Working Memory Training in Survivors of Pediatric Cancer: A Randomized Pilot Study

It is well known that survivors of brain tumors and acute lymphoblastic leukemia (ALL) are at increased risk for neurocognitive late effects [1–3]. More specifically, many survivors develop primary impairments in attention, working memory, and processing speed that are then associated with declines in cognitive and academic functioning [4,5], as well as poor long-term social and vocational outcomes [6–8]. As such, recent efforts have focused on developing and testing interventions designed to ameliorate these deficits [9]. A number of treatment approaches have been evaluated in recent years, including medication, clinic-based cognitive remediation, and home-based computerized cognitive training [9]. Psychostimulant medication, long established as an effective treatment for symptoms of attention-deficit hyperactivity disorder (ADHD), has also been found to reduce attention deficits in survivors [10–16]. Despite these positive results, there remain several concerns about the use of psychostimulants, including a greater susceptibility to side effects in survivors than in children with ADHD [11, 17], unknown long-term effects [18], and a potential reluctance to using psychoactive medications [19]. Cognitive remediation has also been evaluated as a treatment approach for survivors with neurocognitive deficits. Based on an approach developed for use with individuals with traumatic-brain injury (TBI), these programs typically focus on the repetition of tasks thought to develop core cognitive skills (e.g., immediate and working memory), as well as the acquisition and practice of strategies to compensate for deficits in these areas (e.g., organizational skills, self-monitoring) [20]. To date, clinic-based programs involving primarily face-to-face work with one or more providers have been the focus of most empirical study. A multi-center randomized trial [21] of a hospital-based cognitive remediation program was completed with 161 survivors of pediatric cancer. While treatment efficacy was demonstrated through increases in attention and academic achievement, effect sizes were small for a number of functional outcomes. Conclusions about the effectiveness of the program also were mitigated by a sizable percentage of participants who failed to complete the 6-month program [21]. A similar intervention that focused on problem-solving training was piloted with a small group of survivors [22]. Again, preliminary efficacy was demonstrated through improvements on each outcome measure; however, this study was also characterized by a low participation rate and suboptimal adherence. The authors noted that the most frequent reason given for lower adherence was perceived inconvenience of coming to the clinic. Collectively, these results suggest that intensive, therapist-directed, in-person interventions may not be practical or desirable for some subgroups of the survivor population. Given the limitations associated with these treatment approaches, there remains a critical need for efficacious interventions targeting symptoms associated with neurocognitive late effects in pediatric cancer survivors. Home-based, computerized cognitive training has recently emerged as a cognitive remediation paradigm with the potential to address core neuropsychological deficits in survivors [23, 24]. This approach is associated with a low risk of side effects (compared to pharmacological treatment) and may carry a reduced treatment burden (compared to clinic-based interventions) because it can be completed at home, any time of day. Computerized cognitive training employs game-like exercises to target core cognitive skills such as working memory and attention. Such programs have demonstrated efficacy across a wide variety of individuals with cognitive difficulties: children with ADHD [25–31], TBI and stroke [32, 33], schizophrenia [34, 35], extremely low birth weight [36], cochlear implants [37], and borderline intellectual disabilities [38]. A recent study piloted the use of one such intervention with a small group (n = 9) of survivors [23]. Results were promising, with survivors demonstrating improvements in both performance-based and questionnaire measures of attention. However, several limitations were noted, including a small sample size, lack of a control group, and improvement in measures of attention, but not working memory [23]. Kesler and colleagues [24] subsequently investigated the preliminary efficacy of an internet-based cognitive rehabilitation program with a small sample of survivors (n = 23). Survivors demonstrated improvements in processing speed, cognitive flexibility, and visual and verbal declarative memory. However, there were no significant changes observed in either working memory or attention. Of interest, fMRI data documented significant increases in dorsolateral prefrontal cortex activation in participants who completed training [24]. Results from both intervention studies [23, 24] suggest that computerized cognitive training programs are feasible for use and potentially efficacious with survivors of pediatric cancer, though neither used a randomized, controlled design. In order to extend the literature in this area, we evaluated an existing computerized cognitive training program, CogmedRM, with survivors of pediatric cancer. CogmedRM has significant advantages over other computerized cognitive training programs for the survivor population. First, unlike the previous programs evaluated with cancer survivors, its use has been associated with significant efficacy in a number of well-designed and controlled trials with children and adolescents [27, 29–31]. Moreover, CogmedRM specifically targets working memory skills, which have been proposed to underlie the changes in intelligence and academic performance frequently seen in survivors with cognitive late effects [4, 5]. Finally, CogmedRM consists of a fixed “dose” of training (i.e., 25 sessions) and also has an active control version of the program, making it ideally suited for empirical study in a randomized, controlled design. The objectives of this study were to describe the feasibility and preliminary efficacy of this program in a small, randomized clinical trial with survivors of pediatric brain tumors and ALL. Outcomes included an assessment of treatment adherence and acceptability, as well as improvement on parent-rated and performance-based measures of working memory. Specifically, in keeping with prior pilot work using this program, we evaluated a near-transfer task as our primary endpoint (WRAML-2 Symbolic Working Memory) [27,28]. Secondary endpoints included performance-based measures of verbal working memory (WRAML-2 Verbal Working Memory), auditory and visual short-term memory (WRAML-2 Letter Number and Finger Windows), and caregiver ratings of attention and learning problems (Conners’ 3 Rating Scale – Inattention and Learning Problems).