Long Term Neurotoxic Effects of Chemotherapy in Survivors of Bone and Soft Tissue Sarcomas. A Retrospective Study

The aim of the proposed project is to study the long-term impact of adjuvant systemic multi- agent chemotherapy (cisplatin, anthracyclines, vincristine, methotrexate, alkylating agents) in survivors (treated between 1992 and 2014 in UZ Leuven) of paediatric bone or soft tissue sarcomas on neurocognitive functioning using neuropsychological testing in combination with advanced Magnetic Resonance (MR) imaging techniques in a cross-sectional design. The majority of studies focus on either neuropsychological outcomes or structural imaging. In this project we want to combine both methodologies. MR will mainly focus on microstructural changes in white matter and differences in brain connectivity, while with our neuropsychological tests we will assess a broad range of cognitive functioning. From the obtained MR parameters and neuropsychological test results, the proposed study wants to answer the following research questions:

1. Are there subtle differences in neurocognitive function and behavior related to chemotherapy exposure for survivors of paediatric bone or soft tissue sarcomas?
2. Are there differences in morphological/functional MR parameters that could relate to subtle cognitive differences in cognitive functioning after chemotherapy exposure? Can we detect structural treatment-induced WM injury? Can we see differences in brain neural activity/connectivity during rest between the groups?
3. Is there a correlation between the obtained morphological/functional MR parameters and neuropsychological test results?
4. Is there a correlation between the possible difference in white matter microstructure and gender, age at diagnosis and the duration of treatment?

To answer these questions, we will implement the following measurements:

• From the computerized Amsterdam Neuropsychological Tasks (ANT) system we will test simple motor reaction time, sustained, focused and divided attention, inhibitory control and cognitive flexibility and motor coordination.
• Specific verbal-auditory memory and nonverbal, visual-spatial memory functioning will be registered by the Children's Memory Scale (CMS) for subjects younger than 16 years and with the auditory verbal learning test and the Rey visual design learning test for the subjects older than 16 years. Age-adjusted standardized norms are available for each test.
• The BRIEF (Behavior Rating Inventory of Executive Function) explores executive functioning in school (5-17 years), work (+18 years) and home (5-17 years and +18 years) environments.
• The assessment of intellectual functioning consists of the Wechsler Intelligence Scale for Children (WISC-III) for patients between 6 and 16 years and the Wechsler Adult Intelligence (WAIS-III) for adolescents aged 17 years or older.
• Quality of life will be investigated by the PEDSQL generic version for young adults .
• The Achenbach questionnaires (Child Behavior Checklist, Teacher Report Form, Youth Self Report Form, Adult Behavior Checklist, Adult Self Report Form) items for internalizing, externalizing, and total problems will be filled out by the parents, teacher or relatives and patients themselves.
• All participants will complete the Spielberger State-Trait Anxiety Inventory and the Beck Depression Inventory-II.

Currently, the neurocognitive follow-up of paediatric bone and brain tumour patients (NKP21/22c, National Cancer Plan Onkelinx) as well as children with congenital heart disease (IWT-TBM, 3M110068) or treated in a paediatric intensive care unit is also based on this test battery. All these tests and questionnaires have been extensively described and used to quantify neurocognitive development and Quality of life in various paediatric populations. The testing will be performed at least one year after the end of treatment.