Efficacy of Cognitive and Physical Trainings in Pediatric Cancer Survivors
Condition: Pediatric Cancer
Study type: Interventional

Summary: 
      Cancer survival comes at a price: pediatric cancer survivors have a high risk for a wide
      range of cognitive difficulties, particularly survivors of cancer involving the central
      nervous system (CNS, e.g., brain tumors [BT]) are prone to neurocognitive impairments in
      areas such as executive functions, working memory, attention, memory, visuospatial and motor
      skills, processing speed as well as language. The aim of this interdisciplinary longitudinal
      study is to extend empirical knowledge on training and transfer effects in children with a
      history of cancer. It is hypothesized that early cognitive and physical interventions affect
      the remediation of pediatric cancer survivors in terms of cognitive functions. These changes
      are further hypothesized to be associated with white matter changes.
    

Detailed description: 
      Aims and Hypotheses:

      The overall purpose of this study is threefold: first, this study aims to deepen the
      knowledge about particular patterns of long-term cognitive impairment in pediatric cancer
      survivors. Understanding the nature of cognitive deficits in this population will be helpful
      for developing tailored therapeutic strategies. Second, the availability of well-designed
      child-friendly evidence-based training is of major clinical relevance to prevent school
      problems and further decline of cognitive functions. Third, the detection of training-induced
      neuronal changes in white-matter structure will give insight into the functional plasticity
      of the child's brain. In addition, training-induced changes in white matter would build
      strong evidence for the effect of the particular intervention.

      The following hypotheses will be assessed in particular in the present study:

        1. Children with history of brain tumors (BT) show particular problems in memory and
           attention, resulting in a general deficit in several cognitive areas. Children with a
           history of cancer without involvement of the CNS show fewer problems than children with
           a history of cancer with BT in the same cognitive domains but more problems than healthy
           control children.

        2. Standardized working memory training leads to improvement of working memory performance.
           Transfer of the training effect especially to the areas of executive functions, memory
           and attention is expected.

        3. Physical training leads to improvement of coordination, endurance and motor strength. A
           transfer to several cognitive areas (i.e. executive functions) and physical self-concept
           is expected.

        4. After working memory training and physical training, the white matter structure of the
           patients will show significant changes in fractional anisotropy. There will also be
           changes in functional connectivity.

        5. Neuropsychological effects of training will still be present after 6 months post
           training for both experimental groups.

      All comparisons will be carried out on an individual level (intra-individual level, primary
      objective) as well as on an inter-individual level (between-groups comparisons, secondary
      objective). The level of significance is set to α = 0.05.

      Participants:

      Cancer Survivors: Researchers will include 150 children and adolescents aged 7-16 years who
      received an initial diagnosis of cancer with / without CNS (central nervous system)
      involvement in the past 10 years and terminated their treatment (surgery, radiation, and / or
      chemotherapy) at least 12 months prior to their participation in the study. Cancer survivors
      will be recruited at two different specialized pediatric units in Switzerland. In order to
      minimize the heterogeneity of the sample, children with a history of cancer without CNS
      involvement and only surgical removal of the tumor without subsequent radiation and / or
      chemotherapy will be excluded from the study. Because of the increased likelihood of drop-out
      of children with a history of cancer in a longitudinal study, more than the statistically
      required quantity of participants (> 25 children per group) will be recruited to reach
      sufficient statistical power.

      Healthy Controls: 40 healthy children and adolescents (matched for age and gender) will be
      included in the first assessment and serve as a healthy control sample. They will be
      recruited mainly via their siblings, who are included in the cancer survivor group and also
      from personal acquaintances among hospital staff and the study collaborators.

      Design The present study is designed as a randomized stratified controlled trial including
      two intervention groups, one waiting group (children with a history of cancer [both CNS+ and
      CNS-] and a healthy control group (matched for age and gender). Some children of the patient
      group will be allocated to a waiting-control group to determine the training effects (their
      training starts later on). After random assignment to the respective conditions, the
      interventional material (XBOX or computer), will be installed at the participants home.
      Thereby, a supervised first training session will take place. The executive functions before
      and after as well as more details on the effects of a single intervention session (on
      enjoyment, arousal etc.) will be examined. Subsequently, the respective group will either
      follow a standardized, computerized working memory training or a physical training.
      Neuropsychological assessment will be carried out before the intervention / training and
      re-performed with all participants at the end of the memory training or physical training and
      at 6 months posttraining. Structural and functional imaging will be performed prior and
      shortly after working memory training and physical training. A 3 Tesla whole body MRI system
      will be used (Siemens; Erlangen, Germany). Anatomical imaging will be obtained using a
      sequence for T1 weighted structural brain imaging with whole brain coverage. Structural
      connectivity images will be acquired by using a q-ball sequence, functional connectivity will
      be measured by using a multiband echo planar imaging sequence (MB EPI). Pre- and
      post-processing of the structural data will be performed using SPM8 (Welcome Departement of
      Imaging Neuroscience, London) and MATLAB programs (MATLAB version 8.2). In order to perform
      functional connectivity analyses, the CONN fMRI connectivity toolbox 13.1 (Whitfield-Gabrieli
      & Nieto-Castanon, 2012) is used. The fractional anisotropy maps are provide by the Siemens
      software and can be directly used for further statistical evaluation.

      Interventions:

      All 150 participants with a history of cancer will be randomly but in a stratified manner
      assigned to 3 groups (group A, B and C) (see Fig.1).

      Training A: Group A (n1= 25 CNS+, n2 = 25 CNS-) will undergo working memory training program.
      The children will receive individual memory training based on the computer program Cogmed RM
      (Klingberg et al., 2005) and will be supervised by trained neuropsychologists. Its efficacy
      in the use with children with cancer has been recently published (e.g. Hardy et al., 2012).
      The children will undergo 25 training sessions "online"; each session takes about 45 minutes
      and consists of a selection of various tasks that target the different aspects of working
      memory. The difficulty level of the training is always adjusted based on the user's
      performance. The children will perform the memory training program at home over a period of 8
      weeks. The child and a licensed Cogmed RM coach (neuropsychologist) will review and monitor
      the results of each day's training online. In an initial session at the Hospital (Zurich or
      Bern) the Cogmed RM coach plans and structures the training together with the child and the
      parents. The coach will provide weekly supervision and feedback on the child's performance
      and progress via phone call to the child's home. In the closing session with the child and
      the parents, the training experience will be reviewed .

      Training B: Group B (n1= 25 CNS+, n2 = 25 CNS-) will receive a physical training that can be
      executed at home. The training will be based on xbox Kinect games (e.g. Shape Up) and
      comprise games and activities such as jump'n'run games, physical training, and dance
      activities. All material will be provided by the Inselspital Bern. One training session will
      last approximately 45 minutes and will be performed 3days a week over a period of 8 weeks.

      Group C (n1= 25 CNS+, n2 = 25 CNS-) will serve as a waiting control group and will receive
      either the physical or the working memory training program after completion of the
      Neuropsychological Assessment II.
    

Intervention name(s): Working Memory Training; Physical Training
Intervention type(s): Behavioral; Behavioral
Intervention description(s): (Training Details already described above); (Training Details already described above)
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Pediatric Cancer; Training; Working Memory; Physical Activity; Brain Tumor; Physical Exercise