Abstract

Abstract Background

Metastatic extradural spinal cord compression (MESCC) is treated with radiotherapy, corticosteroids, and surgery, but there is uncertainty regarding their comparative effects. This is an updated version of the original Cochrane review published in theCochrane Database of Systematic Reviews (Issue 4, 2008).

To determine the efficacy and safety of radiotherapy, surgery and corticosteroids in MESCC.

In March 2015, we updated previous searches (July 2008 and December 2013) of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, LILACS, CANCERLIT, clinical trials registries, conference proceedings, and references, without language restrictions. We also contacted experts for relevant published, unpublished and ongoing trials.

Randomised controlled trials (RCTs) of radiotherapy, surgery and corticosteroids in adults with MESCC.

Three authors independently screened and selected trials, assessed risk of bias, and extracted data. We sought clarifications from trial authors. Where possible, we pooled relative risks with their 95% confidence intervals, using a random effects model if heterogeneity was significant. We assessed overall evidence‐quality using the GRADE approach.

This update includes seven trials involving 876 (723 evaluable) adult participants (19 to 87 years) in high‐income countries. Most were free of the risk of bias.

Two equivalence trials in people with MESCC and a poor prognosis evaluated different radiotherapy doses and schedules. In one, a single dose (8 Gray (Gy)) of radiotherapy (RT) was as effective as short‐course RT (16 Gy in two fractions over one week) in enhancing ambulation in the short term (65% versus 69%; risk ratio (RR) was 0.93, (95% confidence interval (CI) 0.82 to 1.04); 303 participants; moderate quality evidence). The regimens were also equally effective in reducing analgesic and narcotic use (34% versus 40%; RR 0.85, 95% CI 0.62 to 1.16; 271 participants), and in maintaining urinary continence (90% versus 87%; RR 1.03, 95% CI 0.96 to 1.1; 303 participants) in the short term (moderate quality evidence). In the other trial, split‐course RT (30 Gy in eight fractions over two weeks) was no different from short‐course RT in enhancing ambulation (70% versus 68%; RR 1.02, 95% CI 0.9 to 1.15; 276 participants); reducing analgesic and narcotic use (49% versus 38%; RR 1.27, 95% CI 0.96 to 1.67; 262 participants); and in maintaining urinary continence (87% versus 90%; RR 0.97, 0.93 to 1.02; 275 participants) in the short term (moderate quality evidence). Median survival was similar with the three RT regimens (four months). Local tumour recurrence may be more common with single‐dose compared to short‐course RT (6% versus 3%; RR 2.21, 95% CI 0.69 to 7.01; 303 participants) and with short‐course compared to split‐course RT (4% versus 0%; RR 0.1, 95% CI 0.01 to 1.72; 276 participants), but these differences were not statistically significant (low quality evidence). Gastrointestinal adverse effects were infrequent with the three RT regimens (moderate quality evidence), and serious adverse events or post‐radiotherapy myelopathy were not noted.

We did not find trials comparing radiotherapy schedules in people with MESCC and a good prognosis.

Laminectomy plus RT offered no advantage over RT in one small trial with 29 participants (very low quality evidence). In another trial that was stopped early for apparent benefit, decompressive surgery plus RT resulted in better ambulatory rates (84% versus 57%; RR 1.48, 95% CI 1.16 to 1.90; 101 participants, low quality evidence). Narcotic use may also be lower, and bladder control may also be maintained longer than with than RT in selected patients (low quality evidence). Median survival was longer after surgery (126 days versus 100 days), but the proportions surviving at one month (94% versus 86%; RR 1.09, 95% CI 0.96 to 1.24; 101 participants) did not differ significantly (low quality evidence). Serious adverse events were not noted. Significant benefits with surgery occurred only in people younger than 65 years.

Data from three small trials suggest that high‐dose steroids may not differ from moderate‐dose or no corticosteroids in enhancing ambulation (60% versus 55%; RR 1.08, 95% CI 0.81 to 1.45; 3 RCTs, 105 participants); survival over two years (11% versus 10%; RR 1.11, 95% CI 0.24 to 5.05; 1 RCT, 57 participants); pain reduction (78% versus 91%; RR 0.86, 95% CI 0.62 to 1.20; 1 RCT, 25 participants); or urinary continence (63% versus 53%; RR 1.18, 95% CI 0.66 to 2.13; 1 RCT, 34 participants; low quality evidence). Serious adverse effects were more frequent with high‐dose corticosteroids (17% versus 0%; RR 8.02, 95% CI 1.03 to 62.37; 2 RCTs, 77 participants; moderate quality evidence).

None of the trials reported satisfaction with care or quality of life in participants.

Based on current evidence, ambulant adults with MESCC with stable spines and predicted survival of less than six months will probably benefit as much from one dose of radiation (8 Gy) as from two doses (16 Gy) or eight doses (30 Gy). We are unsure if a single dose is as effective as two or more doses in preventing local tumour recurrence. Laminectomy preceding radiotherapy may offer no benefits over radiotherapy alone. Decompressive surgery followed by radiotherapy may benefit ambulant and non‐ambulant adults younger than 65 years of age, with poor prognostic factors for radiotherapy, a single area of compression, paraplegia for less than 48 hours, and a predicted survival of more than six months. We are uncertain whether high doses of corticosteroids offer any benefits over moderate doses or indeed no corticosteroids; but high‐dose steroids probably significantly increases the risk of serious adverse effects. Early detection; and treatment based on neurological status, age and estimated survival, are crucial with all treatment modalities. Most of the evidence was of low quality. High‐quality evidence from more trials is needed to clarify current uncertainties, and some studies are in progress.

Author(s)

Reena George, Jenifer Jeba Sundararaj, Ramkumar Govindaraj, Ari G Chacko, Prathap Tharyan

Abstract

Plain language summary

Interventions for the treatment of spinal cord compression due to the spread of cancer

Metastatic extradural spinal cord compression (MESCC) due to cancer from other parts of the body affecting the spine and causing compression of the spinal cord often results in pain, impaired functioning including reduced ability to walk, incontinence, and shortened survival. Radiation is the mainstay of treatment, but surgery, and corticosteroids are also used to treat people with MESCC. This update of a previous review published in 2008 evaluates the clinical trial evidence up to 3 March 2015 to determine how effective radiotherapy, surgery and corticosteroids are in improving functioning and survival, and in reducing pain; and how well tolerated they are in adults with MESCC.

We found seven studies conducted in high‐income countries including 876 adults (aged 19 to 87 years) with MESCC. Follow‐up ranged from one month to three years, and the number evaluated in each varied from 29 to 303. Two studies compared different doses of radiation, two compared surgery before radiation versus radiation alone, and three small trials evaluated the effects of high‐dose corticosteroids versus moderate‐dose steroids or placebo.

The key results are: 1. one dose of radiation was as effective as two doses and two doses were as effective as eight doses of radiation in adults with spinal cord compression with stable spines who are expected to live for less than six months. Adults with a better prognosis may require the longer radiation course to prevent local cancer recurrence, but the immediate benefits of shorter courses might be important for people with MESCC who have only a short time to live. No serious adverse events were noted, and the incidence of diarrhoea, nausea and vomiting was low and no different with the different radiation doses. 2. removing part of the vertebra to enlarge the spinal canal (laminectomy) before radiation offered no advantages over radiation alone. Direct decompressive surgery (directly accessing and removing affected parts of the vertebrae and, if required, fixing the spines using bone grafts and instruments) followed by radiation treatment was more effective than radiation alone in carefully selected adults younger than 65 years. Surgery plus radiation did not cause more harmful effects than radiation alone. 3. : beneficial effects were not significantly different with high‐dose versus moderate‐dose steroids or placebo, but serious adverse effects were more frequent with high‐dose steroids.

None of the studies reported on satisfaction with care or quality of life. We also did not find trials comparing different radiation doses in adults with MESCC with a good prognosis. We lacked full confidence in many results since they came from single trials or a few small trials. Also, in the study of decompressive surgery, some of the adults given radiation alone had cancers that were only moderately sensitive to radiation, and a third of patients in both intervention arms had unstable spines. In usual clinical practice, surgery, not radiation, is the preferred option in such instances. The overall GRADE quality of evidence was moderate for all outcomes for the comparisons of different radiation doses and for the adverse effects of high doses of corticosteroids, indicating reasonable confidence in the results, though future research could alter the estimates in this review and our confidence in the estimates. The GRADE quality of evidence was very low for all outcomes in the comparison of laminectomy, and low for the outcome of local tumour recurrence with different radiation doses, for all outcomes in the comparison with decompressive surgery, and for the efficacy outcomes in the comparison of high‐dose corticosteroids. This indicates less confidence in these results, and acknowledges that future research is likely to alter the estimates in this review. More studies are required to clarify these uncertainties and some are in progress.

Author(s)

Reena George, Jenifer Jeba Sundararaj, Ramkumar Govindaraj, Ari G Chacko, Prathap Tharyan

Reviewer's Conclusions

Authors' conclusions

Implications for practice General implications

Early detection and institution of treatment are crucial. Patients and clinicians should be educated about the symptoms of spinal cord compression, and patients should ideally be assessed by a multidisciplinary team, with treatment decisions taking into account the neurologic status, age and estimated survival. Prognostic scores for survival and spinal instability are available.

• Radiotherapy is an essential component of treatment in adults with MESCC. Radiotherapy could be considered as the primary treatment for ambulant people with MESCC and stable spines and for those who do not meet the criteria for decompressive surgery listed below.
• Short courses of radiotherapy (one to two fractions) could be considered for people with MESCC with a predicted survival of less than three to six months, particularly if they are ambulant, and have radio‐sensitive tumours. Evidence from this review indicates that non‐ambulant patients have only a 16% chance of regaining ambulation with a single dose of radiotherapy and 29% with short courses of radiotherapy.
• Since short courses of radiotherapy (8 Gy to 16 Gy in one or two fractions) may be associated with a higher risk of local recurrence than longer courses (8 fractions; 30 Gy) or more, patients with a good prognosis could be considered for longer courses of radiotherapy. In people with MESCC who only have a short time to live, the benefits with the shorter courses may be important.
• The optimum dose and fractionation for RT in people with MESCC who have a good prognosis is currently uncertain.
• Since the overall GRADE quality of evidence for the efficacy and safety outcomes with different radiation doses was only of moderate quality (and low quality for local recurrence), it is possible that future research may impact on our confidence in the estimates of effect, and alter these estimates and the implications for practice.

• Decompressive surgery could be considered in people younger than 65 years with MESCC, who are fit to undergo surgery, have lost motor function for less than 48 hours, have localised cord compression, unfavourable histologies, and an estimated survival of greater than three months.
• Decompressive surgery could also be considered in ambulant patients with poor prognostic factors for radiotherapy (e.g. spinal instability, bony compression, rapidly progressive neurologic deficits, tumours not sensitive to radiation), provided good prognostic factors for survival are present.
• Decompressive surgery should ideally be followed immediately by postoperative radiotherapy for optimal ambulatory and survival outcomes. Postoperative RT was instituted within two weeks after surgery in the trial in this review and the evidence from another observational study also indicates that optimal outcomes with decompressive surgery depend on RT being given within two weeks of decompressive surgery (Rades 2011b). The optimal fractionation schedules and dose for postoperative RT are uncertain.
• Since the overall GRADE quality of evidence for all outcomes with decompressive surgery was of low quality, it is likely that future research could affect the implications for practice.

• High doses of corticosteroids (96 mg to 100 mg dexamethasone) carry a significant risk of serious adverse effects.
• It is uncertain if they offer any additional benefit over moderate doses of steroids (16 mg to 32 mg of dexamethasone) or no steroids.
• The optimal dose and duration of corticosteroid treatment to be given with radiation or decompressive surgery is currently unclear.
• The overall GRADE quality of evidence was moderate for the risk of serious adverse effects and low for all other outcomes; hence it is possible that future research may affect the implications for practice.

Implications for research

The two ongoing trials (ISRCTN97555949; NCT00968643), when completed and reported, will provide more data to help clarify the effects of different short RT regimens in people with MESCC not selected for having a poor prognosis. The first, being conducted in the UK, is comparing a single fraction of 8 Gy to 20 Gy in five fractions (ISRCTN97555949; SCORAD). The second, underway in Ireland, is comparing a single fraction of 10 Gy to 20 Gy in five fractions (NCT00968643; IRCOG).

Adequately powered, multinational RCTs are needed to:

• define appropriate radiotherapy schedules for good‐prognosis patients with MESCC (if deemed necessary after the results of the ongoing trials are included in an update of this review);
• clarify the role of decompressive surgery in different prognostic groups and health care settings;
• determine the optimal radiotherapy dose and fractionation regimens after surgical interventions;
• determine the optimal dosage and duration of corticosteroids. (If future studies comparing different doses of corticosteroids are conducted, they should be adequately powered to ascertain the balance between benefits and adverse effects with different doses of corticosteroids, but should also optimally select patients for their suitability for RT or decompressive surgical interventions as the primary treatment modalities);
• determine the efficacy and safety of minimally invasive surgical techniques, intensity modulated RT, and radiosurgery in the primary treatment of MESCC; and in those with local recurrences.

Trials should report results in accordance with the CONSORT 2010 guidelines. Various prognostic scales are currently available; and stratification by prognostic factors is important in future RCTs comparing different interventions. These trials would need to be adequately powered to detect differences between subgroups. Where appropriate, outcomes and endpoints should be patient‐ and caregiver‐defined.

Additionally, there is need for both qualitative and quantitative research into education, rehabilitation, screening and supportive care for patients with MESCC.