Neurocognitive outcomes in long-term survivors of childhood acute lymphoblastic leukemia treated on contemporary treatment protocols: A systematic review

Abstract

The intensified administration of chemotherapeutic drugs has gradually replaced cranial radiation therapy (CRT) for the treatment of childhood acute lymphoblastic leukemia (ALL). While CRT is often implicated in neurocognitive impairment in ALL survivors, there is a paucity of literature that evaluates the persistence of neurocognitive deficits in long-term survivors of pediatric ALL who were treated with contemporary chemotherapy-only protocols. Results from this systematic review concurred to the probable cognitive-sparing effect of chemotherapy-based protocols over CRT in long-term survivors. However, coupled with multiple intrinsic and extrinsic factors, survivors who received chemotherapy treatment still suffered from apparent cognitive impairment, particularly in the attention and executive function domains. Notably, there is evidence to suggest that the late neurotoxic effect of methotrexate on survivors’ neurocognitive performance may be dose-related. This review also recommends future pharmacokinetic, neuroimaging and genetic studies to illuminate the multifactorial nature of this subject matter and discusses the potential value of neurochemical, physiological, inflammatory and genetic markers for the prediction of susceptibility to neurocognitive impairment in long-term survivors of childhood ALL.

What is known and unknown about chemotherapy‐related cognitive impairment in patients with haematological malignancies and areas of needed research

“…There is considerable published data on CRCI in survivors of paediatric ALL treated without radiation as recently reviewed by Cheung and Krull (2015). Studies were included if they examined ALL survivors at least 5 years from diagnosis or two years from completion of treatment, and at least one study arm must have been treated with chemotherapy only (no cranial radiation).…”

Leukoencephalopathy and long-term neurobehavioural, neurocognitive, and brain imaging outcomes in survivors of childhood acute lymphoblastic leukaemia treated with chemotherapy: a longitudinal analysis

“…1 Contemporary protocols have now replaced CRT with systemic and intrathecal chemotherapy 2, 3 , which has reduced the degree of survivors’ cognitive impairment. 4 Among a large cohort of adults who underwent neurocognitive assessment at 26 years post-diagnosis, the risk for impaired executive function in survivors treated with chemotherapy only was six times less than those treated with 24-Gy CRT. 1 Non-irradiated survivors also had better academic achievement than those who received CRT.…”

“…4–6 Contemporary chemotherapy protocols now employ high-dose intravenous methotrexate (MTX), intrathecal MTX and corticosteroids. In recent literature, these neurotoxic agents are associated with long-term problems in memory, attention, processing speed and executive function.…”

Declines Noted in Cognitive Processes and Association With Achievement Among Children With Leukemia

“…Even with newer ALL treatment protocols, lower performance on measures of attention (Buizer, de Sonneville, van den Heuvel-Eibrink, & Veerman, 2005; Conklin et al, 2012; Jacola et al, 2016; Jansen et al, 2006) and processing speed (Buizer et al, 2005; Mennes et al, 2005) are noted. Consistently, chemotherapy is associated with lower than expected performance among survivors 120 weeks post-consolidation on attention, reading and math achievement, motor processing speed (Edelmann et al, 2014; Jacola et al, 2016) and working memory (Ashford et al, 2010) compared to norm reference groups, for a review see Cheung and Krull (2015). Further, age appears to moderate the effect of treatment on cognition with younger children performing more poorly and girls more affected than boys (Campbell et al, 2007; Ciesielski, Lesnik, Benzel, Hart, & Sanders, 1999; Jain, Brouwers, Okcu, Cirino, & Krull, 2009).…”