Physical activity and play in early childhood are positively associated with healthy growth and gross motor, social, and cognitive development. Preschool children with cancer are at risk of impairments or delays in these interdependent developmental areas. Therefore, it is imperative to find new rehabilitation approaches to ensure preschool children's development during and after treatment. This study is based on the RePlay trial, where results highlight a demand from families for physical activity during cancer treatment and show that preschoolers want to participate. However, there is a need for a more flexible and accessible physical activity initiative at the hospital and greater support and collaboration with parents, also at home.

The purpose of this randomized controlled study is to investigate the effect of 9 months of physical activity at the hospital and at home for 82 preschool children with cancer, aged 1-5 years. The rehabilitation program includes the following components:

1. Facilitated structured active play as group sessions at the hospital
2. A parent education program
3. Online facilitated structured active play in the families' homes The included children will be randomized to either a group only receiving structured active play at the hospital (part 1), or a group receiving both structured active play at the hospital, the parent education program, and online structured active play in the families' homes (parts 1-3).

We will measure the children's in gross motor function 9 months after the start of treatment (primary outcome), as well as parents' attitudes towards physical activity and the children's general physical function (secondary outcomes). We will measure at treatment initiation, and 6, 9, and 12 months after treatment initiation. Additionally, we will qualitatively investigate the parents and children's experiences, the potential of the rehabilitation program for the children's social development, and the importance of the professional in facilitating structured active play.

1. BACKGROUND Physical activity and play in early childhood are positively associated with healthy growth and development, this includes motor development (e.g., gross motor functions); psycho-social health (e.g., personal development of self-concept and self-esteem); cognitive de-velopment (e.g., language); and social development (e.g., social skills and functioning). Preschool children diagnosed with cancer are at risk of impairments or delays in several of these interdependent developmental areas. Studies have shown impairments of fine- and gross motor skills during treatment for preschool children with cancer, including severe walking difficulties and loss of ability to support themselves on their legs which limit their movement possibilities and development. Furthermore, these children are taken out of their usual social context in daycare, which limits their social interactions with their peers. When the children re-enter everyday life in daycare, they have trouble following along with their peers physically, have less confidence in their movement abilities, lack age-specific social competencies, and feel excluded. Additionally, one study has shown that these im-pairments persist up to two years after treatment, where the children struggle with develop-ing balance skills and more complex motor skills requirements that come with age. Pre-school children make up half of the population of children who are diagnosed with cancer each year; thus, finding novel rehabilitation approaches to ensure preschoolers' develop-ment during and after cancer treatment is imperative.

   The present trial is based on the experiences within the research group from the RePlay trial (Rehabilitation including structured active play for preschoolers with cancer); the first and largest trial investigating the effect of structured active play as a physical activity inter-vention specifically developed for preschoolers during cancer treatment. The current find-ings highlight a demand from families for physical activity during cancer treatment and show that preschool children want to participate. However, there is a need for a more flexi-ble and easily accessible (i.e., offered all weekdays, located at the ward close to the pa-tients) physical activity intervention at the hospital to increase participation and support the social potential. Furthermore, emphasis is needed on the home-based part of the interven-tion as treatment protocols and isolation requirements have changed so families are more at home during treatment. Preschool children need to be physically active and move as much as possible every day; thus, this calls for an approach with greater support and col-laboration with parents and increased physical activity at home, such as facilitated online physical activity sessions, which have been shown to increase participation in physical activity in older children with cancer.

   Based on our current knowledge and evidence, we have designed Social and Physical Activity as Rehabilitation for preschool Kids with cancer (SPARK)-a randomized con-trolled trial. SPARK includes facilitated group-structured active play at the hospital, based on the RePlay Model, combined with a parent educational program and facilitated online structured active play sessions at home. With this new study, we aim to:

   • Primarily investigate the effect of a nine-month physical activity intervention consisting of group-structured active play at the hospital combined with a parent educational program and online structured active play sessions at home on preschoolers' gross motor function development compared with children only receiving group-structured active play at the hospital.
   • Secondarily investigate the parents' perception of physical activity and the children's general physical function, and qualitatively explore the children's and parents' experiences with the intervention.

2. METHODS

Design:

SPARK is a single-center, two-armed, randomized controlled trial. We will include 82 preschool children newly diagnosed with cancer, aged 1-5 years old.

Additionally, data from the RePlay study's control group will be included to compare to an inactive historical control group.

Following baseline assessment, the children will be randomized to one of two intervention arms. We will stratify by age (<36 months and ≥36 months) and diagnosis (hematological cancers, extra-cranial solid tumors, and tumors in the central nervous system).

Intervention:

The SPARK trial consists of two intervention arms. The first intervention arm (a) includes standard care and nine months of facilitated group-structured active play at the hospital. The second intervention arm (b) includes standard care and nine months of facilitated group-structured active play at the hospital combined with a parent educational program and online facilitated structured active play at home. The different intervention components are described in detail below. Standard care includes occupational therapy and physio-therapy if needed.

• Facilitated group-structured active play at the hospital The hospital-based part of the intervention includes daily facilitated group-structured active play sessions during the weekdays (i.e., Monday-Friday) at the hospital for 40 weeks. All sessions will be 45 minutes long and structured using the RePlay Model following four core principles: 1) ritual practices; 2) reinforcement of movement through repetition; 3) devel-opment through appropriate challenges; and 4) adjusting activities to accommodate treat-ment-related side effects (13). All activities are performed together, where healthcare pro-fessionals, parents, and children all participate to support social development. The RePlay Model, with examples of different active play activities, is illustrated in The group-structured active play sessions will take place at the pediatric oncology ward and will be facilitated by a health professional (i.e., an exercise professional or physiother-apist). Respecting age-specific development, children will be divided into two groups: < 36 months and ≥36 months. Admitted families treated in isolation or otherwise prevented from participating in a group session are offered an individual session in their hospital room fa-cilitated by the healthcare professional.
• Parents educational program

The parent educational program consists of two educational sessions within the first three months of the child's treatment trajectory. The sessions have the aim of providing the par-ents with knowledge and skills to facilitate structured active play at home:

1. A 30-60-minute session with general information on gross motor function development, common physical side effects of cancer treatment, and the importance of physical activity and active play.
2. A 60-minute practical, interactive introduction to structured active play and the RePlay Model - including inspiration for active play activities they can do at home that challenge different gross motor skills.

The parents will receive practical material on gross motor development stages and skills as well as descriptions of active play activities that target gross motor functions. The research group will facilitate interaction with the parents about any questions and barriers they might have with performing structured active play at home.

• Online facilitated structured active play at home The online facilitated structured active play sessions at home are provided daily during the weekdays (i.e., Monday-Friday) in the afternoon (e.g., 16.00-17.00). A healthcare profes-sional (i.e., an exercise professional or physiotherapist) facilitates these sessions, guiding the families through active play activities following the RePlay Model structure. When the families log on for the online sessions, a healthcare professional will instruct them through different play activities. Each family will receive basic essential home-structured active play equipment (e.g., bean bags, balls, bingo games, items for an obstacle course) for the online sessions. The sessions will be conducted through video connections (Teams or Skype). Families who do not have an iPad or suitable computer will receive an iPad from the research group for the nine-month intervention.

Sample size:

The following sample size calculation is based on baseline data from the RePlay study of the gross motor sum of standard scores from PDMS-2. With a mean of 20.03 in gross mo-tor function and a standard deviation of 7.4 (unpublished data from RePlay, n=37), a 25% difference between groups, an alpha level of 0.05 and a power of 80%, we need to include 68 preschool children with cancer. Based on experiences from RePlay, we assume that 20% will be unable to complete the primary outcome at the primary end-point. Therefore, we aim to include 82 preschool children with cancer. Based on the deficiencies observed within two weeks of treatment initiation (baseline score of 20.03 gross motor function), we expect a 25% increase to be obtainable over 9 months of intervention.

Inclusion Criteria:

• Children newly diagnosed with cancer or cancer-like benign disorders.
• Children between the ages of ≥12 to <72 months at the time of treatment initiation.
• Children undergoing intravenous chemotherapy and/or radiation therapy and/or immuno-therapy at the Department for Pediatrics and Adolescent Medicine at Copenhagen Univer-sity Hospital-Rigshospitalet.

Exclusion Criteria:

• Children diagnosed with severe mental or physical disorders that prevent them from follow-ing instructions in relation to the intervention and testing.
• Children where neither of the parents/guardians can communicate in Danish without a translator.