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.

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.

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

People with metastatic spinal cord compression

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.

Excluded effectiveness studies

Excluded economic studies

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