Cognitive functioning in a cohort of high-grade glioma patients

We analysed the cohort of patients with high grade glioma, treated between March 2019 and December 2021. Their diagnoses (anaplastic astrocytoma, anaplastic oligodendroglioma or glioblastoma) were histological confirmed. Patients were operated in either of the two neurosurgical departments in Slovenia, then they were referred to Institute of Oncology Ljubljana for evaluation regarding the initiation of radiochemotherapy.

At the referral, they consented to be enrolled in the study. Exclusion criteria were histology other than gliomas WHO III/IV, Karnoffsky performance status less than 70% and inability to undergo evaluation (e.g., marked dysphasia). To be included in the study, they had to be 18 years old or older.

The following data were obtained from the medical documentation: age, sex, date of diagnosis, localization of the tumour, type of surgery, extent of surgery, radiotherapy parameters, systemic therapy, use of corticosteroids, histological, genetic and epigenetic characteristics of tumours. All patients also had a molecular and genetic analysis of the tumour tissue performed, so the IDH1 mutations and MGMT promoter methylation status were determined.

To asses cognitive functioning, we used psychometric tests in the domains of verbal memory (Slovenian Verbal Learning Test – TBU, measuring immediate recall, short recall, delayed recall and recognition of distracters)²³, verbal fluency (Slovenian Controlled Oral Word Association Test –SCOWA)²⁴, psycho-motor speed (Trail Making Test, Part A – TMT A), executive functions (Trail Making Test, Part B – TMT B)²⁵, in accordance with the recommendations for use in the studies concerning cognitive functioning of cancer patients.²⁶ The patients also self-evaluated their cognitive functioning on a 0–10 scale (0 = without problems, 10 = extremely intensive problems present).

We used descriptive statistics with the means values and standard deviation for the demographic data. The correlation between variables was tested with Pearson's t test or Spearman's rho test.

For each cognitive test, the test scores were analysed either as standardized (z-scores) or as a dichotomized variable: no impairment present (z > −1.5 below the mean of the control group) vs. impairment observed (the patient had a z-score lower than −1.5 or was unable to perform the test at all). At the individual level, we analysed the percentage of impaired patient's results.

We next compared groups of patients with different IDH1 statuses and MGMT methylation, using either a t-test or Mann-Whitney U-test (in case that Kolmogorov-Smirnov test of normality showed statistically significant departure from normality) for interval variables, a χ² test for categorical variables and ordinal variables with Kendall's Tau test. All hypotheses were tested at a 5-percent alpha error rate.

We used the statistical program SPSS, to calculate the power of the test we used G*Power 3.1.9.7.

Written informed consent was obtained from all the patients before the inclusion in the clinical trial. The study was approved by the Institutional Review Board of the Institute of Oncology Ljubljana and by The National Medical Ethics Committee of the Republic of Slovenia (Approval number 0120-393/2018/10, date 12/12/2018) and was carried out according to the Declaration of Helsinki.

At the time the research was performed, 275 patients were diagnosed with glial tumour. Of those, 90 patients were recruited into the study, representing 33% of all patients. Figure 1 shows reasons for patients entering and not entering the study as recorded by oncologists at the time of the first consultation. Of the 51% of patients incapable of participating, in the study the major reason was poor performance status, followed by other tumour and treatment related impairments, representing 46% of ineligible patients, the other common issue was language barrier.

FIGURE 1.

Participating patients were 30 to 84-year-old (median [M] = 58.78 years, standard deviation [SD] = 11.31 years). There were more males than females (57 vs. 33). On average, female patients were older (M = 57.67 years, SD = 9.35 years, 39–74 years) than male patients (M = 59.42 years, SD = 12.33 years, 30–84 years), but the age difference was not statistically significant (p = 0.481).

Of all 90 patients, 78 had Grade IV tumour (all classified as glioblastoma), 8 had anaplastic astrocytoma, and 4 had anaplastic oligodendroglioma. Fifteen patients had IDH1 mutation (7 anaplastic oligodendroglioma, 4 anaplastic astrocytoma, and 4 glioblastoma). MGMT promoter was methylated in 36 patients (4 anaplastic oligodendroglioma, 5 anaplastic astrocytoma, and 27 glioblastoma), whereas in 1 glioblastoma, 2 anaplastic astrocytomas and 1 anaplastic oligodendroglioma we couldn’t determine the methylation status.

Patients with Grade III tumours had a statistically better performance status – the Karnoffsky performance status was 70 in 2 (17%) patients, 80 in 2 (17%) patients, 90 in 8 (67%) patients with Grade III tumours – when compared with patients with Grade IV tumours (in these group, the Karnoffsky performance status was 70 in 30 patients, 80 in 35 patients, 90 in 10 patients, and 100 in 3 patients; U = 251.000, z = −2.75, p = 0.006). Compared to the group of patients with Grade III tumours, the group with Grade IV tumours had a statistically significantly higher percentage of IDH1-mut tumours (73% vs. 5%, χ²(1) = 56.077, p < 0.001, V = 0.789, 1–b = 0.987) and MGMT promoter methylations (60% vs. 36%, χ²(1) = 7.067, p = 0.008, V = 0.280, 1–b = 0.756).

Table 2 shows the structure of the sample according to the expression of IDH1 mutation and MGMT methylation. Five patients had both genetic markers expressed, two thirds of patients with IDH1-mut also had MGMT-met expressed, and among patients with expressed methylation, IDH1-mut tumours were present in 27% of patients. The difference in the proportion of MGMT methylation in the IDH1-mut and IDH1-wt groups was statistically significant, χ²(1) = 5.333, p = 0.021, V = 0.243, 1–b = 0,82).

The overview of cognitive evaluation is presented in Table 3. The achievements were impaired (z <−1.5) in a large proportion of the patients, especially in the field of short recall, executive functions and psycho-motor speed. The impairment was least frequent in the field of recognition and verbal fluency. The results remained similar, regardless of accounting only those who were capable of completing a specific test or the sample as whole – the biggest difference between these two analysis methods is on the TMT A and TMT B tests.

We examined on how many out of 7 tests the patients had an impaired test score (z < −1.5 or unable to finish the test) and found that 11 patients (12%) had 0–1 impaired test score, 26 (29%) patients had 2–4 impaired test scores, and 53 (60%) patients had more than 5 impaired test scores.

On the 10-point self-evaluation scale of cognitive functioning the mean rating was 3.66, SD = 2.81, min = 0, max = 10; 48 (53%) patients selected rating 0–3, 23 (26%) selected rating 4–6, and 19 (21%) selected a rating higher than 7. Correlations between self-assessment and individual tests of cognitive functioning show that self-assessment is weakly but statistically significantly related only to immediate recall (r = −0.280, df = 79, t = 2,57, p = 0.012).

The cognitive functioning in any of the measured fields was not statistically significantly affected by sex, surgery type and the presence or absence of seizures. The test scores did, however, differ with regard to age, education, and performance status. Age was statistically significantly related to participant's results in the field of verbal fluency (r = −0.278, t = −2.55, df = 79, p = 0.012), immediate recall (r = −0.409, t = −3.96, df = 79, p < 0.001), short delayed recall (r = −0.388, t = 3.72, df = 79, p < 0.001) and delayed recall (r = −0.333, t = 3.12, df = 79, p = 0.003).

Education was significantly related to results in the fields of verbal fluency (r_s = 0.381, t = 3.66, df = 79, p < 0.001), immediate recall (r_s= 0.334, t = 3.13, df = 79, p = 0.002), short delayed recall (r_s = 0.285, t = 2.63, df = 79, p = 0.010), delayed recall (r_s = 0.265, t = 2.42, df = 80, p = 0.017) and recognition (r_s = 0.264, t = 2.42, df = 79, p = 0.018).

Performance status was significantly related to immediate recall (r_s = 0.280, t = 2.57, df = 79, p = 0.012) and delayed recall (r_s = 0.296, t = 2.74, df = 79, p = 0.008).

We analysed the disease and demographic data and the results of psychological tests with regard to IDH1 mutation. Compared to IDH1-wt patients, patients with tumours harbouring IDH1-mut were statistically significantly younger, had better performance status and were more likely to have Grade III tumour and MGMT promoter methylation (Table 4). They functioned better in the field of verbal memory (had a better performance in immediate recall, short delayed recall and delayed recall, measured either with z-scores or as dichotomised test scores) and in the field of executive functioning (measured with dichotomised test scores) (Table 5).

Patients with IDH1-mut had on average a statistically significantly lower number of impaired tests results than patients with IDH1-wt (M = 2.93, SD = 2.25vs. M = 4.93, SD = 1.99; U = 286.000, z = −3.04, p = 0.002). 5 (33%) patients with IDH1-mut tumours and 6 (8%) patients without IDH1-mut had at most one impaired result on cognitive tests; impaired results on 2–4 tests had 5 (33%) vs. 21 (28%). Impaired scores on more than 5 tests had 5 (33%) vs. 48 (64%).

We found no differences between groups with regard to self-evaluation of cognitive functioning problems; the mean rating was 3.60, SD = 2.81, in patients with IDH1-mut tumours vs. 3.67, SD = 2.95 in patients with IDH1-wt (U = 579.000, z = 0.18, p = 0.857); 40 (53%) patients with IDH1-wt tumour gave a self-assessment of 0–3 vs. 8 (53%) patients with IDH1-mut, score 4–6 was given by 18 (24%) vs. 5 (33%) patients and a score above 7 17 (23%) vs. 2 patients (13%).

We also compared demographic characteristics in patients with and without MGMT promoter methylation. The patients differed in the tumour grade. Despite the predominance of Grade IV tumours in our sample, the methylated phenotype was more prevalent in Grade III patients (25% vs. 5%, χ²(1) = 7.067, V = 0.28, 1 − β = 0.757, p = 0.008). In all other demographic characteristics, the groups were comparable.

In the cognitive functioning, there were no differences in mean z-scores or dichotomized test scores between patients with methylated and unmethylated promoter MGMT (Table 7).

There were no statistically significant differences in self-evaluation of cognitive functioning problems; the mean number of impaired results were 4.50 (SD = 1.90) in patients with MGMT un-methylated tumours vs. 4.29 (SD = 1.75), U = 1100.000, z = 1.51, p = 0.251.

There were also no differences in the number of tests in which patients achieved an impaired result (U = 1052.500, z = 0.67, p = 0.501). With the mean 4.69 (SD = 2.31) and 4.54 (SD = 2.07) had 5 (14%) patients with MGMT methylated tumours and 6 (11%) patients MGMT unmethylated tumours at most one impaired result, 2–4 impaired results had 9 (25%) vs. 17 (31%) patients, and on more than 5 tests the results were impaired in 22 (61%) vs. 31 (57%) patients.