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Evidence Tables Evidence Tables Citation: Aoyama,H.; Tago,M.; Kato,N.; Toyoda,T.; Kenjyo,M.; Hirota,S.; Shioura,H.; Inomata,T.; Kunieda,E.; Hayakawa,K.; Nakagawa,K.; Kobashi,G.; Shirato,H. (2007). Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. International Journal of Radiation Oncology Biology Physics, 68, 1388-95. Design: Multi-centre RCT Country: Japan Aim: To assess how stereotactic radiosurgery (SRS) and whole brain radiotherapy (WBRT) compared to SRS alone affect the neurocognitive function of patients with 1-4 brain metastases. Inclusion criteria Patients with - Karnofsky score > 69, and - 1-4 brain metastases that were identified using enhanced MRI and that each measured < 3cm. Exclusion criteria Population • N = 132 randomised to receive WBRT+SRS (n= 65) or SRS alone (n = 67) for brain metastases. • Only patients for whom baseline MMSE (Mini-Mental State Examination) scores were available were analysed (n = 110). • The control group (n = 59, 46 males, 13 females) and the intervention group (n = 51, 36 males, 15 females) did not statistically differ on the following characteristics: Age at diagnosis, gender, Karnofsky performance status, number of brain metastases, brain edema, total volume of brain metastases, primary tumour site (which was lung in 39/50 in the control group and 32/51 in the intervention group), primary tumour status, and status of extracranial metastases (stable/active). Interventions Control group: SRS alone: The SRS dose was prescribed to the tumour margin. Metastases with a maximal diameter of ≤ 2 cm were treated with 22-25 Gy, and those ≥ 2 cm were treated with 18-20 Gy. Intervention group: WBRT + SRS: WBRT: 30 Gy in 10 fractions within 2-2.5 weeks followed by SRS, which was similar to the control group, but with an SRS dose reduction of 30%. Outcomes Primary outcome: MMSE score. • The MMSE was administered before or during brain treatment, 1-3 months after treatment, and, if possible, every 3 months thereafter. A statistically meaningful change was considered to be a change of 3 points (maximum score = 30), a normal score was defined as > 25 Other measures: - Number of brain metastases as assessed by contrast-enhanced MRI, - total volume of brain metastases, - degree of brain edema on T2-weighted MRI (0 = no edema, 1 = edema limited to < one half of one hemisphere, 2 = edema > one half of one hemisphere), - leukoencephalopathy (assessed by MRI according to the criterion in the National Cancer Institute Common Toxicity Criteria, version 2.0) - tumour progression (scored when the tumour had increased in size by 25% or more according to the measurement of the perpendicular diameters). Results MMSE: Baseline (n = 110, 71 of whom had lung cancer): Control group (n = 59, mean = 27.1, standard deviation (SD) = 2.9) not statistically significantly different from the intervention group (n = 51, mean = 26.7, SD = 3.3), p = .86. • When analyses were conducted on the whole sample on the basis of different patient characteristics, it emerged that MMSE scores did not differ between men and women (p = .33), between patients with 1 or 2-4 brain metastases (p = .29), between patients whose primary tumour site was lung or not-lung (p = .86) or between patients with stable or active extracranial disease p = .96); • the MMSE scores were however lower in patients ≥ 65 years at diagnosis (n = 54, mean = 25.9, SD = 3.7) compared to people below 65 years at diagnosis (n = 56, mean = 27.9, SD = 2), and in patients with a Karnofsky performance status of 70-80 (n = 45, mean = 25.5, SD = 3.8) compared to 90-100 (n = 65, mean = 27.9, SD = 1.9), and in patients with a total volume of brain metastases ≥ 3 cm3 (n = 58, mean = 26.1, SD = 3.7) compared to < 3 cm3 (n = 52, mean = 27.8, SD = 1.9). MMSE: Post-treatment: N = 92, median number of follow-ups = 2.5 times, range 1-17; median follow-up period = 5.3 months, average = 11 months, range = .7 - 58.7 months. • MMSE improvement: The 53 patients (from both groups) whose baseline MMSE = 28-30 were excluded as an improvement of 3 or more points would not be detectable. The control group (n = 22, mean = 25.3, SD = 2.1) was not statistically significantly different from the intervention group (n = 17, mean = 24.9, SD = 3.3), p = .65. An improvement of 3 or more MMSE points was observed in 11/20 in the control group and 9/17 in the intervention group, and these proportions were not significantly different (p = .85). The improvement was observed at the mean of 3.6 (SD = 2.8) months in the control group and 6 (SD = 5.9) months in the intervention group (p = .24). The MMSE score of 3 patients deteriorated 3 or more points without improvement and 16 patients experienced change of less than 3 points in their MMSE scores. • MMSE deterioration: This analysis includes patients with baseline MMSE of 27 or more (n = 65) and those whose baseline score was 26 or less, but who improved to a score of 27 or more after the initial brain treatment (n = 17). As the MMSE score of some patients improved after the initial brain treatment, the best MMSE score minus the deteriorated MMSE score was used for the MMSE change measure in this analysis. The patients who did not experience a 3-point deterioration in MMSE score did not differ between the control and intervention groups (p = .73). Deterioration of MMSE score occurred in 12/46 patients in the control group and in 14/36 patients in the intervention group and these proportions did not differ significantly, p = .21. The median time until deterioration was 6.6 (range 1.6 – 12.9) months in the control group and 12 (range 1.8 – 31.1) months in the intervention group and these differed marginally between the groups (p = .05). This deterioration was presumably attributed to brain tumour recurrence in 11 and 3 patients in the control and intervention groups, respectively (p = .0001), and either clinically or radiologically attributed to a toxic radiation event in 0 and 5 patients in the control and intervention groups, respectively. The cause for this deterioration was unclear in the remaining 7 patients. An additional follow-up MMSE was available for 10/26 patients. Of those 10 an improvement of 3 or more MMSE points was observed in 2 patients in the control group and 5 patients in the intervention group (of those 7 patients 1 underwent brain salvage therapy with SRS and 1 with SRS and 5 received close observation or best supportive care (incl., steroids). In patients free of MMSE deterioration when the first event of a decrease was not counted if the MMSE showed significant recovery with additional follow-up the 12-, 24-, and 36-month actuarial free rate of a second event in the 3-point decrease was 59.3 (95% CI 37.5-81.1)%, 51.9 (95% CI 28.6-75.2)%, and 51.2 (95% CI 28.6-75.2)% in the control group and 76.1 (95% CI 58.7-93.5)%, 68.5 (95% CI 47.3-89.7)%, and 14.7 (95% CI 0-39)% in the intervention group, respectively. These differences were not statistically significant, p = .79. The average duration until deterioration was 7.6 (median = 7.4, range 1.6-12.9) months in the control group and 16.5 (median = 15.8, range 1.8-34.5) months in the intervention group, and this difference was marginally significant, p = .05. In patients free of MMSE deterioration to ≤ 26 (an event of a decrease to ≤ 26 was counted as an event unless the MMSE score recovered to ≥ 27 with additional follow-up) the 12-, 24-, and 36-month actuarial MMSE preservation rate (≥ 27) was 53.3 (95% CI 32.9-73.7)%, 42.6 (95% CI 17.9- 67.3)%, and 42.6 (95% CI 17.9-67.3)% in the control group and 78.8 (95% CI 61.6-96)%, 78.8 (95% CI 61.6-96)%, and 22.5 (95% CI 0-49.4)% in the intervention group, respectively. These differences were not statistically significant, p = .46. • Leukoencephalopathy: Abnormality seen in 7 patients all in the intervention group (grade 1: N = 2; grade 2: N = 4; grade 3: N = 1). 4/7 (split over all 3 grades) experienced a decrease in MMSE scores of 3 or more points. General comments In addition to the fact that only 64.5% of the patients analysed in this study had BM from lung cancer, the results of this RCT is compromised by a number of methodological limitations that collectively serve to downgrade the validity of the findings. Although the randomisation procedure appears to be adequate with patients stratified according to number of brain metastases (1 vs 2-4), extent of extracranial disease (active vs stable), and primary tumour site (lung vs other), it is unclear whether allocation concealment and any level of blinding were employed. Although treatment blinding might be practically challenging, blinding of the researcher during outcome assessments should have been employed as far as possible. It is also of concern that for 11/110 patients the MMSE baseline measures were obtained after initialization of the treatment that is hypothesized to affect MMSE scores. A further concern is that fact that the SRS treatment doses differed between the control and intervention group by 30%. This difference makes it difficult to disentangle the unique contributions of WBRT and SRS, respectively, to MMSE performance changes. The authors themselves point out that a potential confounding variable is the use of corticosteroids in the study patients which was not monitored or co-varied for in the analyses and which conceivably exerts its own influence on MMSE performance.
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