Preventing Sensory and Motor Dysfunctions in Children Receiving Neurotoxic Chemotherapy

Study Overview
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Brief Summary
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The investigators would like to conduct a prospective, multicenter, two-armed trial (RCT with follow-up). Patients will be recruited from 7 centers (CH/D). All patients (and their guardians) scheduled to receive chemotherapy containing either a platinum derivate or vinca-alkaloid, will be asked to participate. Willing patients will then be randomized either into an intervention group or a control group. Patients in the intervention group will perform a standardized, age-adjusted, specific playful sensorimotor training (SMT) program twice a week for the duration of their medical therapy, in addition to usual care, while the control group receives treatment as usual. The CG will be given the opportunity to participate in the intervention after therapy. Data will be assessed at 3-4 time points: Prior to chemotherapy (baseline T0), after 12 weeks (T1), after completion of therapy for children that are treated >3 months (Tp) and after 12 months follow-up (T3). Additionally, status of Chemotherapy-induced peripheral neuropathy (CIPN) reported symptoms will be monitored twice in-between (6 weeks). The investigators hypothesize that less children in the intervention group will develop symptoms of CIPN (TNS score) with its debilitating side-effects. Furthermore, children in the intervention group will be able to maintain relevant motor and sensory functions and their associated physical functions which will enable them to receive their planned medical therapy but also to stay on the age-appropriate motor development level, improve their quality life and enhance social reintegration after therapy.

Detailed Description
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Modern therapy has improved survival for children with cancer. However, treatment has unintended consequences. Depending on the neurotoxic agent (platinum derivates or vinca-alkaloids), 52%-100% of children develop a peripheral neuropathy. Diagnosis is underreported and its impact as potentially initial cause for many sensory and motor symptoms underestimated. The severe symptoms such as loss of sensation, numbness, pain, absent reflexes as well as loss of balance control not only delays motor development milestones such as walking, running, jumping or climbing, diminishing children's quality of life and affecting their social reintegration, but is also of high clinical relevance. Additionally, recovery is poor and there are currently no effective options to prevent or treat the symptoms of Chemotherapy-induced peripheral neuropathy (CIPN). Promising results have so far been achieved with specific exercise interventions. The investigators would therefore like to conduct a prospective, multicenter, two-armed trial (RCT with follow-up). Patients N=131 will be recruited from 7 centers: University Children's Hospital of Basel, the Inselspital Bern, Kantonsspital Aarau, Children Hospital for Eastern Switzerland St. Gallen, University Children Hospital Freiburg and the National Center for tumor diseases (NCT), University Children Hospital Heidelberg, Charité Berlin. All patients (and their guardians) scheduled to receive chemotherapy containing either a platinum derivate or vinca-alkaloid, will be asked to participate. Willing patients will then be randomized either into an intervention group or a control group (CG). Patients in the intervention group will perform a standardized, age-adjusted, specific playful sensorimotor training (SMT) program twice a week for the duration of their medical therapy, in addition to usual care, while the control group receives treatment as usual. The CG will be given the opportunity to participate in the intervention after therapy. Data will be assessed at 3-4 time points: Prior to chemotherapy (baseline T0), after 12 weeks (T1), after completion of therapy for children that are treated >3 months (Tp) and after 12 months follow-up (T3). Additionally, status of CIPN reported symptoms will be monitored twice in-between (6 weeks). The investigators hypothesize that less children in the intervention group will develop symptoms of CIPN (TNS score) with its debilitating side-effects. Furthermore, children in the intervention group will be able to maintain relevant motor and sensory functions and their associated physical functions which will enable them to receive their planned medical therapy but also to stay on the age-appropriate motor development level, improve their quality life and enhance social reintegration after therapy.

Official Title
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Preventing Sensory and Motor Dysfunctions in Children Receiving Neurotoxic Chemotherapy - a Randomized Controlled, Multi-center Trial

Conditions
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Chemotherapy-induced Peripheral Neuropathy, Pediatric Cancer

Intervention / Treatment
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* Behavioral: Playful sensorimotor training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All tumor patients, aged 6-18 years, who are scheduled to receive neurotoxic chemotherapy with a platinum-derivate or vinca- alkaloid (e.g. vincristine, vinblastin mono, carboplatinum, cisplatin). Exclusion Criteria: Exclusion criteria are known neuropathies of other cause (e.g. diabetes), disabilities or lack of German language that prevent the understanding of the informed consent as well as the instructions for training.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study will follow a prospective, multicenter, two-armed, randomised, controlled, assessor-blinded trial trial (RCT with follow-up).
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br>Patients in the intervention group will perform a standardized, age-adjusted, specific playful sensorimotor training (SMT) program twice a week for the duration of their medical therapy, in addition to usual care. | Behavioral: Playful sensorimotor training<br>* For the max. duration of the first in-hospital phase (3weeks), all children will receive supervised training. When children go home they will be supplied with a manual, specific exercises and the necessary training devices. Regular supervision will allow to ensure that the training is performed at maximum benefit. Each session will last for about 20 to 30 minutes in total, including a child-specific warm-up and cool-down. The children will be asked to maintain balance in a previously acquired short-foot-position, knees slightly flexed (30°), without shoes. Training will consist of 5 playful balance exercises chosen from a standardized pool of exercises according to the child's age, with increasing difficulty in order to allow for individual, optimal progression. Each of the 5 exercises will contain of 5 repetitions for 10sec. allowing for a 20sec. rest in between each set and a 1min rest between each exercise in order to avoid neural fatigue.<br>|
| No Intervention: Control group<br>The control group receives treatment as usual. The control group will be given the opportunity to participate in the intervention after therapy. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre-/Post incidence of neuropathic symptoms via Ped-mTNS score | Primary endpoint is the Ped-mTNS score. It contains a short questionnaire as well as a clinical test battery. The questionnaire is composed of three sets of questions on sensory symptoms and pain, motor function, and autonomic function, and a five- part neurologic exam. The clinical test battery contains light touch sensation, evaluated with Semmes-Weinstein-monofilaments, pin sensibility (MediPin), vibration sensibility assessed with a biothesiometer, deep tendon reflexes of Achilles and patellar tendons and muscular strength examined by a manual muscle test36, each category is rated on a likert scale from 0-4 (0 indicating no symptoms and 4 severe symptoms). | Baseline (T0), subjective screening for symptoms of CIPN (via phone cell), 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 Months (TFU) | 
| Pre/Post change of signs and symptoms of a neuropathy (VAS (0-10)) | Signs and symptoms of CIPN | Baseline (T0), Screening for symptoms of CIPN (via phone cell), 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 Months (TFU) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Outcomes - Pre/post change of postural control | postural control - sway path on the Leonardo force plate | Baseline (T0), after 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 months after last dose of Chemotherapy (TFU) | 
| Pre/post change of Dorsiflexion | dorsiflexion function, assessment of foot drop with a goniometer and hand-held dynamometer | Baseline (T0), after 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 months after last dose of Chemotherapy (TFU) | 
| Pre/post change of strength in the lower extremity - knee extension | knee extension strength will be assessed with a hand-held dynamometer | Baseline (T0), after 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 months after last dose of Chemotherapy (TFU) | 
| Pre/post change of lower limb power | lower limb power will be assessed with the countermovement jump | Baseline (T0), after 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 months after last dose of Chemotherapy (TFU) | 
| Pre/post change of gait speed | 10m walk test / walk to run transition time | Baseline (T0), after 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 months after last dose of Chemotherapy (TFU) | 
| Pre/post change of neuropathic pain | CIPN-related pain will be assessed on a child-appropriate visual analogue scale (VAS) | Baseline (T0), after 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 months after last dose of Chemotherapy (TFU) | 
| Pre/post change of level of physical activity | participation of exercise-related leisure activities | Baseline (T0), after 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 months after last dose of Chemotherapy (TFU) | 
| Pre/post change of physical self-concept | childrens' physical self concept via questionnaire | Baseline (T0), after 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 months after last dose of Chemotherapy (TFU) | 
| Pre/post change of patients' self-reported, health-related quality of life | childrens quality of life via questionnaire | Baseline (T0), after 12 weeks (T1), within 7days after last dosage of medical therapy (Tp), 12 months after last dose of Chemotherapy (TFU) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer, Lymphoma, Leukemia, Non-Hodgkin Lymphoma, Children, Exercise, Chemotherapy-induced peripheral neuropathy, CIPN, Sensorimotor Training