Randomised controlled trials (included in the Loblaw 2005 systematic review)

Sørensen, S., Helweg-Larsen, S., Mouridsen, H. & Hansen, H. H. (1994) Effect of high-dose dexamethasone in carcinomatous metastatic spinal cord compression treated with radiotherapy: a randomised trial. European journal of cancer (Oxford, England : 1994), 30A: 22–27
Design: Randomised Controlled trial (therapy), evidence level: 1−
Country: Denmark,
Setting: Tertiary care

Aim: To investigate the potential effect of high-dose dexamethasone, as an adjunct to radiotherapy, on gait function in patients with confirmed metastatic spinal cord compression from solid tumours. To record and evaluate the dexamethasone toxicity (secondary).
Inclusion criteria
Exclusion criteria
Lymphoma, meningeal carcinomatosis, treatment with surgery, previous treatment for epidural metastasis, infectious disease or peptic ulcers
Population
Number of patients = 57 (18 men and 39 women), age range = 25–82 years, mean age = 62 years
Interventions
  • Between May 1987 and April 1989 participants were randomized to high dose dexamethasone (27 pts), as an adjunct to radiotherapy, or no steroidal treatment (30 pts).
  • The treatment group was given a dose of 96 mg dexamethasone for 4 days, intravenous bolus immediately after the diagnosis and then orally for 3 days, when possible in 4 divided doses, tapered in 10 days.
  • Prophylactic medication against ulceration was not performed routinely.
  • All patients received a radiation dose of 28 Gy delivered in 7 consecutive days, with the first fraction within 1–20 hours after the diagnosis.
Outcomes
  • Gait function
  • Walking ability preserved in ambulatory patients and restored within 3 months in non- ambulatory patients was defined as successful treatment result.
  • Pain was not recorded systematically
Follow up
Patients were clinically evaluated by the same neurologist who wasn’t informed whether or not they had received dexamethasone treatment (single blind RCT), before treatment, after the completion of radiotherapy, at 3 weeks, at 3 months and then every 3 months for 2 years or until death.
Results
Gait function
  • There was a trend to a better outcome at 3 months in the group of patients treated with dexamethasone (81% vs. 63%, P = not provided),
  • At follow-up 6 months after treatment 16 patients (59%) who had been treated with dexamethasone were still ambulatory compared to 10 patients (33%) in the group who had not received dexamethasone therapy2 = 3.850; P = 0.05).
  • One year after treatment for spinal cord compression, 8 patients (30%) in the dexamethasone group were alive and ambulatory compared to 6 patients (20%) in the no dexamethasone therapy group (χ2 = 0.711; P = 0.40).
Survival
  • Treatment with steroids, as an adjunct to radiotherapy, didn’t influence the course of the cancer disease, since there were no differences both in median (6 months vs 6 months) and >2 years survival (11% vs 10%) between the two treatment groups.
  • The median survival was 6 months in both groups, and 3 patients in both groups were still alive at the end of the study (survival > 2 years after spinal cord compression).
  • After subgroup analysis, this difference remains the same in breast cancer patients (94% Vs 69%, 0.05 < P < 0.10) particularly in those with thoracic disease (92% vs. 50%, P = 0.05).
Toxicity
  • Side-effects were observed in 3 (11% Vs 0%, P not provided) of the patients receiving a short course of high-dose dexamethasone. These included: psychosis, gastric ulcer perforation requiring surgery, hypomania.
  • 3 (11% Vs 0%, P not provided) more patients stopped treatment because of similar side effects.
  • Prophylactic treatment against gastrointestinal ulceration might reduce the frequency of side effects
General comments
  • This is a small (53 patients) single blind (neurologist who performed the clinical evaluation) RCT but the only one conducted comparing high dose versus no steroidal therapy.
  • The way of randomisation is not reported.
  • The inclusion of all randomized (in dexamethasone) patients in the comparison, irrespective of receiving steroids according to the schedule, and the fact that prophylactic medication against ulceration was performed only in patients with a history of peptic ulcers or dyspepsia and not routinely could have influenced the dexamethasone treatment toxicity effects.
Vecht, C. J., Haaxma-Reiche, H., van Putten, W. L., de, V. M., Vries, E. P. & Twijnstra, A. (1989) Initial bolus of conventional versus high-dose dexamethasone in metastatic spinal cord compression. Neurology., 39: 1255–1257.
Design: Randomized Controlled trial (therapy), evidence level: 1
Country: The Netherlands (Multi-centred study).
Setting: Tertiary care

Aim: To investigate the potential differences in the effect of initial high-dose or conventional dexamethasone, as an adjunct to radiotherapy, on contrast passage following myelography, neurologic function (ambulation and bladder function) and pain relief in patients with confirmed by myelography metastatic spinal cord compression from solid or lympho-reticular malignancies.
Inclusion criteria
Exclusion criteria
Not reported
Population
Number of patients = 37 (26 men and 11 women), age range = 22 – 87 years, mean age = 61 years
The types of malignancy were equally divided in the treatment arms.
Interventions
  • Participants were randomized to initial high (22 pts) or conventional dose dexamethasone (15 pts) as an adjunct to radiotherapy.
  • An initial high dose (100 mg dexamethasone iv bolus) immediately after the fluoroscopically confirmation of a complete blockage for contrast flow up to 10 minutes after instilment, was compared with a low-dose (conventional −10 mg iv bolus), both followed by 4mgr 4 times a day orally.
  • All patients received a radiation dose of 21 or 30 Gy delivered in 7 or 10 fractions in 10 to 16 days, with the first fraction within 12 hours after the diagnosis.
Outcomes
  • Influence of initial bolus iv dose on contrast passage following myelography.
  • Pain, scored from 0–10.
  • Neurologic function (ambulation and bladder function)
Ambulation, recorded as:

grade I : walking independently

grade II : walking with aid

grade III : walking is impossible, both legs can be lifted from the bed

grade IV : muscle contractions in legs present, lifting of legs impossible

grade V : absence of contractions in legs.

Improvement or deterioration denotes at least 1 grade of difference in the above mentioned ambulation grade.
Bladder function, recorded as normal or abnormal (incontinence or catheter-dependent)
Follow up
  • Contrast passage following myelography was evaluated fluoroscopically and documented with x-rays 30 minutes after the administration of dexamethasone.
  • Patients’ pain and neurologic function were clinically evaluated immediately before and at 3 hours, 24 hours and 1 week after dexamethasone administration.
Results
  • There were no differences between the two groups on contrast passage, pain, ambulation or bladder function.
  • Changes over time in ambulation and bladder function were similar, with no effect of dose on worsening or improving of neurological functions.
Contrast passage
  • Within 30 minutes following dexamethasone administration six pts, 3/22 pts in the high-dose group and 3/15 in the conventional-dose group, showed passage of contrast (14% Vs 20%, P not reported)
  • Both gravity and time could influence this effect.
  • Five of these remained neurological stable and one patient improved.
Pain
  • The average pain score of 31/37 pts with pain before the start of the treatment was 5.2 (SD = 2.8) and decreased significantly (P<0.001) to 3.8 at 3 hours 2.8 at 24 hours and 1.4 after 1 week.
  • Six patients did not have any pain.
  • A substantial and similar effect of dexamethasone on pain within 24 hours was observed in both groups: 67% of patients improved.
  • There were no significant differences in pain decrease between both groups.
  • The difference at 24 hours was 0.1 (95% confidence interval, −1.6 to +1.8).
  • No patient experienced an increase in pain.
  • Pain was decreased after 3 hours in 9/17pts in the high-dose group and in 5/12 pts in the conventional dose group (53% Vs 41%, P not reported).
  • Pain was decreased after 24 hours in 10/17 pts in the high-dose group and in 10/13 pts in the conventional dose group (59% Vs 77%, P not reported).
  • There was a decrease in pain in 11/14 pts in the high-dose group and in 10/11 pts in the conventional dose group (77% Vs 91%, P not reported) after 1 week.
Ambulation
  • There was no change in ambulatory status after treatment in most patients.
  • No advantage of the high-dose over conventional dose was observed.
  • Average ambulation score difference at 24 hours was 0.1 (95% confidence interval, −0.4 to +0.6).
  • At entry 14/22 (64%) in high dose group and 7/15 (47%) in the low dose group were ambulatory.
  • At 24 hours 14/22 (64%) in high dose and 6/15 (40%) in the low dose group were able to walk.
  • At 1 week 11/20 (55%) in high dose and 7/13 (54%) in the low dose group were ambulatory.
Bladder function
  • There were clear differences in bladder function before dexamethasone administration between the two groups. Bladder dysfunction was significantly (p < 0.05) more frequent in the conventional dose group.
  • There were no significant differences between both groups during the follow-up period.
  • At 3 hours there was no change in all participants, except 1 deterioration in the high-dose group.
  • At 24 hours 1 patient in the low-dose group was improved and 3 pts in the high-dose were deteriorated.
  • At 1 week most pts remained unchanged. 5 pts were improved compared with the start (1 vs 4) and 3 pts deteriorated (2 vs 1).
Comparison in MSCC pts after treatmentHigh-dose dexamethasone therapy (22 pts)Conventional-dose dexamethasone therapy (15 pts)
Contrast passage 30 minutes after treatment03/22 (14%)03/15 (20%)
Pain evaluation after treatmentHigh-dose dexamethasone therapy (18 pts)Conventional-dose dexamethasone therapy (13 pts)
Pain improvement after 3 hours09/17 (53%)05/12 (41%)
Pain improvement after 24 hours10/17 (59%)10/13 (77%)
Pain improvement after 1 week11/14 (77%)10/11 (91%)
Pain deterioration00/00 (00%)00/00 (00%)
Gait function evaluation after treatmentHigh-dose dexamethasone therapy (22 pts)Conventional-dose dexamethasone therapy (15 pts)
Ambulatory at entry14/22 (64%)07/15 (47%)
Ambulatory at 24 hours14/22 (64%)06/15 (40%)
Ambulatory at 1 week11/20 (55%)07/13 (54%)
Improved at 3 hours00/2100/14
Improved at 24 hours02/2200/15
Improved at 1 week05/2001/13
Deteriorated at 3 hours00/2101/14
Deteriorated at 24 hours02/2202/15
Deteriorated at 1 week06/2002/13
Stable at 3 hours21/2113/14
Stable at 24 hours18/2213/15
Stable at 1 week09/2010/13
General comments
  • This is small (37 pts) Randomized Controlled Trial, but the only one conducted comparing initial bolus high-dose versus conventional dexamethasone therapy.
  • The previous-mentioned way of randomisation is not definitely well conducted and it is not reported who rated the outcomes and if he/she was aware or not of the treatment arm the patients belonged to.
  • The exclusion criteria are not mentioned.
  • There are obvious differences between two groups concerning both number of participants (22pts vs 15pts) and bladder dysfunction (31% vs 66%).
  • The absence of a standard procedure of myelography could have influenced the contrast passage effect.
  • The presence of some missing data both in ambulation and pain recording could also influence the results.
Missing data during pain recording (31 pts with pain)High-dose dexamethasone therapy (18 pts)Conventional-dose dexamethasone therapy (13 pts)
Pain recording at 3 hrs01/18 (5.5%)01/13 (7.7%)
Pain recording at 24 hours01/18 (5.5%)00/13 (7.7%)
Pain recording in 1 week04/18 (22.2%)02/13 (15.4%)
Missing data during ambulation recording (37 pts)High-dose dexamethasone therapy (22 pts)Conventional-dose dexamethasone therapy (15 pts)
Ambulation recording at 3 hrs01/22 (4.5%)01/15 (6.6%)
Ambulation recording at 1 week02/22 (9%)02/15 (13.3%)
The inclusion of 11 patients with lymphoreticular malignancies in this small study (taking into account the well-known lympho-cytotoxic activity of steroids) as well as some missing data makes this study statistically weak (26 carcinoma pts).

From: Chapter 6, Treatment Selection and Strategies

Cover of Metastatic Spinal Cord Compression
Metastatic Spinal Cord Compression: Diagnosis and Management of Patients at Risk of or with Metastatic Spinal Cord Compression.
NICE Clinical Guidelines, No. 75.
National Collaborating Centre for Cancer (UK).
Copyright © 2008, National Collaborating Centre for Cancer.

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