Evidence reviews for radiotherapy

Evidence reviews for radiotherapy

Spinal metastases and metastatic spinal cord compression

Evidence review M

NICE Guideline, No. 234

London: National Institute for Health and Care Excellence (NICE); 2023 Sep.

ISBN-13: 978-1-4731-5323-3

Radiotherapy

Review question

How effective is radiotherapy, including both fractionated and unfractionated radiotherapy, for the management of spinal metastases, direct malignant infiltration of the spine or associated spinal cord compression?

Introduction

External beam radiotherapy is widely used for the treatment of painful spinal metastases. A variety of regimen and techniques have been used, and there is some uncertainty over which are the most appropriate. Radiotherapy regimens range from a single dose of 8Gy to fractionated regimens delivered in multiple doses. Different techniques have also been used: for example stereotactic radiotherapy delivers a precise focused dose compared to conventional external beam radiotherapy – but it is unclear whether this leads to improved outcomes.

Summary of the protocol

See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.

Table 1

Summary of the protocol (PICO table).

For further details see the review protocol in appendix A.

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document (supplementary document 1).

Declarations of interest were recorded according to NICE’s conflicts of interest policy.

Effectiveness

Included studies

Nineteen studies were included in this review reporting results from 13 randomised controlled trials (Hoskin 2019 [SCORAD-III trial], Howell 2013 [RTOG 97-14 trial], Lee 2018 [ICORG 05-03 trial], Majumder 2012, Maranzano 2005, Maranzano 2009, Patchell 2005, Rades 2016 [SCORE-2 trial], Rades 2018 [SCORE-2 trial], Rades 2019 [SCORE-2 trial], Roos 2005 [TROG 96-05 trial], Sahgal 2021, Sprave 2018 – a, b, c [IRON-1 trial], Sprave 2018d, e, f [NCT- 02358720], Steenland 1999 [Dutch bone metastasis trial]).

The included studies are summarised in Table 2.

Four randomised controlled trials (Howell 2013 [RTOG 97-14], Majumder 2012, Roos 2005 [TROG 96-05], Steenland 1999 [Dutch Bone Metastasis trial]) compared single fraction radio-therapy to multiple fraction radiotherapy in patients with spinal metastases (without evidence of cord compression).

Three randomised controlled trials (Hoskin 2019 [SCORAD-III trial]), Lee 2018 [ICORG 05-03 trial], Maranzano 2009), compared single fraction radiotherapy to multiple fraction or split-course radiotherapy in patients with metastatic spinal cord compression.

One randomised controlled trial (Sprave 2018a, b, c [IRON-1 trial]) compared image guided intensity modulated radiotherapy (IMRT) to conventional radiotherapy (CRT) in patients with spinal metastases (without evidence of cord compression).

Two randomised controlled trials (Sahgal 2021, Sprave 2018d, e, f [NCT- 02358720]) compared stereotactic ablative body radiotherapy (SABR) to CRT in patients with spinal metastases (without evidence of cord compression).

Two randomised controlled trials compared different regimens of radiotherapy (Maranzano 2005, Rades 2016 [SCORE-2 trial], Rades 2018, Rades 2019 [SCORE-2 trial]) in patients with metastatic spinal cord compression; and 1 randomised controlled trial compared surgery + radiotherapy to radiotherapy alone (Patchell 2005) in patients with metastatic spinal cord compression.

See the literature search strategy in appendix B and study selection flow chart in appendix C.

Excluded studies

Studies not included in this review are listed, and reasons for their exclusion are provided in appendix K.

Summary of included studies

Summaries of the studies that were included in this review are presented in Table 2.

Table 2

Summary of included studies.

See the full evidence tables in appendix D and the forest plots in appendix E.

Economic evidence

Included studies

One economic study was identified which was relevant to this review question. (Turner 2018) The study compared surgery and radiotherapy to radiotherapy alone.

A single economic search was undertaken for all topics included in the scope of this guideline. See supplement 2 for details.

Excluded studies

Economic studies not included in this review are listed, and reasons for their exclusion are provided in supplement 2.

Summary of the evidence

People with painful spinal bone metastases (but no evidence of spinal cord compression)

Single fraction verses multiple fraction radiotherapy

There was very low to low quality evidence of no important difference between single fraction radiotherapy and multiple fractions in terms of pain reduction, spinal stability and overall survival. There was very low quality evidence of an important benefit with single fraction radio-therapy which had fewer treatment related adverse events than multiple fractions.

IMRT verses 3D-CRT

There was no evidence of an importance difference between IMRT and 3D-CRT in terms of quality of life, pain response, treatment related morbidity or overall survival in one small trial. This evidence was very low quality.

SABR verses conventional radiotherapy

There was an important benefit with SABR when compared to conventional RT (EBRT or 3D-CRT) in reducing pain. There was no evidence of important differences in quality of life, treatment related morbidity or overall survival. This evidence was all low quality.

People with metastatic spinal cord compression

Single fraction verses multiple fraction radiotherapy

There was moderate to high quality evidence of no important difference between single fraction radiotherapy and multiple fractions in terms of neurological and functional status, quality of life, pain, overall survival and treatment toxicity.

Short course verses split or long course radiotherapy

There was low to high quality evidence of no important difference between short course radiotherapy and split or long course radiotherapy in terms of neurological and functional status, pain response and treatment related morbidity.

Surgery plus radiotherapy verses radiotherapy alone

There was moderate to high quality evidence of an important benefit for surgery + radiotherapy over radiotherapy alone for neurological and functional status (ability to walk, continence and muscle strength).

See appendix F for full GRADE tables.

Summary of included economic evidence

Table 3

Economic evidence profile of an economic evaluation of the addition of radiotherapy for people undergoing surgery for metastatic spinal cord compression.

Economic model

No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation.

Evidence Statement

Turner 2018 was a cost utility analysis which reported outcomes in terms of cost per QALY gained for surgery and radiotherapy versus radiotherapy alone in people with symptomatic spinal metastases.

The study found surgery and radiotherapy to be cost saving and health improving compared to radiotherapy alone. This was robust to deterministic sensitivity analysis. The study was deemed to be directly applicable to the review question with potentially serious methodological limitations.

The committee’s discussion and interpretation of the evidence

The outcomes that matter most

Health related quality of life, pain and neurological and functional status were chosen as critical outcomes because untreated malignant spinal disease can impact on quality of life due to severe pain and impaired neurological and functional status. Overall survival was also a critical outcome because radiotherapy can potentially prolong life.

The committee agreed that treatment related morbidity is an important outcome, due to side effects of radiotherapy, and is an important consideration when choosing radiotherapy dose and fractionation. Spinal stability was also an important outcome, because different radio-therapy doses and fractionations may have differing impact on re-ossification rates of unstable spinal bone metastases. Fitness for subsequent anti-cancer therapy was an important outcome because morbidity due to radiotherapy could delay further anti-cancer therapy until the person recovers fitness.

The quality of the evidence

The quality of the evidence for outcomes was assessed with GRADE and ranged from very low to high. The main issues that lowered the quality of the evidence were risk of bias as per Cochrane RoB 2 and imprecision of the effect estimates. In one case evidence quality was downgraded for indirectness because the study included some people with non-spinal bone metastases.

The committee considered the quality of evidence was sufficient to make recommendations on fractionation and on SABR for painful spinal metastases. They used their clinical experience to make recommendations where there was a lack of evidence on the timing of radio-therapy, radiotherapy for people with asymptomatic spinal metastases and the use of SABR for MSCC.

Benefits and harms

Radiotherapy and fertility

The committee agreed that the impact on future fertility of both the cancer and the radiotherapy treatment should be discussed with the person and, if appropriate (for example, depending on age and preferences), a referral should be made to a fertility. The committee discussed that treatment of MSCC is usually urgent and fertility treatment can take time to organise and undertake in practice and that it is therefore important to bear in mind that MSCC treatment should not be delayed awaiting further discussions with a fertility specialist. They also acknowledged that radiotherapy fields for MSCC would usually not affect the gonads so, urgent radiotherapy treatment might not impact as much on fertility as radiotherapy does for other cancers which is another reason why urgent treatment should not be delayed.

Radiotherapy to treat painful spinal metastases or DMI of the spine and prevent MSCC

Evidence supported the recommendation for single fraction radiotherapy in people with painful spinal metastases (without MSCC). They acknowledged that there are people who can have their pain controlled in other ways, too, but this is covered by Evidence Review I. Single fraction radiotherapy appeared as effective as multiple fractions in terms of reducing pain but with fewer adverse effects. Although the evidence was very low quality, the committee discussed that a strong recommendation was supported because single fractionation would likely be more acceptable to patients with fewer visits and transfers required to complete the treatment. There was limited evidence from 2 small RCTs that stereotactic ablative body radio-therapy (SABR) is more effective than conventional radiotherapy in reducing pain for people with spinal metastases without MSCC. Although the evidence was very low quality the committee agreed that the ability of SABR to deliver a precise dose while sparing damage to healthy tissue supported their recommendation. The committee agreed that this could be an option for a subgroup of people who have a good overall prognosis because they can tolerate this radiotherapy and it would not be too risky. They also discussed that those with limited metastatic disease (based on expertise they thought currently up to 3 discrete metastases would be considered standard for oligometastases in accordance with NHS commissioning of stereotactic ablative body radiotherapy) could benefit from this. They agreed that this number would balance the potential that all cancer sites could be controlled with an acceptable level of toxicity.

Although there was a lack of evidence about the impact of radiotherapy on stem cell harvest in people with haematological cancers, the committee agreed that in their experience it could lower the chance of a successful procedure. For this reason they recommended a discussion with the relevant haematology MDT whenever this was being considered to allow for careful consideration of the risks and benefits for each individual.

Radiotherapy to treat MSCC

Although there was no evidence on the timing of radiotherapy for people with MSCC, the committee agreed that MSCC can be an oncologic emergency and rapid access to radiotherapy would be needed in some cases to prevent neurological impairment (as soon as possible and within 24 hours). The committee discussed that in patients with MSCC who are not candidates for surgery, radiotherapy may help prevent further neurological damage and alleviate pain. In this situation radiotherapy should be given urgently – unless the person already has paraplegia or tetraplegia for 2 weeks or longer and their pain is controlled or their overall prognosis is poor. In these cases, the benefits of radiotherapy are unlikely to outweigh the harms.

There was evidence that single fractionation was as effective as multiple fractions for people with MSCC, but with the benefit of increased patient convenience and reduced costs. The committee agreed that a strong recommendation was appropriate based on the evidence and because this would lead to less time spent in multiple hospital visits which can be particularly important in a patient group with reduced life expectancy. This would also use fewer resources in relation to appointments and staff time.

The committee agreed, based on their experience, that it can be technically difficult to treat multilevel disease in a single dose and that radiologists avoid large single dose treatment fields which cover a large proportion of the spinal cord due to toxicity. For these reasons in some cases multiple fraction radiotherapy would be more appropriate.

The committee agreed to make a research recommendation stereotactic ablative body radiotherapy for the treatment of MSCC, given a lack of evidence about its use in this indication.

Radiotherapy for asymptomatic spinal metastases

There was a lack of evidence about the use of radiotherapy in people with asymptomatic spinal metastases. The committee agreed that benefits of radiotherapy were less clear cut in this population whereas the harms of radiotherapy are known. They recommended radiotherapy only in limited circumstances: for those with limited metastatic disease (where radiotherapy could be used to control disease), if there are radiological signs of impending cord compression by an epidural or intradural tumour (where presumably radiotherapy may prevent progression to symptomatic MSCC) and for those in a randomised trial.

Postoperative radiotherapy

There was evidence showing that radiotherapy and surgery had an important benefit in relation to neurological and functional status over radiotherapy alone. The committee noted also that this is now routine practice in most services and is suitable for most people with MSCC post surgery. To standardise this practice and based on the evidence they recommended that postoperative radiotherapy should be offered.

Further radiotherapy

The committee also discussed retreatment with radiotherapy in people who had previously had radiotherapy. No evidence was identified so the committee, based on experience, decided to recommend this treatment option in some cases but also to highlight some of the factors linked to treatment toxicity (dose, timing and volume of treatment field) that should be taken into account when making decisions about whether or not to offer further radiotherapy treatment.

Providing urgent radiotherapy services

The committee discussed that their recommendation regarding radiotherapy within 24 hours would require some configuration of services that would help enable this to happen. Based on experience they therefore recommended that MSCC services need to ensure that radio-therapy and simulator facilities are available for urgent (within 24 hours) daytime sessions, 7 days a week. This would enable treatment to be given within this timeframe.

Cost effectiveness and resource use

The economic evidence showed that giving post-operative radiotherapy to people who have undergone surgery will be cost saving and health improving compared to radiotherapy alone. These savings and health improvements are largely being driven through people being ambulant for longer periods of time, improving quality of life and reducing costs to community services which are involved with non-ambulant people.

Stereotactic ablative body radiotherapy (SABR) is not widely used for painful spinal metastases in the NHS and would represent a change in practice. The technology is already available in the NHS for other cancers and all cancer centres will already have access to this technology. These recommendations will increase the use of stereotactic ablative body radiotherapy but this is similar in cost to alternative radiotherapy and the committee agreed this will not lead to a significant resource impact. There may be an initial cost of setting up pathways for people with painful spinal metastases to access SABR, as these are not currently established, but this will be a one-off cost and would not lead to significant resource impact. There was also evidence that SABR will reduce pain leading to reduced use of analgesics and other treatments for pain, decreasing costs and increasing quality of life. The committee therefore concluded that SABR was likely to be cost neutral or potentially cost saving once the initial set-up costs had been incurred.

Recommendations supported by this evidence review

This evidence review supports recommendations 1.1.21, 1.10.1 to 1.10.10 and research recommendation 1 on the effectiveness of stereotactic ablative body radiotherapy in the treatment of MSCC, in the guideline.

References – included studies

Effectiveness

Hoskin 2019 [SCORAD-III trial]
Hoskin P, Hopkins K, Misra V, et al. Effect of Single-Fraction vs Multifraction Radiotherapy on Ambulatory Status Among Patients With Spinal Canal Compression From Metastatic Cancer: the SCORAD Randomized Clinical Trial. JAMA 322, 2084–2094, 2019 [PMC free article: PMC6902166] [PubMed: 31794625]
Howell 2013 [RTOG 97-14 trial]
Howell D, James J, Hartsell W, et al. Single-fraction radiotherapy versus multifraction radio-therapy for palliation of painful vertebral bone metastases - Equivalent efficacy, less toxicity, more convenient: A subset analysis of Radiation Therapy Oncology Group trial 97-14. Cancer 119, 888–896, 2013 [PMC free article: PMC5746185] [PubMed: 23165743]
Lee 2018 [ICORG 05-03 trial]
Lee K, Dunne M, Small C, et al. (ICORG 05-03): prospective randomized non-inferiority phase III trial comparing two radiation schedules in malignant spinal cord compression (not proceeding with surgical decompression); the quality of life analysis. Acta Oncologica, 1–8, 2018 [PubMed: 29419331]
Majumder 2012
Majumder D, Chatterjee D, Bandyopadhyay A, et al. Single Fraction versus Multiple Fraction Radiotherapy for Palliation of Painful Vertebral Bone Metastases: A Prospective Study. Indian Journal of Palliative Care, 18, 202–6, 2012 [PMC free article: PMC3573475] [PubMed: 23440009]
Maranzano 2005
Maranzano E, Bellavita R, Rossi R, et al. Short-course versus split-course radiotherapy in metastatic spinal cord compression: results of a phase III, randomized, multicenter trial. Journal of Clinical Oncology 23: 3358–65, 2005 [PubMed: 15738534]
Maranzano 2009
Maranzano E, Trippa F, Casale M, et al. 8Gy single-dose radiotherapy is effective in metastatic spinal cord compression: results of a phase III randomized multicentre Italian trial. Radiotherapy and Oncology 93, 174–9, 2009 [PubMed: 19520448]
Patchell 2005
Patchell R, Tibbs P Regine W, et al. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial. Lancet 366, 643–8, 2005 [PubMed: 16112300]
Rades 2016 [SCORE-2 trial]
Rades D, Šegedin B, Conde-Moreno A, et al, Radiotherapy With 4 Gy × 5 Versus 3 Gy × 10 for Metastatic Epidural Spinal Cord Compression: final results of the SCORE-2 Trial (ARO 2009/01). Journal of Clinical Oncology 34, 597–602, 2016 [PubMed: 26729431]
Rades 2018 [SCORE-2 trial]
Rades D, Conde-Moreno A, Cacicedo J et al. Comparison of Two Radiotherapy Regimens for Metastatic Spinal Cord Compression: subgroup Analyses from a Randomized Trial. Anti-cancer Research 38, 1009–1015, 2018 [PubMed: 29374734]
Rades 2019 [SCORE-2 trial]
Rades D, Segedin B, Conde-Moreno A, et al. Patient-Reported Outcomes-Secondary Analysis of the SCORE-2 Trial Comparing 4 Gy x 5 to 3 Gy x 10 for Metastatic Epidural Spinal Cord Compression. International Journal of Radiation Oncology, Biology, Physics, 105, 760–764, 2019 [PubMed: 31415797]
Roos 2005 [TROG 96-05 trial]
Roos D, Turner S, O’Brien, P, et al. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiotherapy and Oncology 75, 54–63, 2005 [PubMed: 15878101]
Sahgal 2021
Sahgal A, Myrehaug S, Siva S, et al. Stereotactic body radiotherapy versus conventional external beam radiotherapy in patients with painful spinal metastases: an open-label, multicentre, randomised, controlled, phase 2/3 trial. Lancet Oncology 22, 1023–1033, 2021 [PubMed: 34126044]
Sprave 2018a [IRON-1 trial]
Sprave T, Verma V, Förster R et al. Radiation-induced acute toxicities after image-guided intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for patients with spinal metastases (IRON-1 trial): first results of a randomized controlled trial. Strahlen-therapie und Onkologie 194, 911–920, 2018 [PubMed: 29978307]
Sprave 2018b [IRON-1 trial]
Sprave T, Verma V, Förster R et al. Quality of Life and Radiation-induced Late Toxicity Following Intensity-modulated Versus Three-dimensional Conformal Radiotherapy for Patients with Spinal Bone Metastases: results of a Randomized Trial. Anticancer Research 38, 4953–4960, 2018 [PubMed: 30061275]
Sprave 2018c [IRON-1 trial]
Sprave T, Verma V, Förster R, et al. Bone density and pain response following intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy for vertebral metastases - secondary results of a randomized trial. Radiation Oncology, 13, 212, 2018 [PMC free article: PMC6208115] [PubMed: 30376859]
Sprave 2018d [NCT - 02358720]
Sprave T, Verma V, Forster R, et al, Quality of Life Following Stereotactic Body Radiotherapy Versus Three-Dimensional Conformal Radiotherapy for Vertebral Metastases: Secondary Analysis of an Exploratory Phase II Randomized Trial. Anticancer Research 38, 4961–4968, 2018 [PubMed: 30061276]
Sprave 2018e [NCT - 02358720]
Sprave T, Verma V, Forster R, et al, Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy. Radiotherapy and Oncology 128, 274–282, 2018 [PubMed: 29843899]
Sprave 2018f [NCT - 02358720]
Sprave T, Verma V, Forster R, et al, Local response and pathologic fractures following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy for spinal metastases - a randomized controlled trial. BMC Cancer 18, 859, 2018 [PMC free article: PMC6119304] [PubMed: 30170568]
Steenland 1999 [Dutch Bone Metastasis trial]
Steenland E, Leer J, van Houwelingen H, et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch Bone Metastasis Study. Radiotherapy and Oncology, 52, 101–109, 1999 [PubMed: 10577695]

Economic

Turner 2018
Turner I, Kennedy J, Morris S, et al. Surgery and radiotherapy for symptomatic spinal metastases is more cost effective than radiotherapy alone: a cost utility analysis in a UK Spinal Center. World Neurosurgery, 109, e389–e397, 2018. [PubMed: 28987846]

Appendices

Appendix G. Economic evidence study selection

Study selection for: How effective is radiotherapy, including both fractionated and unfractionated radiotherapy, for the management of spinal metastases, direct malignant infiltration of the spine or associated spinal cord compression?

A global search of economic evidence was undertaken for all review questions in this guideline. See Supplement 2 for further information

Appendix H. Economic evidence tables

Economic evidence tables for review question: How effective is radiotherapy, including both fractionated and unfractionated radiotherapy, for the management of spinal metastases, direct malignant infiltration of the spine or associated spinal cord compression? (PDF, 140K)

Appendix I. Economic model

Economic model for review question: How effective is radiotherapy, including both fractionated and unfractionated radiotherapy, for the management of spinal metastases, direct malignant infiltration of the spine or associated spinal cord compression?

No economic analysis was conducted for this review question.

Appendix J. Excluded studies

Excluded studies for review question: How effective is radiotherapy, including both fractionated and unfractionated radiotherapy, for the management of spinal metastases, direct malignant infiltration of the spine or associated spinal cord compression?

Excluded effectiveness studies

Table 14

Excluded studies and reasons for their exclusion.

Excluded economic studies

A global search of economic evidence was undertaken for all review questions in this guideline. See Supplement 2 for further information

Appendix K. Research recommendations – full details

Research recommendations for review question: How effective is radiotherapy, including both fractionated and unfractionated radiotherapy, for the management of spinal metastases, direct malignant infiltration of the spine or associated spinal cord compression? (PDF, 157K)

Final

These evidence reviews were developed by NICE

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK595812PMID: 37824688

Table 1Summary of the protocol (PICO table)

Population	Adults with: metastatic spinal disease direct malignant infiltration of the spine Adults with confirmed spinal cord or nerve root compression because of: metastatic spinal disease direct malignant infiltration.
Intervention	Radiotherapy (RT): Unfractionated RT (including stereotactic techniques) Fractionated RT
Comparison	No RT (with or without surgery) Repeated single site treatments versus one multi-site treatment Surgery with post-op RT versus RT alone Different fractionation Different dosage Different RT technique
Outcome	Critical Health related quality of life Neurological and functional status including: Bowel & bladder function Mobility or ambulatory status Overall survival Pain Important Treatment related morbidity Spinal stability (especially in those who did not have surgery) Fitness for subsequent anti-cancer therapy

: RT: radiotherapy.

Table 2Summary of included studies

Study/trial

Population

Intervention

Comparison

Outcomes

Hoskin 2019 (SCORAD-III trial)

RCT

Australia and United Kingdom

N=686.

Patients with MRI or CT confirmed metastatic spinal cord compression.

Age, median, years (range): single fraction 70 (23 to 96); multiple fraction 70 (33 to 95). Mean and SD not reported.

Sex: female n=183, male n=503.

Single fraction RT

8 Gy in 1 fraction beginning on day of simulation.

Multiple fraction RT

20 Gy in 5 fractions.

Health related quality of life
Functional status
Overall survival
Pain
Treatment related morbidity

Howell 2013

RCT

United States

N=235.

Patients with painful spinal metastases.

Age, median, years (range): Single fraction 69 (36 to 92); multiple fraction 68 (33 to 91). Mean and SD not reported.

Sex: female n=105, male n=129.

Single fraction RT

8 Gy in 1 fraction.

Multiple fraction RT

30 Gy in 10 fractions.

Survival
Pain
Treatment related morbidity
Treatment failure

Lee 2018 (ICORG 05-03 trial)

RCT

Ireland and Northern Ireland

N=104.

Patients with MRI documented metastatic spinal cord compression/cauda equina not proceeding with surgical decompression.

Age, mean, years (SD): 66.7 (13.1) (not reported by group).

Sex: female n=38, male n=66.

Single fraction RT

10 Gy in 1 fraction beginning on day of simulation.

Multiple fraction RT

20 Gy in 5 fractions beginning on day of simulation.

Health related quality of life
Functional status
Pain
Treatment related morbidity

Majumder 2012

RCT

India

N=64.

Patients with histopathologically proven primary malignancy having symptomatic secondary deposits to the vertebra.

Age, median, years (range): multiple fraction 58 (55.64); single fraction 60 (56.64). Mean and SD not reported.

Sex: female n=11, male n=53.

Single fraction RT

8 Gy in 1 fraction.

Multiple fraction RT

30 Gy in 10 fractions.

Pain
Treatment related morbidity

Maranzano 2005

RCT

Italy

N=300 randomised (n=276 assessable).

Patients with MRI or CT diagnosed metastatic spinal cord compression and short life expectancy.

Age, median, years (range): short course 66 (30-87); split course 68 (34-89). Mean and SD not reported.

Sex: female n=85, male n=191.

Short course RT

16 Gy in 2 fractions over 1 week.

Split course RT

30 Gy in 8 fractions over 2 weeks.

Functional status
Pain
Survival
Treatment related morbidity

Maranzano 2009

RCT

Italy

N=303.

Patients with MRI or CT confirmed metastatic spinal cord compression with a short life expectancy.

Age, median, years (range): single fraction 67 (33-87); multiple fraction 67 (39-87). Mean and SD not reported.

Sex: female n=106, male n=197.

Single fraction RT

8 Gy in 1 fraction.

Split course RT

16 Gy in 2 fractions.

Functional status
Pain
Bowel and bladder function
Overall survival
Treatment related morbidity

Patchell 2005

RCT

United States

N=101.

Patients with metastatic spinal cord compression.

Age, median, years (range): Surgery + RT 60; RT only 60. No further details reported.

Sex: female n=31, male n=70.

Surgery plus radiotherapy

Direct decompressive surgery within 24 hours of randomisation followed by RT (30 Gy in 10 fractions administered 14 days after surgery).

Radiotherapy only

30 Gy in 10 fractions beginning within 24 hours of randomisation.

Mobility or ambulatory status
Overall survival
Functional status
Bowel and bladder function
Pain

Rades 2016, Rades 2018, Rades 2019 (SCORE-2 trial)

RCT

Germany

N=203.

Patients with MRI or CT confirmed metastatic spinal cord compression but no previous surgery or radio-therapy to spinal cord.

Poor or intermediate survival prognosis.

Age, years, n: ≤ 68 n=103, ≥ 68 n=100. Mean and SD not reported.

Sex: female n=79, male n=124.

20 Gy in 5 fractions

30 Gy in 10 fractions

Functional status
Pain

Roos 2005 (TROG 96-05 trial)

RCT

Australia, New Zealand, United Kingdom

N=272.

Patients with painful spinal metastases and life expectancy of at least 6 weeks.

Age, median, years (range): single fraction 67 (29-86); multiple fraction 68 (32-89). Mean and SD not reported.

Sex: female n=76, male n=196.

Single fraction RT

8 Gy in 1 fraction.

Multiple fraction RT

20 Gy in 5 fractions.

Pain
Treatment failure
Adverse events

Sahgal 2021

RCT

Canada and Australia

N=229.

Patients with painful MRI-confirmed spinal metastases.

Age, n: 18 to 59 n=83; 60 to 69 n=61; ≥70: n=85.

Sex: female n=109, male n=120.

Stereotactic ablative body RT

24 Gy in 2 consecutive daily fractions.

Conventional RT

20 Gy in 5 daily fractions.

Health related quality of life
Overall survival
Progression free survival
Pain
Treatment related morbidity

Sprave 2018a, b, c (IRON-1 trial)

RCT

Germany

N=60.

Patients with spinal metastases with indication for palliative radio-therapy.

Age, mean, years (SD): IMRT: 66.1 (10.5); conventional RT: 62.5 (11.8).

Sex: female n=27, male n=33.

Image guided intensity modulated RT (IMRT)

30 Gy in 10 fractions.

Conventional RT

30 Gy in 10 fractions

Health related quality of life
Functional status
Pain
Treatment related morbidity

Sprave 2018d, e, f (NCT-02358720)

RCT

Germany

N=55

Histologically confirmed tumour diagnosis, with secondary diagnosed solitary/multiple spinal bone metastases and indication for radio-therapy of the spinal bone metastases.

Age, mean, years (SD): Stereotactic body RT 61 (8.2); conventional RT 63.9 (10.8).

Sex: female n=27, male n=28.

Stereotactic ablative body RT

High dose singlefraction stereotactic ablative body radiation therapy (24 Gy to the 80% isodose line).

Conventional RT

30 Gy in 10 fractions.

Health related quality of life
Functional status
Pain
Treatment related morbidity

Steenland 1999 (Dutch Bone Metastasis trial)

RCT

Netherlands

N=1157.

Patients with painful bone metastases from a solid tumour.

Age, mean, years (SD): single fraction 65 (SD not reported); multiple fraction 65 (SD not reported).

Sex: female n=533, male n=624.

Single fraction RT

8 Gy in 1 fraction.

Multiple fraction RT

24 Gy in 6 fractions.

Treatment related morbidity

: CT: computed tomography; Gy: Gray; IMRT: image guided intensity modulated radiotherapy; RCT: randomised controlled trial; MRI, magnetic resonance imaging; RT: radiotherapy, SD: standard deviation.

Table 3Economic evidence profile of an economic evaluation of the addition of radiotherapy for people undergoing surgery for metastatic spinal cord compression

Study	Limitations	Applicability	Other comments	Incremental			Uncertainty
Study	Limitations	Applicability	Other comments	Costs	Effect	Cost effectivenss	Uncertainty
Turner 2018 Surgery and radio-therapy versus radio-therapy	Potentially serious limitations¹	Directly applicable²	Radiotherapy arm was based on modelling using values from Patchell 2005	− £12,839	0.32 QALYs	Surgery and radiotherpay dominant³	Various deterministic sensitivity analyses always favoured surgery and radiotherapy

1: Limited exploration of uncertainty.

2: UK NHS perspective with QALYs valued using EQ-5D questionnaire scored using the UK population value set

3: Surgery and radiotherapy both less costly and more effective

Table 14Excluded studies and reasons for their exclusion

Study	Reason for exclusion
(2013) Xofigo (radium-223 dichloride; Bayer HealthCare Pharmaceuticals Inc.) for treatment of bone metastases in castration-resistant prostate cancer. Lansdale, PA: HAYES, Inc	Publication type does not match review protocol – conference abstract
(2011) Robotically assisted stereotactic radiosurgery (SRS) for spinal and extracranial head and neck indications. Lansdale, PA: HAYES, Inc	Publication type does not match review protocol – conference abstract
Amouzegar-Hashemi, F, Behrouzi, H, Kazemian, A et al. (2008) Single versus multiple fractions of palliative radiotherapy for bone metastases: a randomized clinical trial in Iranian patients. Current oncology (toronto, ont.) 15(3): 36–39 [PMC free article: PMC2442760] [PubMed: 18596887]	Population does not match review protocol
Bakar, D., Tanenbaum, J. E., Phan, K. et al. (2016) Decompression surgery for spinal metastases: a systematic review. Neurosurgical Focus 41: e2 [PubMed: 27476844]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Barrie, U., Elguindy, M., Pernik, M. et al. (2020) Intramedullary Spinal Metastatic Renal Cell Carcinoma: Systematic Review of Disease Presentation, Treatment, and Prognosis with Case Illustration. World Neurosurgery 134: 584–593 [PubMed: 31734421]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Bilsky, M. H.; Laufer, I.; Burch, S. (2009) Shifting paradigms in the treatment of metastatic spine disease. Spine 34: S101–7 [PubMed: 19829269]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Broder, M. S., Gutierrez, B., Cherepanov, D. et al. (2015) Burden of skeletal-related events in prostate cancer: unmet need in pain improvement. Supportive Care in Cancer 23(1): 237–247 [PubMed: 25270847]	Population does not match review protocol
Cellini, F., Manfrida, S., Deodato, F. et al. (2019) Pain REduction with bone metastases STereotactic radiotherapy (PREST): A phase III randomized multicentric trial. Trials 20(1) [PMC free article: PMC6816218] [PubMed: 31661034]	Publication type does not match review protocol – study protocol
Chang, J. H., Shin, J. H., Yamada, Y. J. et al. (2016) Stereotactic Body Radiotherapy for Spinal Metastases: What are the Risks and How Do We Minimize Them?. Spine 41suppl20: S238–S245 [PMC free article: PMC5552170] [PubMed: 27488294]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Chen, B., Xiao, S., Tong, X. et al. (2015) Comparison of the Therapeutic Efficacy of Surgery with or without Adjuvant Radiotherapy versus Radiotherapy Alone for Metastatic Spinal Cord Compression: A Meta-Analysis. World Neurosurgery 83(6): 1066–1073 [PubMed: 25536156]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Chi, J. H., Gokaslan, Z., McCormick, P. et al. (2009) Selecting treatment for patients with malignant epidural spinal cord compressiondoes age matter? Results from a randomized clinical trial. Spine 34(5): 431–435 [PubMed: 19212272]	Other protocol criteria - posthoc analysis of Patchell 2005 trial
Chow, E., Harris, K., Fan, G. et al. (2007) Palliative radiotherapy trials for bone metastases: a systematic review. Journal of Clinical Oncology 25: 1423–36 [PubMed: 17416863]	Population does not match review protocol
Chow, E., Hoskin, P. J., Wu, J. et al. (2006) A phase III international randomised trial comparing single with multiple fractions for re-irradiation of painful bone metastases: National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) SC 20. Clinical Oncology 18(2): 125–128 [PubMed: 16523812]	Population does not match review protocol
Chow, E., van der Linden, Y. M., Roos, D. et al. (2014) Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, non-inferiority trial. Lancet Oncology 15: 164–71 [PubMed: 24369114]	Population does not match review protocol
Chow, E., Zeng, L., Salvo, N. et al. (2012) Update on the systematic review of palliative radiotherapy trials for bone metastases. Clinical Oncology (Royal College of Radiologists) 24: 112–24 [PubMed: 22130630]	Population does not match review protocol
Dhamija, B.; Batheja, D.; Balain, B. S. (2021) A systematic review of MIS and open decompression surgery for spinal metastases in the last two decades. Journal of Clinical Orthopaedics & Trauma 22: 101596 [PMC free article: PMC8488238] [PubMed: 34631409]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Donovan, E. K., Sienna, J., Mitera, G. et al. (2019) Single versus multifraction radiotherapy for spinal cord compression: A systematic review and meta-analysis. Radiotherapy & Oncology 134: 55–66 [PubMed: 31005225]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Dy, S. M., Asch, S. M., Naeim, A. et al. (2008) Evidence-based standards for cancer pain management. Journal of Clinical Oncology 26(23): 3879–3885 [PubMed: 18688056]	Population does not match review protocol
Falkmer, U., Jarhult, J., Wersall, P. et al. (2003) A systematic overview of radiation therapy effects in skeletal metastases. Acta Oncologica 42(5–6): 620–633 [PubMed: 14596519]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Feyer, P., Sautter-Bihl, M. L., Budachs, W. et al. (2010) DEGRO practical guidelines for palliative radiotherapy of breast cancer patients: Brain metastases and leptomeningeal carcinomatosis. Strahlentherapie und Onkologie 186(2): 63–69 [PubMed: 20127222]	Population does not match review protocol
Garcia-Torralba, E., Spada, F., Lim, K. H. J. et al. (2021) Knowns and unknowns of bone metastases in patients with neuroendocrine neoplasms: A systematic review and meta-analysis. Cancer Treatment Reviews 94 (no pagination) [PubMed: 33730627]	Population does not match review protocol
George, R, Sundararaj, JJ, Govindaraj, R et al. (2015) Interventions for the treatment of metastatic extradural spinal cord compression in adults. Cochrane Database of Systematic Reviews [PMC free article: PMC6513178] [PubMed: 26337716]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Gerszten, P. C.; Mendel, E.; Yamada, Y. (2009) Radiotherapy and radiosurgery for metastatic spine disease: what are the options, indications, and outcomes?. Spine 34: S78–92 [PubMed: 19829280]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Ghia, A. J., Chang, E. L., Bishop, A. J. et al. (2016) Single-fraction versus multifraction spinal stereotactic radiosurgery for spinal metastases from renal cell carcinoma: secondary analysis of Phase I/II trials. Journal of Neurosurgery Spine 24: 829–36 [PubMed: 26799117]	Study design - phase I or II trials - patients not randomly allocated to treatment
Glicksman, R. M., Tjong, M. C., Neves-Junior, W. F. P. et al. (2020) Stereotactic Ablative Radiotherapy for the Management of Spinal Metastases: A Review. JAMA Oncology 6: 567–577 [PubMed: 31895403]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Gong, Y., Xu, L., Zhuang, H. et al. (2019) Efficacy and safety of different fractions in stereotactic body radiotherapy for spinal metastases: A systematic review. Cancer Medicine 8: 6176–6184 [PMC free article: PMC6797563] [PubMed: 31489788]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Goodwin, C. R., Sankey, E. W., Liu, A. et al. (2016) A systematic review of clinical outcomes for patients diagnosed with skin cancer spinal metastases. Journal of Neurosurgery: Spine 24(5): 837–849 [PubMed: 26544595]	Intervention does not match review protocol
Hamouda, W. E.; Roshdy, W.; Teema, M. (2007) Single versus conventional fractionated radiotherapy in the palliation of painful bone metastases. The gulf journal of oncology 1: 35–41 [PubMed: 20084712]	Population does not match review protocol
Hernandez-Duran, S., Hanft, S., Komotar, R. J. et al. (2016) The role of stereotactic radiosurgery in the treatment of intramedullary spinal cord neoplasms: a systematic literature review. Neurosurgical Review 39(2): 175–183 [PubMed: 26219855]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Holt, T., Hoskin, P., Maranzano, E. et al. (2012) Malignant epidural spinal cord compression: the role of external beam radiotherapy. Current Opinion in Supportive & Palliative Care 6: 103–8 [PubMed: 22156794]	Study design does not match review protocol – expert review/narrative
Howell, DD, James, JL, Hartsell, WF et al. (2009) Randomized trial of short-course versus long-course radiotherapy for palliation of painful vertebral bone metastases: a retrospective analysis of RTOG 97-14. Journal of clinical oncology 27(15sparti): 488	Publication type does not match review protocol – conference abstract
Husain, Z. A., Sahgal, A., De Salles, A. et al. (2017) Stereotactic body radiotherapy for de novo spinal metastases: systematic review. Journal of Neurosurgery Spine 27: 295–302 [PubMed: 28598293]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Jeremic, B. (2001) Single fraction external beam radiation therapy in the treatment of localized metastatic bone pain. A review. Journal of Pain and Symptom Management 22(6): 1048–1058 [PubMed: 11738168]	Population does not match review protocol
Jeremic, B, Shibamoto, Y, Acimovic, L et al. (1998) A randomized trial of three single-dose radiation therapy regimens in the treatment of metastatic bone pain. International journal of radiation oncology, biology, physics 42(1): 161–167 [PubMed: 9747834]	Population does not match review protocol
Kim, J. M., Losina, E., Bono, C. M. et al. (2012) Clinical outcome of metastatic spinal cord compression treated with surgical excision +/- radiation versus radiation therapy alone: a systematic review of literature. Spine 37: 78–84 [PMC free article: PMC3876411] [PubMed: 21629164]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Klimo Jr, P., Thompson, C. J., Kestle, J. R. W. et al. (2005) A meta-analysis of surgery versus conventional radiotherapy for the treatment of metastatic spinal epidural disease. Neuro-Oncology 7(1): 64–76 [PMC free article: PMC1871618] [PubMed: 15701283]	Intervention and comparator do not match review protocol
Kumar, N., Madhu, S., Bohra, H. et al. (2020) Is there an optimal timing between radiotherapy and surgery to reduce wound complications in metastatic spine disease? A systematic review. European Spine Journal 29: 3080–3115 [PubMed: 32556627]	Outcomes do not match review protocol
Lee, C. H., Kwon, J. W., Lee, J. et al. (2014) Direct decompressive surgery followed by radiotherapy versus radiotherapy alone for metastatic epidural spinal cord compression: a meta-analysis. Spine 39: E587–92 [PubMed: 24503688]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Leer, JWH; Steenland, E; van Houwelingen, H (1999) Pain control for bone metastases. European journal of cancer 35(abstract462): 129	Publication type does not match review protocol – conference abstract
Loblaw, D. A. and Laperriere, N. J. (1998) Emergency treatment of malignant extradural spinal cord compression: An evidence-based guideline. Journal of Clinical Oncology 16(4): 1613–1624 [PubMed: 9552073]	Publication type does not match review protocol – duplicate publication - updated version available
Loblaw, D. A., Mitera, G., Ford, M. et al. (2012) A 2011 updated systematic review and clinical practice guideline for the management of malignant extradural spinal cord compression. International Journal of Radiation Oncology, Biology, Physics 84: 312–7 [PubMed: 22420969]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Loblaw, D. A., Perry, J., Chambers, A. et al. (2005) Systematic review of the diagnosis and management of malignant extradural spinal cord compression: the Cancer Care Ontario Practice Guidelines Initiative’s Neuro-Oncology Disease Site Group. Journal of Clinical Oncology 23: 2028–37 [PubMed: 15774794]	Publication type does not match review protocol – duplicate publication - updated version available
Lohre, E. T.; Lund, J.; Kaasa, S. (2012) Radiation therapy in malignant spinal cord compression: what is the current knowledge on fractionation schedules? A systematic literature review. BMJ supportive & palliative care 2(1): 51–56 [PubMed: 24653500]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Lutz, S., Balboni, T., Jones, J. et al. (2017) Palliative radiation therapy for bone metastases: Update of an ASTRO Evidence-Based Guideline. Practical Radiation Oncology 7: 4–12 [PubMed: 27663933]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Ma, Y., He, S., Liu, T. et al. (2017) Quality of Life of Patients with Spinal Metastasis from Cancer of Unknown Primary Origin: A Longitudinal Study of Surgical Management Combined with Postoperative Radiation Therapy. Journal of Bone & Joint Surgery - American Volume 99: 1629–1639 [PubMed: 28976427]	Study design does not match review protocol – non-randomised study
Maranzano, E., Trippa, F., Casale, M. et al. (2011) Reirradiation of metastatic spinal cord compression: definitive results of two randomized trials. Radiotherapy & Oncology 98: 234–7 [PubMed: 21295881]	Study design does not match review protocol - post-hoc analysis (patients not randomised to re-treatment with radiotherapy)
Migliorini, F., Eschweiler, J., Trivellas, A. et al. (2021) Better pain control with 8-gray single fraction palliative radiotherapy for skeletal metastases: a Bayesian network meta-analysis. Clinical and Experimental Metastasis 38(2): 197–208 [PMC free article: PMC7987640] [PubMed: 33559808]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Moller, T. (1996) Skeletal metastases. Acta oncologica (Stockholm, Sweden) 35suppl7: 125–136 [PubMed: 9154105]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Moulding, H. D. and Bilsky, M. H. (2010) Metastases to the craniovertebral junction. Neurosurgery 66(SUPPL. 3): A113–A118 [PubMed: 20173512]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Myrehaug, S., Sahgal, A., Hayashi, M. et al. (2017) Reirradiation spine stereotactic body radiation therapy for spinal metastases: systematic review. Journal of Neurosurgery Spine 27: 428–435 [PubMed: 28708043]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Niewald, M., Tkocz, H. J., Abel, U. et al. (1996) Rapid course radiation therapy vs. more standard treatment: a randomized trial for bone metastases. International Journal of Radiation Oncology, Biology, Physics 36: 1085–9 [PubMed: 8985030]	Population does not match review protocol - data for spinal metastases group not reported
Ozsaran, Z, Yalman, D, Anacak, Y et al. (2001) Palliative radiotherapy in bone metastases: results of a randomized trial comparing three fractionation schedules. Journal of B.U.ON. 6(1): 43–48	Population does not match review protocol
Pontoriero, A., Lillo, S., Caravatta, L. et al. (2021) Cumulative dose, toxicity, and outcomes of spinal metastases re-irradiation: Systematic review on behalf of the Re-Irradiation Working Group of the Italian Association of Radiotherapy and Clinical Oncology (AIRO). Strahlentherapie und Onkologie 197: 369–384 [PubMed: 33635395]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Qu, S., Meng, H. L., Liang, Z. G. et al. (2015) Comparison of shortcourse radiotherapy versus long-course radiotherapy for treatment of metastatic spinal cord compression: A systematic review and meta-analysis. Medicine (United States) 94(43) [PMC free article: PMC4985404] [PubMed: 26512590]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Quraishi, N. A., Giannoulis, K. E., Edwards, K. L. et al. (2012) Management of metastatic sacral tumours. European Spine Journal 21: 1984–93 [PMC free article: PMC3463705] [PubMed: 22729363]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Rades, D. (2010) Dose-fractionation schedules for radiotherapy of bone metastases. Breast Care 5(5): 339–344 [PMC free article: PMC3132960] [PubMed: 21779218]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Rades, D., Cacicedo, J., Conde-Moreno, A. J. et al. (2021) Comparison of 5 x 5 Gy and 10 x 3 Gy for metastatic spinal cord compression using data from three prospective trials. Radiation Oncology 16: 7 [PMC free article: PMC7788916] [PubMed: 33413492]	Patients were not randomly allocated to treatment groups
Rich, S. E., Chow, R., Raman, S. et al. (2018) Update of the systematic review of palliative radiation therapy fractionation for bone metastases. Radiotherapy & Oncology 126: 547–557 [PubMed: 29397209]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Roos, D. E., O’Brien, P. C., Smith, J. G. et al. (2000) A role for radiotherapy in neuropathic bone pain: preliminary response rates from a prospective trial (Trans-tasman radiation oncology group, TROG 96.05). International Journal of Radiation Oncology, Biology, Physics 46: 975–81 [PubMed: 10705020]	Other protocol criteria - data from preliminary analysis reported in Roos 2005 which has been included in this review
Roos, D. E., Davis, S. R., Turner, S. L. et al. (2003) Quality assurance experience with the randomized neuropathic bone pain trial (Trans-Tasman Radiation Oncology Group, 96.05). Radiotherapy & Oncology 67: 207–12 [PubMed: 12812852]	Population does not match review protocol - data for spinal metastases group not reported
Roque i Figuls, M., Martinez-Zapata, M. J., Scott-Brown, M. et al. (2017) Radioisotopes for metastatic bone pain. Cochrane Database of Systematic Reviews 2017(3) [PMC free article: PMC6464104] [PubMed: 28334435]	Publication type does not match review protocol – duplicate publication - withdrawn version of a Cochrane review
Sahgal, A., Myrehaug, S. D., Siva, S. et al. (2020) CCTG SC.24/TROG 17.06: A Randomized Phase II/III Study Comparing 24Gy in 2 Stereotactic Body Radiotherapy (SABR) Fractions Versus 20Gy in 5 Conventional Palliative Radiotherapy (CRT) Fractions for Patients with Painful Spinal Metastases. International journal of radiation oncology, biology, physics 108(5): 1397–1398 [PubMed: 33427654]	Publication type does not match review protocol – conference abstract
Sande, T. A., Ruenes, R., Lund, J. A. et al. (2009) Long-term follow-up of cancer patients receiving radiotherapy for bone metastases: results from a randomised multicentre trial. Radiotherapy & Oncology 91: 261–6 [PubMed: 19307034]	Population does not match review protocol
Sapkaroski, D.; Osborne, C.; Knight, K. A. (2015) A review of stereotactic body radiotherapy - is volumetric modulated arc therapy the answer?. Journal of Medical Radiation Sciences 62(2): 142–151 [PMC free article: PMC4462986] [PubMed: 26229679]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Sharma, R., Sagoo, N. S., Haider, A. S. et al. (2021) Iodine-125 radioactive seed brachytherapy as a treatment for spine and bone metastases: A systematic review and meta-analysis. Surgical Oncology 38 (no pagination) [PubMed: 34153905]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Singh, R., Lehrer, E. J., Dahshan, B. et al. (2020) Single fraction radiosurgery, fractionated radiosurgery, and conventional radiotherapy for spinal oligometastasis (SAFFRON): A systematic review and meta-analysis. Radiotherapy & Oncology 146: 76–89 [PubMed: 32114269]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Smith, B. W., Joseph, J. R., Saadeh, Y. S. et al. (2018) Radiosurgery for Treatment of Renal Cell Metastases to Spine: A Systematic Review of the Literature. World Neurosurgery 109: e502–e509 [PubMed: 29038086]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Sohn, S. and Chung, C. K. (2012) The role of stereotactic radiosurgery in metastasis to the spine. Journal of Korean Neurosurgical Society 51: 1–7 [PMC free article: PMC3291699] [PubMed: 22396835]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Soltys, S. G., Grimm, J., Milano, M. T. et al. (2021) Stereotactic Body Radiation Therapy for Spinal Metastases: Tumor Control Probability Analyses and Recommended Reporting Standards. International Journal of Radiation Oncology, Biology, Physics 110: 112–123 [PubMed: 33516580]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Souchon, R., Wenz, F., Sedlmayer, F. et al. (2009) DEGRO practice guidelines for palliative radiotherapy of metastatic breast cancer: bone metastases and metastatic spinal cord compression (MSCC). Strahlentherapie und Onkologie 185: 417–24 [PubMed: 19714302]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Stebbing, J. and Ngan, S. (2010) Breast cancer (metastatic). BMJ clinical evidence [PMC free article: PMC3217794] [PubMed: 21418674]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Suppli, MH, Munck Af Rosenschold, P, Dahl, B et al. (2020) Premature Termination of a Randomized Controlled Trial on Image-Guided Stereotactic Body Radiotherapy of Metastatic Spinal Cord Compression. Oncologist 25(3): 210–e422 [PMC free article: PMC7066690] [PubMed: 32162821]	Outcomes do not match review protocol – no outcomes reported (trial was closed prematurely)
Sze, W. M., Shelley, M., Held, I. et al. (2004) Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy - a systematic review of the randomised trials. Cochrane Database of Systematic Reviews: cd004721 [PMC free article: PMC6599833] [PubMed: 15106258]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Thirion, P. G., Dunne, M. T., Kelly, P. J. et al. (2020) Non-inferiority randomised phase 3 trial comparing two radiation schedules (single vs. five fractions) in malignant spinal cord compression. British Journal of Cancer 122: 1315–1323 [PMC free article: PMC7188681] [PubMed: 32157242]	Other protocol criteria - secondary publication of ICORG 05-03 trial (Lee 2018), but no additional relevant outcome data reported that match the protocol for this review
Trilling, G. M., Cho, H., Ugas, M. A. et al. (2012) Spinal metastasis in head and neck cancer. Head and Neck Oncology 4(1) [PMC free article: PMC3448515] [PubMed: 22716187]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
van der Linden, YM, Dijkstra, SP, Vonk, EJ et al. (2005) Prediction of survival in patients with metastases in the spinal column: results based on a randomized trial of radiotherapy. Cancer 103(2): 320–328 [PubMed: 15593360]	Intervention does not match review protocol
Van Der Linden, YM, Steenland, E, Post, WJ et al. (2002) Singledose irradiation of painful bone metastases is as effective as multiple fractions. Outcome of the Dutch Bone Metastasis Study. Nederlands tijdschrift voor geneeskunde 146(35): 1645–1650	Other protocol criteria – not available in English
Verbiest, A., De Meerleer, G., Albersen, M. et al. (2018) Non-surgical ablative treatment of distant extracranial metastases for renal cell carcinoma: A systematic review. Kidney Cancer 2(1): 57–67	Intervention does not match review protocol
Westhoff, P. G., de Graeff, A., Monninkhof, E. M. et al. (2018) Effectiveness and toxicity of conventional radiotherapy treatment for painful spinal metastases: a detailed course of side effects after opposing fields versus a single posterior field technique. Journal of Radiation Oncology 7: 17–26 [PMC free article: PMC5856865] [PubMed: 29576859]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Wild, A. T. and Yamada, Y. (2017) Treatment Options in Oligometastatic Disease: Stereotactic Body Radiation Therapy - Focus on Colorectal Cancer. Visceral Medicine 33: 54–61 [PMC free article: PMC5465794] [PubMed: 28612018]	Publication type does not match review protocol – expert review/narrative
Wowra, B, Zausinger, S, Muacevic, A et al. (2009) Radiosurgery for spinal malignant tumors. Deutsches Aerzteblatt International 106(7): 106–112 [PMC free article: PMC2696242] [PubMed: 19562022]	Study design does not match review protocol – expert review/narrative
Yang, J., Yan, J., Zeng, M. et al. (2020) Bone metastases of gastrointestinal stromal tumor: A review of published literature. Cancer Management and Research 12: 1411–1417 [PMC free article: PMC7049741] [PubMed: 32161493]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Yao, A., Sarkiss, C. A., Ladner, T. R. et al. (2017) Contemporary spinal oncology treatment paradigms and outcomes for metastatic tumors to the spine: A systematic review of breast, prostate, renal, and lung metastases. Journal of Clinical Neuroscience 41: 11–23 [PubMed: 28462790]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies
Young, RF; Post, EM; King, GA (1980) Treatment of spinal epidural metastases. Randomized prospective comparison of laminectomy and radiotherapy. Journal of neurosurgery 53(6): 741–748 [PubMed: 7441333]	Publication date before cutoff in review protocol
Zuckerman, S. L., Lim, J., Yamada, Y. et al. (2018) Brachytherapy in Spinal Tumors: A Systematic Review. World Neurosurgery 118: e235–e244 [PubMed: 29966796]	Study design does not match protocol criteria - systematic review without pooled results/quantitative data, checked for relevant studies

Evidence reviews for radiotherapy

Radiotherapy

Review question

Introduction

Summary of the protocol

Table 1

Methods and process

Effectiveness

Included studies

Excluded studies

Summary of included studies

Table 2

Economic evidence

Included studies

Excluded studies

Summary of the evidence

People with painful spinal bone metastases (but no evidence of spinal cord compression)

Single fraction verses multiple fraction radiotherapy

IMRT verses 3D-CRT

SABR verses conventional radiotherapy

People with metastatic spinal cord compression

Single fraction verses multiple fraction radiotherapy

Short course verses split or long course radiotherapy

Surgery plus radiotherapy verses radiotherapy alone

Summary of included economic evidence

Table 3

Economic model

Evidence Statement

The committee’s discussion and interpretation of the evidence

The outcomes that matter most

The quality of the evidence

Benefits and harms

Radiotherapy and fertility

Radiotherapy to treat painful spinal metastases or DMI of the spine and prevent MSCC

Radiotherapy to treat MSCC

Radiotherapy for asymptomatic spinal metastases

Postoperative radiotherapy

Further radiotherapy

Providing urgent radiotherapy services

Cost effectiveness and resource use

Recommendations supported by this evidence review

References – included studies

Effectiveness

Economic

Appendices

Appendix A. Review protocols

Appendix B. Search strategy (clinical/economic)

Appendix C. Effectiveness evidence study selection

Appendix D. Evidence tables

Appendix E. Forest plots

Appendix F. GRADE tables

Appendix G. Economic evidence study selection

Study selection for: How effective is radiotherapy, including both fractionated and unfractionated radiotherapy, for the management of spinal metastases, direct malignant infiltration of the spine or associated spinal cord compression?

Appendix H. Economic evidence tables

Appendix I. Economic model

Economic model for review question: How effective is radiotherapy, including both fractionated and unfractionated radiotherapy, for the management of spinal metastases, direct malignant infiltration of the spine or associated spinal cord compression?

Appendix J. Excluded studies

Excluded studies for review question: How effective is radiotherapy, including both fractionated and unfractionated radiotherapy, for the management of spinal metastases, direct malignant infiltration of the spine or associated spinal cord compression?

Excluded effectiveness studies

Table 14

Excluded economic studies

Appendix K. Research recommendations – full details

Table 1Summary of the protocol (PICO table)

Table 2Summary of included studies

Table 3Economic evidence profile of an economic evaluation of the addition of radiotherapy for people undergoing surgery for metastatic spinal cord compression

Table 14Excluded studies and reasons for their exclusion