with AstraZeneca, Elekta AB, Varian (CNS
to be learned about the dose-complication relationship spe- Teaching Faculty), BrainLAB, Medtronic Kyphon, Accuray,
cific to the brachial and lumbosacral plexus before firm rec- Seagen Inc.; Research Grant: Elekta AB, Varian, Seagen Inc.;
ommendations can be made.TagedEn Travel accommodations/expenses: Elekta, Varian, BrainLAB.TagedEn
TagedPThe diagnosis and treatment of radiation plexopathy
remains a challenge and is mainly clinical-based. In the authors’
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