The impact of therapy for childhood acute lymphoblastic leukaemia on intelligence quotients; results of the risk-stratified randomized central nervous system treatment trial MRC UKALL XI

Abstract

BackgroundThe MRC UKALLXI trial tested the efficacy of different central nervous system (CNS) directed therapies in childhood acute lymphoblastic leukaemia (ALL). To evaluate morbidity 555/1826 randomised children underwent prospective psychological evaluations. Full Scale, verbal and performance IQs were measured at 5 months, 3 years and 5 years. Scores were compared in; (1) all patients (n = 555) versus related controls (n = 311), (2) low-risk children (presenting white cell count (WCC) < 50 × 109/l) randomised to intrathecal methotrexate (n = 197) versus intrathecal and high-dose intravenous methotrexate (HDM) (n = 202), and (3) high-risk children (WCC ≥ 50 × 109/l, age ≥ 2 years) randomised to HDM (n = 79) versus cranial irradiation (n = 77).ResultsThere were no significant differences in IQ scores between the treatment arms in either low- or high-risk groups. Despite similar scores at baseline, results at 3 and 5 years showed a significant reduction of between 3.6 and 7.3 points in all three IQ scores in all patient groups compared to controls (P < 0.002) with a higher proportion of children with IQs < 80 in the patient groups (13% vs. 5% at 3 years p = 0.003).ConclusionChildren with ALL are at risk of CNS morbidity, regardless of the mode of CNS-directed therapy. Further work needs to identify individuals at high-risk of adverse CNS outcomes.Trial registrationISRCTN: ISRCTN16757172

Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: a review and meta-analysis

“…Six of the studies conclusively showed that ALL survivors experienced deficits in neurocognitive functioning when compared with age-matched healthy controls (Table 1), which was attributed to their chemotherapy-only treatment. 19,28,[31][32][33] The other 4 studies found either very small differences or differences that were not statistically significant when compared with the healthy control group. Intelligence or overall cognitive ability was measured by 8 studies.…”

“…Of the 42 studies, 13 were excluded because patients were less than 5 years since diagnosis or 2 years since the end of treatment, 8 because they lacked a healthy control group, 6 because some/all patients received cranial radiation, and 5 because they did not directly assess neurocognitive outcomes of interest (summarized in Figure 1). Ten studies 11,19,[26][27][28][29][30][31][32][33][34] remained that met all the predefined inclusion criteria (Table 1).…”

“…27,28,[31][32][33][34] The other 4 studies used a longitudinal design, identified patients at diagnosis, and completed periodic neurocognitive assessments during treatment and off therapy. 11,19,29,30 Collectively, the study population included in the analyses had a mean age at diagnosis of 4.4 years (median, 4.0), a mean age at last evaluation of 11.7 years (median, 10.3), and a mean time since diagnosis of 8.0 years (median, 8.2). Four studies had a mean time since diagnosis of less than 6 years.…”

“…Furthermore, because many of these neurocognitive measures are correlated with demographic factors, such as socioeconomic status, comparison with an appropriate healthy control group is particularly important. 19 We therefore conducted a systematic review and meta-analysis to objectively and quantitatively evaluate the existing literature using more stringent criteria to overcome some of the limitations of earlier reviews. The aim was to determine the pattern and severity of long-term neurocognitive functioning impairments following chemotherapy-only treatment among survivors of childhood ALL.…”

“…Intelligence or overall cognitive ability was measured by 8 studies. 11,19,28,[30][31][32][33] IQ was measured and assessed across 3 dimensions of the Wechsler Intelligence Scales (version dependent on age of patient): FSIQ, VIQ, and PIQ. For FSIQ, 432 ALL survivors met eligibility to be included in the treatment group and were compared with 465 healthy control subjects.…”